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CAChe User Guide

1. 21 2 BioMedCAChe User Guide Understanding Residue Names The nucleotides are defined in this table Name ie ed Formula Mol wt Adenosine A A CIOHI4NS5O7P1 347 22 Cytidine C C C9 H14 N3 O8 P1 323 20 Guanosine G G C10 H14 N5 O8 PI 363 22 Inosine I I C10 H13 N4 08 P1 348 21 Thymidine T T C10 H15 N2 08 P1 322 21 Uridine U U C9 H13 N2 09 P1 324 18 a When 3 letter codes are displayed in the Sequence View nucleotides are displayed as single letters D i i s N i D BioMedCAChe User Guide 21 3 Chapter 21 CAChe BioComputations Understanding Protein Secondary Structure Definition This section provides reference information about the way CAChe defines secondary structure from the geometry of a protein Secondary structure concepts Regions of proteins can be described as alpha helicies beta sheets and turns Alpha helicies and beta sheets are stable structures created by hydrogen bonds and first predicted in 1951 by Linus Pauling and Robert Corey These regions can be readily observed when proteins are displayed in the CAChe workspace Defining secondary structure CAChe uses hydrogen bonds to classify regions of proteins as helical beta sheets or turns Hydrogen bonds are determined by distance criteria between N H and C O groups The method used is that of Kabsch and Sander 1 Wolfgang Kabs
2. 2 Choose View Hide Unselected The protein remains visible all other objects disappear Choose Analyze Crevice surface After a few seconds a progress dialog appears and then the surface is drawn on the protein The surface that is drawn is one that would be accessible to or touched by a 1 4A sphere rolling over the protein Since water is approximately 1 4A in size this surface is sometimes called the solvent accessible surface The blue areas map deep crevices in the protein surface The depth is measured from an outer smoother surface accessible to a 2 9A sphere Blue areas are points farther than 3 0A from the outer surface The cream areas map areas that are within 3 0A of the outer surface Relatively large deep and complex shaped canyons are potential binding sites for ligands NS To hide the crevice surface 1 9 14 Choose Analyze Show Surfaces BioMedCAChe User Guide Viewing biomolecules The Show Surfaces dialog appears Show Surfaces 12 x Displayed surfaces oy crevicel acs Cancel 2 Uncheck the acs surface and choose OK The dialog closes and the surface disappears To delete the protein crevice surface 1 With the protein crevice surface displayed click on the acs surface label Both the surface label and the surface highlight all other objects dim 2 Choose Edit Delete The surface and its label disappear from the screen and are removed from the
3. Changing an atom s hybridization using the Beautify menu Another way to change an atom s hybridization is to select the atom and choose Beautify Hybridization or Beautify Comprehensive Both these menu options employ valence rules to change atomic hybridization to match the existing bond type and atomic charge However because the valence of the atoms must be satisfied before you change hybridization Beautify Comprehensive is the best menu option to use if there is unsatisfied valence in your sample Beautify Comprehensive corrects the valence hybridization ring structure and geometry of your sample in one step lt 4 Refer to Chapter 4 Creating Chemical Samples for more information on the Beautify menu To change an atom s hybridization using the Beautify menu 1 Select the atom or group of atoms whose hybridization you want to change by clicking on the atoms with a selection tool The atom or group of atoms are highlighted to show that they are selected 2 Do one of the following o Choose Beautify Comprehensive if there is unsatisfied valence in your sample o Choose Beautify Hybridization if you have already satisfied the valence rules for your sample CAChe changes the atomic hybridization of the selected atom or group of atoms to match bond type and atomic charge 5 24 CAChe for Windows User Guide Changing atom and bond properties Checking an atom s hybridization u
4. Rotating objects around the x and y axes To rotate workspace objects around the x and y axes 1 Position the Rotate tool inside the black circle in the workspace 2 Click and drag in the workspace to the left and right with the Rotate tool Workspace objects are rotated around the y axis Click and drag up and down in the workspace with the Rotate tool Workspace objects are rotated around the x axis Click and drag up and down diagonally in the workspace with the Rotate tool Workspace objects are rotated around the x and y axes Rotating objects around the z axis To rotate workspace objects around the z axis Defining the center of rotation I Position the Rotate tool outside of the black circle in the workspace Click and drag in the workspace to the left or down with the Rotate tool Workspace objects are rotated around the z axis in a clockwise direction Click and drag in the workspace to the right or up with the Rotate tool Workspace objects are rotated around the z axis in an anti clockwise direction You can control the operation of the Rotate tool by changing the center of rotation about which the tool operates BioMedCAChe User Guide Using the manipulation tools Center rotation around the center of the workspace the center of currently selected objects NS To define the center of rotation for the Rotate tool 1 Choose Options Rotation Settings to display
5. 3 Choose a different sequence from each list and select OK An exact pairwise sequence alignment is performed between the two selected sequences using the Needleman Wunsch algorithm with BLOSUM5O matrix Gaps are inserted between residues to bring the sequences into alignment BioMedCAChe User Guide 9 39 Chapter 9 Manipulating Biomolecules You may adjust the alignment manually by inserting gaps as appropriate To align a residue manually 1 Open the sequences of two or more chemical samples as described in Viewing sequence residues p 9 18 2 With the Residue tool place the flashing I beam where you want to insert the gap 3 Type either the space bar or the minus symbol for each new gap you want to insert New gaps are inserted to the left of the I beam cursor No changes are made to the 3D structure in the workspace To delete a gap 1 With the Residue tool place the I beam cursor to the right of gaps you want to delete 2 Type the backspace key to delete the gap No changes are made to the 3D structure in the workspace Matching selections The active sites in homologous proteins are often conserved When you have two aligned homologous proteins and the active site in one is selected you can identify the active site in the second protein by selecting the matching residues To match a sequence selection 1 From the Sequence View choose Edit Match Selection 9 40 BioMedCAChe U
6. If you accept the default status by selecting the OK button without making any selection then all packages will be loaded CAChe for Windows User Guide Creating a group procedure package Refreshing the experiment environment After creating or importing packages you can refresh the experiment environment to include those new packages Alternatively you can specify any packages which you do not wish to include The Packages tab of the Property dialog box for the Experiment Environment component is used Properties xi General Packages Set Check Boxes to Indicate Packages to be Loaded Sec User C CACheSUserkE xpE nvironmentpackages x User CI Group SExpEnvironment packages Sq System C CACheSExpEnvironment packages Bx System To refresh the experiment environment 1 In the tree view of the Navigator window select the folder named Environment 2 Choose File Properties to display the Properties dialog box Select the Packages tab All the available packages are shown with check boxes by each one 4 To include a package check the check box next to it To exclude a package uncheck the check box next to it 6 When you have made your selection select the Apply button to refresh the experiment environment The specified selection of packages is loaded CAChe for Windows User Guide 11 35 Chapter 11 Using the Procedure Editor Returning to original settings You can se
7. Show Surfaces 21x Displayed surfaces FURAN CSF M013 FURAN CSF MO14 of FURAN CSF EFonD FURAN CSF EonD Cancel The Show Surfaces dialog box lists all the surfaces generated for the chemical sample file CAChe for Windows User Guide 15 9 Chapter 15 Investigating Electron Distribution 7 Select one or more surfaces by clicking on the required surfaces in the Displayed surfaces list A check mark is displayed next to the selected surfaces 8 Select OK to close the Show Surfaces dialog box CAChe processes surface information for the chemical sample and displays the surface superimposed on the molecule in the workspace The example below shows electrophilic susceptibility for furan superimposed on a furan molecule O C PROGRAM FILES OXFORD MOLECULAR CACHE USER FURAN CSF Hiding a surface You can hide surfaces individually or choose to hide all surfaces in a chemical sample file To hide surfaces individually 1 Choose Analyze Show Surfaces to display the Show Surfaces dialog box All surfaces currently displayed in the chemical sample file are shown in the Displayed surfaces list with a check mark next to the surface name 15 10 CAChe for Windows User Guide Viewing a surface 2 Select the surface that you want to hide by clicking on it in the Displayed surfaces list The check mark is no longer displayed next to the surface name 3 Select OK to close the Show Surfa
8. Susceptibility provides clues about which parts of your chemical sample are vulnerable to an attack by three different type of species electrophiles nucleophiles and radicals After an optimization step the electron distribution of orbitals near your sample s frontier orbitals molecular orbitals near the highest occupied molecular orbital or HOMO and lowest unoccupied molecular orbital or LUMO are evaluated A three dimensional electron density isosurface is created that can be superimposed over your chemical sample Shape and color give you clues to the relative reactivity of different sites Reactive centers can be easily identified as the centers of brightly colored bullseye patterns on the isosurface Susceptibility and superdelocalizability experiments described in the next section give similar results but susceptibility experiments are recommended because they are widely applicable The following example shows a line drawing of a furan molecule and an electron density surface for the same molecule colored to show susceptibility to attack by an electrophile NN CAChe for Windows User Guide Investigating electron density surfaces Generating an electron density surface colored by superdelocalizability You can generate an electron density surface colored by nucleophilic superdelocalizability e electrophilic superdelocalizability radical superdelocalizability Superdelocalizability is
9. describes the keyboard shortcuts and commands you can use in CAChe and describes each button in the toolbar Appendix B CAChe File Management lists the directory structure and file content of your Cache folder n Q 2 5 S D 2 2 lt A Keyboard and Toolbar Shortcuts Overview This appendix contains details of keyboard shortcuts and the corresponding toolbar buttons that replace menu options keyboard commands that provide operations for which there are no menu options toolbar buttons and the menu options that each button performs 2 2 Ss i o Qa a lt Contents Keyboard shortcuts A 2 Menu option shortcuts A 3 Miscellaneous keyboard commands A 4 Toolbar shortcuts A 6 Appendix A Keyboard and Toolbar Shortcuts Keyboard shortcuts A 2 Keyboard commands and toolbar buttons are available as shortcuts for some menu options Some keyboard shortcuts provide operations not available through menus or dialog boxes Keyboard shortcuts and their corresponding toolbar buttons are shown on the following pages alongside the menu options that the shortcut or toolbar button performs Also miscellaneous other keyboard commands are summarized CAChe for Windows User Guide Keyboard shortcuts Menu option shortcuts Keys Ctrl N Ctrl O Ctrl Z Ctrl S Alt F4 Ctrl P Ctrl F Ctrl C Ctrl X Ctrl V Del Ctrl D Ctrl L Ctrl K CAChe for Windows User Guide Action
10. Changing element color You can change the color assigned to any element in CAChe by editing the settings of the periodic table Changes you make this way apply to all chemical sample files not just the active document in the workspace NS To change element color 1 Choose Options Periodic Table Settings The Periodic Table Settings dialog box is displayed Periodic Table Settings BE Charge Color Beautify Color i Factory Settings Cancel Factory Settings for All CAChe for Windows User Guide 6 37 Chapter 6 Viewing Chemical Samples 2 Do one of the following to select an element whose color you want to change o Select an element in the Periodic Table Settings element list o Double click on Periodic Table to display the Periodic Table dialog box and select an element by clicking on it and selecting OK to close the Periodic Table dialog box 3 Select the Color tab to display the Color box Select the arrow button in the Color box and choose a color from the drop down list of 12 colors 5 Select OK to close the Periodic Table Settings dialog box The new element color is applied to objects of the element type you chose from the drop down list Color changes apply to all saved chemical sample files and all new objects of that element type drawn in the workspace NOTE Select Factory Settings to restore default settings for element color for the element currently chosen in the Period
11. Chapter 11 Using the Procedure Editor The Procedure Editor interface The Procedure Editor consists of three types of window e the Navigator window e the Procedure window e the Parameter Data window In addition there is a menu bar and a toolbar The menu bar changes as you Select different types of Procedure Editor window The Navigator window By default the Navigator window is displayed when you start the Procedure Editor EL ProcedureE ditor CAChe Experiment Environment ioj xj File Edit View Window Help oem Sale CAChe Experiment Environment E 633 Environment i Workspace Parameter Data Parameter Data Collection 2 chemical sample Procedure Index Procedure Collection B optimized geometry ProjectLeader ProjectLeader Experiment Colle ay standard procedure 0G_MOPAC PM3 workspace Workspace Experiment Collect y fastest procedure 0G_MM MM3 ay MM geometry MM2 OG_MM MM2 ay MM geometry MM3 OG_MM MM3 gy MM AM1 geometry 0G_MM_MOPAC AM1 gy MM PM3 geometry 0G_MM_MOPAC PM3 gy MM PMS5 geometry 0G_MM_MOPAC PM5 g MM MNDOd geometry OG_MM_MOPAC MI ay AM1 geometry OG_MOPAC AM1 oy PM3 geometry OG_MOPAC PM3 ay PM5 geometry OG_MOPAC PM5 y MNDOd geometry OG_MOPAC MNDOd ay AM1 transition state geometry 0G_MOPAC ay PM3 transition state geometry OG_MOPAC F ay PMS transition state geometry OG_MOPAC F ay MNDOd transition state geometry OG_MOP a AM1 MOZYME geom
12. HOMO and LUMO 2 14 HOMO and LUMO energies calculating 15 7 Homolog creating 19 15 GPCR 19 15 Hybridization changing 5 20 changing an atoms 5 24 5 25 correcting 4 13 Hybridization box 3 9 3 11 4 5 Hydrogen atoms hiding 6 19 Hydrogens deleting 4 15 hiding 6 19 view settings 6 48 I Identifying procedure numbers 10 9 Import MDL SD files dialog box 12 13 Importing an experiment 11 28 Improper torsion angles specifying 8 17 Infra red spectra 18 2 Insert residue tool 9 25 Installation B 1 Interpreting surface color 15 11 Intrinsic reaction coordinate 17 4 20 19 Inverting chiral centers 8 3 Investigating atom and bond properties 16 1 electron density surfaces 15 2 electron distribution 15 1 low energy conformations 14 1 molecular geometry 8 1 molecular orbital energies 15 7 peptide conformations 19 3 reaction path structures 18 2 reactions 17 1 transition state structures 17 2 1 7 Index Ionic bonds 5 33 Ionization energy 15 7 IR transitions 10 6 IR Transitions window 18 3 Isosurfaces 15 17 K Keyboard commands A 4 shortcuts A 1 A 2 Kinetic energy 17 4 L Label chiral centers 8 2 Label Wizard geometry 8 41 Labels 15 21 atom 8 33 16 8 atoms 6 8 geometry 8 19 8 24 8 29 in scatter plots 12 29 search 8 37 8 43 Legends 15 16 Ligand docking 19 22 Limitations size and element 10 31 Locked geometry disabling 8 35 Locking atoms 8 32 geometry labels 8 29 Locks geometry 8 31
13. Connect Atoms menu option The connecting bond cycles through the following bond types every time you choose this menu option e single e double e triple weak 5 30 CAChe for Windows User Guide Changing atom and bond properties To change bond type while connecting atoms 1 Select the two atoms participating in the bond by clicking on the first atom with the Select tool then holding down the Shift key and clicking on the second atom with the Select tool The atoms are highlighted to show that they are selected 2 Do one of the following o Choose Edit Connect Atoms o Press Ctrl K o Select the Connect Atoms toolbar button shown to the left The selected bond changes to one of the following bond types single double triple or weak 3 Do one of the following o Continue to choose Edit Connect Atoms o Continue to press Ctrl K o Continue to select the Connect Atoms toolbar button until the selected bond changes to the bond type you require Reversing a coordinate bond CAChe enables you to reverse the direction of a coordinate bond NS To reverse a coordinate bond 1 Select the molecule that contains the coordinate bond s by clicking on the molecule with the Select Molecule tool The molecule is highlighted to show that it is selected 2 Choose Edit Reverse Coordinate Bonds The coordinate bond s are reversed CAChe for Windows User Guide 5 31 Chapter 5 Modifying Chemica
14. SAMPLE MAP SAMPLE MAP SAMPLE MAP Creator Mechanics MOPAC Dynamics Mechanics MOPAC MOPAC MOPAC MOPAC Type Description binary rigid or optimized map binary Dynamics trajectory binary sequence of conformations binary reaction path binary reaction path binary reaction path binary reaction path 10 39 Chapter 10 Performing Workspace Experiments Viewing log files and output files 10 40 Each CAChe computational application produces both a log file and output file when you use an experimental procedure that involves that computational application The exception is Tabulator which only produces an output file Log files log contain details such as the date and time of the experiment computation time and final result of the experiment Output files out contain details of the calculations carried out on the chemical sample step by step and the resulting values You can view both log files and output files in any text editor or word processor Log files and output files are overwritten each time you perform another experiment on the chemical sample file using the same computational application If you want to keep a particular experimental log or output file save it under another name in your text editor or word processor CAChe for Windows User Guide 11 Using the Procedure Editor Overview This chapter describes the Procedure E
15. You can define the following criteria for selecting similar atoms e element type e hybridization e charge e number of bonded atoms e number and type of bonds You can define the following criteria for selecting similar bonds e bond type element of bonded atoms CAChe for Windows User Guide 5 11 Chapter 5 Modifying Chemical Samples To do this you use the Select Similar Settings dialog box Select Similar Settings x Atoms Bonds m Select Similar Atoms By IV Hybridization I Charge I Number of Bonded Atoms I Number and Types of Bonds Cancel To define similarity criteria for the Select Similar tool 1 Choose Options Select Similar Settings The Select Similar Settings dialog box is displayed 2 Select the Atoms tab to display a list of atom property check boxes Select the required check boxes so that they are enabled 4 Select the Bonds tab to display a list of bond property check boxes 5 Select the required check boxes so that they are enabled Select OK to close the Select Similar Settings dialog box The Select Group tool Use the workspace s Select Group tool to e select an atom and all the atoms with which it shares a group deselect an atom and all atoms in the group e select an RMS label e select bonds in a group To select the Select Group tool 5 12 CAChe for Windows User Guide Selecting workspace objects 1 Se Select the Se
16. a Click and drag the scroll bar in the scrolling list to locate the file you wish to open then click on it to select it 9 Select Open to open the chemical sample file CAChe for Windows User Guide 4 3 Chapter 4 Creating Chemical Samples Drawing a molecule in the workspace In CAChe the active chemical sample file window is referred to as the workspace Each workspace contains a palette of tools which you can use to draw and manipulate your molecule Use the Atom Bond tool to draw the atoms and bonds of your molecule and use the style bar boxes at the top of the workspace to choose the properties of the atoms and bonds you draw You can choose these properties either e before you draw the atom or bond using the Atom Bond tool e after you draw the atom or bond using the selection tools Refer to Chapter 5 Modifying Chemical Samples for details about using the selection tools to change the atom and bond type on a molecule you have already drawn The following section describes how to draw a molecule by choosing atom and bond properties from the style bar e drawing the atoms and bonds in the workspace using the Atom Bond tool Refer to Chapter 3 CAChe Basics for details about using the style bar boxes Using the Atom Bond tool lt This section describes how to use the Atom Bond tool to draw atoms and bonds Use the Atom Bond tool to e draw an atom by clicking the Atom Bond tool in the
17. A lt t gt Refer to Chapter 7 Manipulating Molecules for information on this Options menu option Adjust Enable Locks A lt t gt Refer to Chapter 7 Manipulating Molecules for information on this Adjust menu option CAChe for Windows User Guide 6 51 Chapter 6 Viewing Chemical Samples A lt t gt Yv e all settings in the Periodic Table Settings dialog box displayed by choosing Options Periodic Table Settings Refer to the following for information on this Options menu option Changing view Settings p 6 37 Chapter 4 Creating Chemical Samples Chapter 5 Modifying Chemical Samples Changing settings using a dialog box 6 52 The following settings become default settings by selecting Make Default in the relevant dialog box e all colors in the Define Colors dialog box color palette displayed by choosing View Color Palette Refer to Changing view settings p 6 37 for information on this View menu option e all settings in the Atom Attributes dialog box displayed by choosing View Atom Attributes Refer to Changing the appearance of atoms p 6 8 for information on this View menu option e all settings in the Bond Attributes dialog box displayed by choosing View Bond Attributes Refer to Changing the appearance of bonds p 6 21 for information on this View menu option e all settings in the Geometry Label Attributes dialog box dis
18. A popup menu is displayed 3 Choose Regression from the menu The best fit line is drawn through the results of the regression analysis and the regression equation is given underneath the scatter plot Exporting the plot To copy the plot to another application 1 Select the scatter plot that you want to copy then choose Edit Copy 2 Switch to another application and choose Edit Paste to paste an image of the plot BioMedCAChe User Guide 12 31 Chapter 12 Using ProjectLeader Printing the plot NS To print the plot a Select the scatter plot that you want to print then choose File Print Closing the plot If a ProjectLeader project is closed while scatter plot windows are open the plots are saved to the project file When the project is reopened the scatter plot windows are redisplayed 12 32 BioMedCAChe User Guide Changing workbook display options Changing workbook display options You can change the display of the following items in a ProjectLeader workbook chemical samples can be displayed by their file name or as line drawings that you can enlarge to view more clearly rows can be sorted e grid lines can be hidden or displayed as dotted shaded gray or solid black lines e font size and type and alignment of text can be changed and text can be displayed as a molecular formula i e numbers as subscripts numbers can be displayed in scientific or standard notation the
19. Activate the document window whose contents you want to preview by clicking on the window 2 Choose File Print Preview to enter print preview mode The contents of the workspace are displayed framed in a page as they would appear in a printout 3 To zoom into the printout choose Zoom In CAChe zooms into the displayed printout The cursor changes to the print preview magnifying glass Click to continue to zoom into the printout in increments 4 To zoom out from the printout do one of the following Choose Zoom Out CAChe zooms out from the displayed printout in increments Continue to click the print preview cursor until the printout display reverts to its original size CAChe for Windows User Guide Printing files 5 To exit print preview mode choose Close CAChe returns you to the document window Choosing print options You can change the following print options in CAChe which printer to use and its properties e page orientation of a printout e paper size and source To specify a printer and its properties 1 Choose File Print Setup to display the Print Setup dialog box Print Setup MEI m Printer Properties Name HP Laserdet 4 4M Plus PS Status Default printer Ready Type HP Laseret 4 4M Plus PS Where SHP_Network_Printers carryon Comment m Paper r Orientation Size Ad X Portrait Source AutoSelect Tray 7 Landscape Cancel 2 To use a di
20. Is more than Is in range Is not in range Real numbers Equals Is less than Is more than Is in range Is not in range 5 Type the criteria values in the text box Range criteria e g Is in Range or Equals display two text boxes to specify the range When entering a range enter the lower and upper values When comparing real numbers equality enter the value you are searching for and the interval that defines equality 6 optional Check Look in selection only to restrict the search to the currently selected objects TIP To find objects that match search criteria for one property AND a different property use the Find command twice On the second use check Look in selection only to find objects that match the search criteria for the first property and the second property 7 optional Check Add to selection if you want to extend the current selection with the newly selected items TIP To find objects that match search criteria for one property OR a different property use the Find command twice On the second use check Add to selection to find objects that match the search criteria for the first property or the second property 8 Check Show selection only to hide all objects that are not selected 9 Check Zoom to selection to fit the selected objects in the workspace once they are found This option is grayed unless the Find command was invoked from a workspace 10 Click Cancel to exit without
21. Low energy structures 10 5 LUMO 10 6 12 3 18 7 1 8 M Manipulating molecules 7 1 7 9 search labels 8 43 Manipulation tools 7 2 Map file windows 14 12 Map files analyzing 14 22 animating 14 26 display options 14 15 open 14 12 saving 14 30 Map reaction 2 16 17 1 Maps energy 14 2 Matching properties to procedures 10 15 Matching selections 9 40 MCAR 19 15 19 22 Mechanics 20 5 classical 13 3 concepts 20 2 optimizing with 20 3 quantum 13 3 13 4 Mechanics application 2 21 Melanocortin 4 receptor MC4R 19 17 Melanocortin 4 recptor MC4R 19 15 Menu bar 3 4 using 3 20 Menu option 3 20 shortcuts A 3 Minimum energy geometries 20 17 Mirroring molecules 8 5 MM multiple passes 20 6 one pass 20 6 MM2 20 3 MO polarity 15 14 Model types 6 4 Modeling solvent effects 20 19 styles 2 3 Modifying BioMedCAChe User Guide atoms and bonds 5 2 chemical samples 5 1 Molecular connectivity index 12 3 Molecular formula 12 3 Molecular geometry investigating 8 1 Molecular orbital energies 15 7 calculating 15 8 Molecular orbitals 2 14 10 6 15 17 20 11 color 15 13 surfaces 18 6 Molecular refractivity 12 3 Molecular weight 12 3 Molecules comparing biomolecules 9 39 completing 4 9 deleting portions 7 18 deselecting 5 8 drawing 4 4 duplicating 7 13 manipulating 7 1 7 9 mirroring 8 5 optimizing portions 13 6 perfecting 4 10 selecting 5 7 specifying angles and distances 8 12 superimposing 8 6 MOPAC 2 21 20 11 20 1
22. Manipulating Biomolecules Working in the Sequence View window The sequence data for a protein 3D structure that is open in CAChe is displayed in the Sequence View window When you open multiple proteins their sequence data are added to the Sequence View window Only one Sequence View window can be open at one time You use the sequence window to e view the sequence color the sequence by property e mutate residues e edit the sequence build peptides and proteins from residues e analyze secondary structure e adjust the conformation or secondary structure of a protein e align sequences e match selections and select conserved residues superimpose sequences NOTE The Sequence View is available only with CAChe WorkSystem Pro BioCAChe or BioMedCAChe Viewing sequence residues To view a sequence 1 From a workspace window choose Analyze Sequence to display the sequence window The Sequence View window displays sequences in rows that begin with the chemical sample 9 18 BioMedCAChe User Guide Working in the Sequence View window name Title bar Style bar F 7 USE Tool palette MLL TE VAVI G 34 35 36 37 38 39 2 4 G LGGLY L 53 l 45 A M The sequence has a direction starting from the N terminus of the first residue to the C terminus of the last one Hetero groups are always displayed but water molecules HOH are never displayed When you view a sequence the Se
23. Positioning the Atom Bond tool over an existing atom in the workspace 3 Clicking and dragging to another atom The type of bond you draw is determined by the current selection in the style bar s Bond Type drop down list To draw a bond between two existing atoms 1 Select the arrow button in the Bond Type box at the left of the style bar as shown below H Hydrogen 7 sp3 tetrahedron mej Sinale Coordinate A drop down list of bond types is displayed 2 Choose a bond type from the drop down list The bond you are going to draw will be of the chosen bond type 3 Position the Atom Bond tool over an atom you have already drawn 4 Click and drag the Atom Bond tool across the workspace to another atom you have already drawn A bond of the chosen bond type is displayed between the two atoms The example to the left shows a single bond between two atoms of the same element If a bond already exists between the two atoms the next higher order bond type is formed Bond order cycles through single double triple weak and back to single bonds when you repeat bond formation CAChe for Windows User Guide 4 7 Chapter 4 Creating Chemical Samples Drawing a bond with an atom Drawing a bond with an atom involves 1 3 Choosing a bond type from the Bond Type drop down list in the style bar Positioning the Atom Bond tool over an existing atom in the workspace Clicking and dragg
24. Quantum mechanical methods are used to optimize the sample and determine the partial charge for all atoms Both partial charge and bond order are calculated at the same time so you do not need to run separate experiments to get both properties After you run a partial charge experiment you can choose to view your chemical sample with atoms sized to reflect their partial charge This enables you to view possible reactivity sites more clearly and shows you which bonds in your sample are most polar The example below shows phenol with atoms sized to reflect partial charge Most acidic hydrogen If you know the partial charges on atoms in two reagents you have a good idea about which part of each molecule is likely to interact You can also view the relative acidity of different hydrogens more clearly because the largest positive partial charge is likely to be the most acidic CAChe for Windows User Guide Calculating atomic partial charge If you have run an experiment that employed a quantum mechanical procedure previously this information is already present in the chemical sample file and you do not need to re compute it unless you have changed the geometry of the molecule CAChe procedures for calculating atomic partial charge also enable you to optimize the geometry of the molecule first using classical mechanics quantum mechanics or a combination of both You can combine all of the optimization procedures with calc
25. Select Open to open the CrystalStructure file The crystal structure is displayed in the workspace CAChe for Windows User Guide Building crystal structures If you entered thermal tensor data into the CrystalStructure file you can build a crystal and represent atoms as thermal ellipsoids using the Thermal Ellipsoid command in the Shape tab of the Atom Attributes dialog box q gt Refer to Changing atom shape p 6 11 for further information ShelX files You can build crystal structures by opening a ShelX Instruction file To open a ShelX Instruction file 1 Choose File Open to display the Open dialog box 2 From the Files of type drop down list select ShelX Instruction ins Select the file 4 From the scrolling list locate the file and click on it to select it Select Open to open the ShelX file The structure displays asymmetric atoms lacking bonds Information about fractional coordinates the space group and descriptors are included in the file This enables you to easily reconstruct the original crystal using the Crystal Shape dialog box If you entered thermal tensor data into the ShelX file you can build a crystal and represent atoms as thermal ellipsoids using the Thermal Ellipsoid command in the Shape tab of the Atom Attributes dialog box lt t gt Refer to Changing atom shape p 6 11 for further information Importing data from a text file Data may be copied from te
26. Select a conformation in the conformational analysis window by clicking on the conformation in the list An asterisk appears next to the selected conformation in the list The conformation in the conformation window displays the conformation you selected in the list The spherical marker in the graph window moves to the corresponding energy value in the CAChe for Windows User Guide Viewing map files CAChe for Windows User Guide graph You may need to move the conformational analysis window to one side by clicking and dragging on its title bar to view the graph window and conformation window of the map file The parameter bar at the bottom of the conformational analysis window displays a parameter value for the selected conformation Select the arrow button in the right hand box of the parameter bar to choose another parameter from a drop down list Select the up or down arrow button in the left hand box of the parameter bar to increase or decrease the value of the selected parameter in increments The conformation window displays the conformation with the selected increased or decreased parameter value The spherical marker in the graph window moves to the corresponding energy value in the graph The resulting conformation no longer corresponds with the conformation you selected in the conformational analysis window The asterisk next to the selected conformation in the list disappears indicating that the graph location
27. The results are saved as an assemblage file drcl map drc 1 map ircl map irc 1 map 20 18 BioMedCAChe User Guide Understanding MOPAC With an Intrinsic Reaction Coordinate IRC you calculate the path in which all kinetic energy is lost at every step As the potential energy changes the kinetic energy generated is annihilated so that the potential and total energies are the same An IRC follows the reaction path from the transition state geometry to either the reactants or products of the reaction It simulates one effect of a reaction in a solution in which all excess kinetic energy would be lost at every step of the trajectory Other effects such as the solvent dielectric are not simulated by the IRC The IRC is intended to be used with a transition state geometry as the starting point You choose a vibrational mode for the initial motion This vibration is usually the reaction coordinate You also choose whether the initial geometry is displaced in the positive or negative direction along this vibrational mode With a Dynamic Reaction Coordinate DRC you calculate the dynamics trajectory that conserves energy As potential energy is lost the kinetic energy increases so that the total energy is constant DRC calculations may be run from any geometry An internal coordinate can be specified for the initial displacement If the initial geometry is a transition state an initial displacement along a particular vibrationa
28. Tools atom bond 3 14 3 19 3 30 4 4 manipulation 3 14 3 20 manipulation tools 7 2 residue 9 25 residue tool 9 25 rotate 3 14 3 30 3 32 3 38 7 2 7 3 scale 3 14 3 30 3 33 3 39 7 2 scaling 7 8 select 3 30 3 31 3 33 select group 5 4 5 12 select molecule 3 30 3 31 5 4 5 6 select molecule chain 9 24 select similar 3 30 3 31 5 4 5 9 select similar residue 9 24 selecting 3 30 selection tools general rules 5 4 translate 3 14 3 30 3 33 3 38 7 2 7 5 using workspace selection tools 3 29 workspace selection 5 3 Torsion angles improper 8 17 Total energy 12 3 Trajectory 20 9 dynamics 10 8 Transition state 10 8 structures investigating 17 2 Transition state geometry optimizing 13 6 Transition state structures 10 5 Transition states generating 17 1 MOPAC 20 17 refining 17 1 verifying 17 1 Transitions electronic 18 6 vibrational 18 2 Translate tool 3 14 3 30 3 33 3 38 7 2 7 5 Translating a scatter plot 12 28 Triple covalent bonds 5 33 Troubleshooting experiments 10 32 Turn type 1 21 7 type 1 21 7 type 2 21 7 type 2 21 7 U Undo command 7 19 Ungroup atoms 7 28 Unlock atoms 8 33 User guide about 1 4 conventions 1 6 navigation aids 1 8 User interface 3 3 UV visible spectra 18 6 transitions 2 14 10 6 UV visible Transitions window 18 7 Vv BioMedCAChe User Guide Valence correcting 4 10 defining rules 4 10 view settings 6 48 Valence command Beautify menu 4 10 Valence
29. change or create features of selected parts of your molecule e residue type secondary structure type e Phi and Psi angles ALA J z Prif Psi 41 8 Residue Type drop down Secondary structure drop down Phiangle box Psi angle box Example style bar Use the style bar in conjunction with the workspace selection and inserting tools to e display the residue type and Phi Psi angles of a selected residue e mutate a residue from one type to another change Phi and Psi angles e set a motif BioMedCAChe User Guide 9 21 Chapter 9 Manipulating Biomolecules The Residue Type box The Residue Type drop down box lists the twenty standard amino acids MET PHE PRO THR TRP TYR VAL Once you choose a residue from the Residue Type drop down box you can e insert a residue of that type mutate a selected residue to the type you select The Secondary Structure box The Secondary Structure box provides a drop down list of secondary structures that you can apply to e the next residue you insert a selected residue Beta Sheet begin Right handed alpha a Right handed omega Right handed pi Right handed gamma Right handed 310 Left handed alpha Left handed omega Left handed gamma 27 ribbon helix Polyproline Beta anti paralel 9 22 BioMedCAChe User Guide Working in the Sequence View window The Phi and Psi boxes The Phi and Psi boxes are text boxes tha
30. modifying The instruction to call the second procedure is added as a step within the procedure The Procedure Call Settings dialog box is used Procedure Call Settings i271 xi Procedure to Call ms eoUpt Browse Edit Procedure Arguments Supply 1 argument s to MM_Geo0pt fs ample 1 v Cancel Original Settinas 11 20 CAChe for Windows User Guide Modifying a procedure To calla procedure from another procedure 1 From the Procedure window select the step in the procedure after which you want to insert the call to another procedure 2 Select the New button to display a popup menu Choose Procedure Call to display the Procedure Call Settings dialog box 4 Select the procedure that you wish to call from the Procedure to Call text box Alternatively you can select the Browse button and choose from the list of available procedures 5 If required change the procedure arguments in the Procedure Arguments drop down list 6 Select OK to confirm the procedure that you wish to call and to close the dialog box A step calling the selected procedure is inserted into the list of steps Running a procedure After modifying a procedure you can execute the procedure using the Run Procedure dialog box Sample 1 i Sample text boxes Browse L Sample 2 ER Browse Status m Output CAChe for Windows User Guide 11 21 Chapter 11 Using the Procedure Ed
31. rather than the combination of low and high energy structures that an optimized map produces Instead of evaluating and optimizing the energy of all possible combinations of search label values the sequence of conformations finds the lowest energy value of each search label in turn and locks each label at its lowest value before proceeding to the next one In this way only low energy conformations are generated The following procedures are available for a sequence of conformations experiment one pass search which evaluates only one low energy value for each search label e multiple pass search which evaluates up to three low energy values for each search label Sequential searches are often an efficient way to get closer to the global minimum energy value for a molecule The resulting map file contains local energy minima without high energy barriers between them Sequential searches always generate a two dimensional graph regardless of the number of search labels in the chemical sample file The horizontal axis is simply the sequence in which the conformations were evaluated and the vertical axis displays the potential energy for the particular conformation CAChe for Windows User Guide 14 9 Chapter 14 Investigating Low energy Conformations TIP Sequential searches can only be performed by Mechanics using classical mechanical methods You can use an unlimited number of search labels in a sequence of conf
32. select every object in the workspace BioMedCAChe User Guide 3 29 Chapter 3 CAChe Basics Selecting a tool To select a tool from the tool palette click on it When you select a tool the cursor changes to represent the selected tool as shown in the following table Workspace tool name Tool palette Cursor icon Select tool default h Select Molecule tool Select Similar tool Select Group tool Atom Bond tool Rotate tool Translate tool E EKEKA R Scale tool P 3 30 BioMedCAChe User Guide Using CAChe Introducing the selection tools BioMedCAChe User Guide Use the selection tools to select workspace objects individually in groups of similar objects or molecule by molecule CAChe allows you to hide atoms bonds and other objects The select tools operate on visible objects Usually hidden objects are not selected A hidden object is selected only if the Select Molecule tool or Select Group tool is used to choose a visible atom or bond and the hidden object is a part of the selected molecule or group The Select tool The Select tool is the default workspace tool Use it to select one or more visible objects such as individual atoms or bonds e deselect one or more objects e select all visible objects by clicking on the background The Select tool and Select cursor are shown to the left Refer to Using the Select tool p 3 33 for further details The Select Mol
33. select portions of a current workspace selection Set diagrams in the Group Atoms dialog box illustrate the set operations with the left circle representing the set S selected atoms in the workspace and the right circle representing the set G a named atom group The shaded region in each set diagram represents the workspace atoms that will be selected by the set operator The example set diagrams to the left represent the selection of all items belonging to a named atom group far left and the selection of everything but the atoms in a named group left To select an existing group of atoms BioMedCAChe User Guide 1 Choose Edit Group Atoms to display the Group Atoms dialog box 2 Click on the group that you want to select in the Defined Groups list Select G only 4 Select OK to close the Group Atoms dialog box The atoms belonging to the chosen group are highlighted in the workspace to show that they are selected 7 25 Chapter 7 Manipulating Molecules To select all workspace objects apart from an atom group 1 Choose Edit Group Atoms to display the Group Atoms dialog box 2 Select the group whose atoms you do not want to be selected in the workspace by clicking on the group in the Defined Groups list Select All but G 4 Select OK to close the Group Atoms dialog box Every workspace object is selected apart from the atoms belonging to the group you chose in the Group Atoms dialog bo
34. viewing map files CAChe for Windows User Guide 17 5 Chapter 17 Investigating Reactions 17 6 CAChe for Windows User Guide 1 8 Investigating Spectra Overview This chapter explains how to perform CAChe experiments to generate and view e infrared vibrational spectra e UV visible electronic spectra Contents Investigating infrared spectra 18 2 Viewing infrared spectra 18 2 Investigating UV visible spectra 18 6 Viewing UV visible spectra 18 7 Chapter 18 Investigating Spectra Investigating infrared spectra NOTE CAChe enables you to view vibrational spectra for a molecule created by coordinated motions of the atoms as electromagnetic radiation in the infrared IR region is absorbed by the molecule Absorption bands observed in the infrared are associated with the bending and stretching of particular types of bonds so viewing these infrared transitions aids the analysis of molecular structure CAChe uses quantum mechanics to compute the force necessary to distort the molecule from its equilibrium geometry and predict the frequency of vibrational transitions When you select a point on the vibrational spectrum motion vectors for every atom appear in the workspace as shown in the following example You can edit the spectra to adjust the peak width wavelength and area of a selected transition UV visible and vibrational spectra generation are not available in Personal CAChe and BioCA
35. workspace e draw further bonds and atoms by clicking and dragging the Atom Bond tool in the workspace e continue to draw atoms and bonds until your molecule is complete CAChe for Windows User Guide Drawing a molecule in the workspace To select the Atom Bond tool 1 Select the Atom Bond tool by clicking on it in the tool palette F The mouse cursor changes to the Atom Bond tool shown to the left Once you have selected the Atom Bond tool you are ready to start drawing the atoms and bonds of your molecule Drawing an atom Drawing an atom involves 1 Choosing atom properties from the style bar drop down lists 2 Clicking in the workspace with the Atom Bond tool NOTE When the Atom Bond tool is the active tool clicking anywhere in the workspace draws an atom The type of atom is determined by the current selections in the style bar s element type hybridization and charge drop down lists NSS To draw an atom 1 Select the arrow button in the Element Type box at the left of the style bar A drop down list of elements is displayed PA ee SU 0 Oxygen H Hydrogen Na Sodium S Sulfur N Nitrogen F Fluorine Periodic T able 2 Choose an element type from the drop down list The atom you draw will be of the chosen element type 3 Select the arrow button in the Hybridization box in the style bar A drop down list of hybridization options is displayed C
36. 26 27 28 29 30 31 32 33 34 35 36 Rb Sr Y Nb Mo Tc Ru Rh Pd Ag Cd In Sn Sb Te i Xe 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 Cs Ba La HE Ta W Re Os Ir Pt Au Hg Tl Ph Bi Po At Rn 55 56 57 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 Fr Ra Ae 87 88 89 Te Pr Nd Pm Sm Eu Gd b Dy Ho Er Tm Yb lu 58 59 60 61 62 63 64 65 66 67 68 69 70 71 Th Pa U Np Pu Am Cm Bk Cf Es Fm Md No Lr 90 31 92 93 94 95 96 97 98 99 100 101 102 103 Cancel 7 Select an element by double clicking on it or clicking on it and selecting OK The Periodic Table dialog box closes and the element you have chosen is displayed in the Element box in the Atom Attributes dialog box 8 Select the arrow button in the Hybridization box and choose the hybridization you require from the drop down list 9 Do one of the following o Select the up or down arrow button in the Charge text box to display the positive or negative atomic charge you require o Click in the text box and enter the atomic charge you require 10 Select OK to close the Atom Attributes dialog box The selected atom or group of atoms changes to the element type hybridization and positive or negative atomic charge that you have chosen in the Atom Attributes dialog box CAChe for Windows User Guide 5 23 Chapter 5 Modifying Chemical Samples
37. 400 atoms 4 Do one of the following o Choose Edit Paste o Press Ctrl V A copy of the selected object is pasted in the center of the active workspace The copy is highlighted in the workspace to show that it is selected while all other workspace objects are grayed out The copied object remains on the Windows Clipboard until you copy or cut another object so you can continue to paste copies of the object until you have the required number of copies BioMedCAChe User Guide 7 17 Chapter 7 Manipulating Molecules Deleting portions of your molecule CAChe provides two ways to delete selected workspace objects e cutting an object placing it in the Windows Clipboard to paste into another file or Windows application e deleting an object without placing a copy in the Windows Clipboard Cutting workspace objects Tocuta workspace object 1 Select the object that you want to cut by clicking on it with a selection tool The object is highlighted to show that it is selected 2 Do one of the following o Choose Edit Cut o Press Ctrl X o Select the toolbar button shown to the left The selected object is copied to the Windows Clipboard and disappears from the workspace The object remains in the Windows Clipboard until another selected object is copied or cut or until you quit CAChe 3 Do one of the following gt Choose File Open to open a CAChe file if you want to paste the object from the Win
38. 6 2 4 1 0 1 3 2 3 1 1 3 2 1 1 0 3 1 3 3 4 5 2 4 3 4 1 0 4 1 1 1 3 1 1 4 3 3 1 i 1 0 0 1 0 1 3 3 0 2 3 1 1 0 1 0 1 1 1 1 2 2 1 1 1 1 1 3 3 4 5 5 1 3 3 3 3 2 3 1 3 1 2 1 2 3 3 1 2 3 2 1 1 8 1 1 0 1 3 1 3 1 4 1 1 1 3 1 3 1 4 1 4 1 4 1 1 1 3 1 1 1 1 1 3 1 2 1 0 1 3 1 1 1 5 1 4 1 alignment However it may not be unique There may be other alignments with the same score If the two sequences are of length n and m respectively then the time and memory required for the alignment are proportional to nm For protein sequences that are typically less than 1 000 residues long alignment is quick 21 14 sequences BioMedCAChe User Guide Gotoh O J of Mol Bio 1996 264 823 838 An improved algorithm for matching biological Durbin R Eddy S R Krough A Mitchison G Biological sequence analysis Probabilistic models of proteins and nucleic acids Cambridge University Press 1998 19 22 3 Q x 3 LOHd y eee Appendices The following appendices describe the shortcuts you can use in CAChe and the files that are added to your computer when you install your CAChe product Appendix A Keyboard and Toolbar Shortcuts
39. 9 Manipulating Biomolecules To display a backbone only 1 Choose Edit Select Backbone All atoms that are marked as backbone atoms are selected and highlighted All other atoms connected to the backbone are deselected 2 Choose View Hide Unselected Atoms not in the backbone are hidden and only the backbone is displayed Displaying the backbone N C C trace 4 To display the N C C protein backbone 1 Choose View Backbone N C C Trace The N C C atoms in each residue are selected and all other atoms connected to the backbone are deselected and hidden NS To redisplay all atoms 1 Choose View Show All All objects are displayed Displaying ribbons To display the protein backbone as a ribbon 1 Choose View Backbone Ribbon Backbone Ribbon a v None Atom Attributes ange lee Threads Bond Attributes G sical ete Flat Ribbon Geometry Label Attributes Solid Ribbon Color Palette Threaded Spools Threaded Pods Chau Flastans 2 Choose the style Single Thread Threads Flat Ribbon Solid 9 10 BioMedCAChe User Guide Viewing biomolecules Ribbon Threaded Spools Threaded Pods A splined ribbon in the chosen style and using the color set with View Residue Colors is drawn The cubic B spline follows the N C C atoms in each residue All amino acid residues connected to the backbone are deselected and hidden Nucleic acids HET groups and waters remain visible
40. 9 Calculating current energy 13 10 Investigating Low energy Conformations 14 1 Generating energy maps 14 2 Viewing map files 14 11 Investigating Electron Distribution 15 1 Investigating electron density surfaces 15 2 BioMedCAChe User Guide vi Generating an electrostatic potential surface Investigating molecular orbital energies Viewing a surface Investigating Atom and Bond Properties 16 1 Calculating atomic partial charge Calculating bond properties Viewing atom and bond properties Investigating Reactions 17 1 Investigating transition state structures Investigating reaction path structures Investigating Spectra 18 1 Investigating infrared spectra Investigating UV visible spectra Investigating Biomolecules 19 1 Investigating peptide conformations Creating a homology model of the MC4R Docking Agouti Related Protein into the MC4R CAChe Computational Applications 20 1 nderstanding Mechanics nderstanding Dynamics nderstanding MOPAC nderstanding Tabulator nderstanding DGauss Understanding CONFLEX CAChe BioComputations 21 1 Understanding Residue Names Understanding Protein Secondary Structure Definition Understanding Dihedral Angles for Building Peptides Understanding Sequence Property Predictions CG U U U U Keyboard and Toolbar Shortcuts A 1 Keyboard shortcuts Toolbar shortcuts CAChe File Management B 1 CAChe folders and files Index 15 6 15 7 15 9 16 2 16 4 16 7 17 2 17 4 18
41. Atoms calculating partial charge 16 2 change the charge of 5 21 changing the appearance of 6 8 changing the color of 6 14 changing the radius 5 26 changing the shape of 6 11 6 13 color 16 10 displaying 6 18 drawing 4 5 fusing 7 21 grouping 7 24 hiding 6 18 hiding locked labels 8 33 interpreting properties 16 7 labeling 6 8 labels 16 8 lock 8 32 measuring distance 8 13 modifying 5 2 properties 16 1 selecting locked atoms 8 34 specifying distance 8 13 ungroup 7 28 unlock 8 33 Axis attributes changing 14 18 Axis attributes dialog box 14 18 B Beautify menu 5 24 5 25 5 26 Beta sheet 21 6 BioComputations 21 1 Biomolecules 9 1 investigating 19 1 Bond attributes dialog box 6 24 16 11 Bond order 2 15 10 7 BioMedCAChe User Guide Bond orders 20 11 Bond properties 10 7 changing 5 19 Bond strain 2 15 10 7 15 14 bond type 3 9 Bond Type box 3 12 Bond types 5 32 Bonds calculating order 16 4 calculating properties 16 4 calculating strain 16 5 changing 5 28 changing the appearance of 6 21 changing the color of 6 25 6 26 changing the shape of 6 21 changing type 5 30 color 15 14 coordinate covalent 5 33 displaying 6 28 double covalent 5 32 drawing 4 6 drawing between two exisiting atoms 4 7 drawing with an atom 4 8 fusing 7 22 hiding 6 28 interpreting properties 16 7 ionic 5 33 modifying 5 2 order 15 14 15 15 16 7 16 11 m coordination bond 5 34 properties 16 1 radius 16 11 single covalent 5 32 specifying
42. Chapter 6 Viewing Chemical Samples Text Width Cai 00 i 2 Select a text width by clicking on the button that displays the width you require The currently active text width button is depressed to show that it is enabled 3 Select a line width by clicking on the button that displays the width you require The currently active line width button is depressed to show that it is enabled 4 Select OK to close the Drawing Settings dialog box Text and lines in the active workspace are displayed in the width you chose Changing workspace perspective and distance You can change the perspective in which you view your chemical sample by aligning the view with an axis or plane in your molecular structure You can also edit the viewing distance and front and back clipping depths Align your workspace view with the following e x axis enables you to view your chemical sample looking down the chemical sample s x axis e y axis enables you to view your chemical sample looking down the chemical sample s y axis e zaxis enables you to view your chemical sample looking down the chemical sample s z axis CAChe for Windows User Guide Changing view settings e through selected atoms enables you to view your chemical sample looking down the axis formed by two selected atoms or normal to the plane formed by three selected atoms You must have either two or three atoms selected when you choose the View S
43. Charge F Atom Number I Chirality for Asymmetric Carbons T Locked State F Alphanumeric Label M Display Atoms Cancel Make Default 3 Select the Label tab to display a list of labeling options for atoms 4 Select the Partial Charge check box so that it is enabled 5 Select OK to close the Atom Attributes dialog box Atoms in the workspace are labeled with partial charge as shown in the following example CAChe for Windows User Guide 16 9 Chapter 16 Investigating Atom and Bond Properties Displaying partial charge with scaled and colored atoms To view partial charge with scaled and colored atoms 1 16 10 Run an atomic partial charge or calculated bond order experiment on your chemical sample file Choose View Atom Attributes to display the Atom Attributes dialog box Select the Color tab to display a list of labeling options for atoms Select the Partial Charge Polarity check box so that it is enabled Select OK to close the Atom Attributes dialog box Atoms in the workspace are colored by partial charge polarity where positively charged atoms are displayed on screen in red and negatively charged atoms are displayed on screen in yellow as shown in the following example CAChe for Windows User Guide Viewing atom and bond properties Displaying bond order and partial charge To view atomic partial charge and calculated bond order 1 Run an atomic partial cha
44. Display Atoms Cancel _ Make Defaut Select the Label tab to display the following list of labeling options for atoms o atomic symbol o hybridization o charge o partial charge o atom number o chirality for asymmetric carbons o presence of locks on the atom o the alphanumeric label o name If the chemical sample is from a PDB file the Name is the PDB atom name Select the check box next to the display features you require for CAChe for Windows User Guide Changing the appearance of atoms each selected atom 5 Select OK to close the Atom Attributes dialog box The labels you chose are displayed against the atoms you selected Changing atom shape View atoms as three types of spheres e shaded spheres atoms are displayed as a shaded space filling representation CAChe for Windows User Guide 6 11 Chapter 6 Viewing Chemical Samples e wireframe spheres atoms are displayed as a wireframe space filling representation e dotted spheres atoms are displayed as a dotted space filling representation Change the radius of a sphere to represent e the van der Waal s radius e the covalent radius e aradius proportional to the calculated atomic partial charge property only available if you have run a partial charge or calculated bond order experiment on your chemical sample 6 12 CAChe for Windows User Guide Changing the appearance of atoms Scale a sphere by specifying a
45. Energy Calculations Optimizing chemical samples NOTE 13 2 Optimization involves finding the most stable geometry or minimum energy structure of a chemical sample The lowest energy or optimum structure of a conformation of a molecule displays characteristics and properties that are more likely to reflect the true behavior of a chemical sample Therefore using optimization in CAChe enables you to achieve more accurate results when analyzing molecular characteristics Because of this most CAChe experimental procedures begin with optimizing your chemical sample You might not always want to optimize the sample for example if the sample is already in a low energy geometry from a previous experiment In this situation choose the existing geometry and wavefunction procedure for your experiment This procedure uses existing geometry and wavefunction data from previous experiments on the chemical sample CAChe uses both classical molecular mechanics and semi empirical quantum mechanics to find minimum energy conformations of your molecule You can combine both methods of optimization in a CAChe experiment For example you can optimize a molecule using classical mechanics first and then refine the structure using quantum mechanics CAChe optimization procedures also enable you to e include solvation effects of water while optimizing your molecule Refer to Modeling solvent effects with COSMO p 20 19 for
46. Guide 6 41 Chapter 6 Viewing Chemical Samples 4 Select OK to close the Color dialog box The new color replaces the color you selected in the Define Colors dialog box scrolling list 5 Select OK to close the Define Colors dialog box All workspace objects represented by that color index number are displayed in the new color To change a color to a new custom color 1 Select the color you want to change by clicking on it in the Define Color dialog box scrolling list A box is displayed around the list option to show that it is selected 2 Select Set to display the Color dialog box 3 Select Define Custom Colors to display a color picker square in an extended Color dialog box Color Basic colors E S im Jo E o Fae j imini i mi I i ee E E on E E E E E Ennn E Custom colors Em eae Hue f133 Bed 83 E EE EE ae Sat 150 Green 156 Deine easton lalate gt gt ColorlSalid Lum fi 44 Blue A 7 E E E ee 4 Do one of the following Click and drag the crosshairs around the color picker square to choose a new color Click and drag the slider at the right of the color picker square to adjust the luminosity value The values in the Red Green and Blue text boxes and the Hue and Sat text boxes change as you drag the crosshairs around the square The 6 42 CAChe for Windows User Guide Changing view settings value in the Lum text box changes as you drag the slider up or down
47. H l J K a Atom List ID Formal x Y Z Partial Name Temperature Atom Hybridization Charge Coordinate Coordinate Coordinate Charge Factor Position angstrom angstrom angstrom 1 N1 1 0 16 864 14 059 3 442 0 000 N 6 220 BB sp3 2 c2 2 0 16 868 12 814 4 233 0 000 CA 4 450 BB sp3 E c3 3 0 15 583 12 775 4 990 0 000 c 4 390 BB sp2 4 04 4 0 15 112 13 824 5 431 0 000 0 7 040 0 sp 5 c5 5 0 18 060 12 807 5 200 0 000 CB 5 420 0 sp3 6 06 6 0 19 233 12 892 4 380 0 000 0G1 7 870 0 sp 7 Cc 7 0 18 117 11 578 6 092 0 000 CG2 6 880 0 sp3 8 H8 8 0 16 007 14 241 3 093 0 000 1H 6 170 0 s 9 H9 3 0 17 087 14 800 3 997 0 000 2H 5 690 0 s a0 H10 10 0 17 481 14 013 2 750 0 000 3H 5 690 0 s 11 H11 11 0 16 940 12 048 3 605 0 000 HA 4 300 0 12 H12 12 0 18 008 13 641 5 765 0 000 HB 5 820 0 13 H13 13 0 19 761 13 553 4 647 0 000 HG1 6 620 Oo s 14 H14 14 0 17 940 10 768 5 540 0 000 1HG2 6 360 0 s 15 H15 15 0 18 983 11 488 6 531 0 000 2HG2 6 130 0 s a L Atoms Bonds Groups Notes Orbitals In the chemical sample atoms and their properties appear in the Atoms worksheet bonds in the Bonds worksheet and residues in the Groups worksheet The Orbitals worksheet keeps track of nonbonded electron pairs so that the valence can be checked The Calculations worksheet tracks the sequence of modeling calculations that have been performed CAChe for Windows User Guide 6 33 Chapter 6 Viewing Chemical Samples The sample prope
48. NH3 or OH Before you generate automatic search labels you might want to lock the coordinates of an atom near the center of the molecule to prevent the sample from moving to the far edges of the workspace during the generation of the varying conformations Refer to Locking atoms p 8 32 for details about locking the workspace coordinates of atoms To define dihedral search labels using the Geometry Label Wizard 1 Do one of the following o Select the whole molecule by clicking on it with the Select Molecule tool o Select the bonds for which you want to generate search labels by clicking on one bond with the Select tool holding down the Shift key and clicking on the rest of the bonds CAChe for Windows User Guide 8 41 Chapter 8 Investigating Molecular Geometry 8 42 2 Choose Adjust Geometry Label Wizard to display the Geometry Label Wizard dialog box Generate dihedral search labels for IV Single lonic and Coordinate bonds searching between er fiso and pa degree in 15 steps IV Double bonds searching between Help 180 and fa0 degree in f3 steps I Weak bonds searching between 180 and fi 50 degree in 5 steps T Include terminal groups Make Default To include single ionic and coordinate bonds in the search label generation select the Single lonic and Coordinate bonds searching between check box so that the radio button is enabled A range of default va
49. New Step 3 Choose the name of the compute server that you wish to use The selected step is added to the procedure and the Settings dialog box for the selected compute engine is displayed lt t gt Refer to Editing the settings of a compute engine p 11 23 for details about editing these settings Deleting a step You can delete a step from a procedure To delete a step 1 Select the step that you wish to remove 2 Select the Delete button The selected step is removed from the list of steps Moving a step You can move a step from a procedure so that it appears nearer the beginning or end of a set of steps NS To move a step 1 Select the step that you wish to move 2 Select the Up button to move the step upwards CAChe for Windows User Guide 11 19 Chapter 11 Using the Procedure Editor 3 Select the Down button to move the step downwards The selected step is moved up or down respectively Viewing the settings of a step You can view the settings of a selected step To view the settings of a step 1 Select the step that you wish to view 2 Select the Open button to display the Settings dialog box Alternatively choose File Edit Step A lt 4 gt If you wish to change the settings of the compute engine used in an existing step refer to Editing the settings of a compute engine p 11 23 Calling a procedure You can call a procedure from within the procedure that you are
50. Parameter bar 14 14 hiding 14 16 Parameter data editing 11 30 Parameter Data window 11 7 Partial charge 15 14 16 7 16 10 16 11 20 11 color 15 13 Path reaction 10 9 Peptide building 19 3 conformations 19 3 generating 19 6 19 8 Perfecting molecules 4 10 Performing experiments 10 1 12 1 Periodic table dialog box 4 11 Periodic table settings dialog box 4 11 5 27 6 37 Perspective changing 6 44 Phi and Psi angle box 9 21 Phi and Psi boxes 9 23 1 10 Pi helix 21 7 Plotting a scatter plot 12 27 variables along an axis 14 16 Polarity 15 14 Polyatomic molecules 20 8 Potential energy maps exhaustive versus sequential 20 6 Potential energy surface 20 3 Potential polarity 15 14 Previewing printouts 4 22 12 43 Print preview File menu 4 22 Print dialog box 4 25 Print Setup dialog box 4 23 Print to File dialog box 4 27 Printing a CAChe window 4 25 files 4 22 options 4 23 orientation 4 24 print to a file 4 27 scatter plots 12 32 Procedure Editor 2 19 11 1 overview 11 2 quitting 11 38 starting 11 3 Procedure window 11 6 Procedures adding a step 11 19 calling a procedure 11 20 deleting a step 11 19 identifying numbers 10 9 matching properties 10 15 modifying procedures 11 17 moving a step 11 19 property investigation 10 9 running a procedure 11 21 table 10 10 viewing a step 11 20 ProjectLeader overview 12 2 printing 12 40 BioMedCAChe User Guide projects 12 11 quitting 12 45 Sample Properties t
51. S andG S butnotG Cancel 3 Drag the atom names to place them in the required order Atoms are placed after the atom they are dropped on To move an atom to the top position in the list drag it on top of the group name 4 Select OK to close the Group Atoms dialog box The atoms belonging to the chosen group are highlighted in the workspace to show that they are selected and the order of the atoms in the group has been changed Showing residues in Group Atoms dialog box Residues are special atom groups that are added automatically when biomolecules are imported from PDB files or built with the Sequence View window To view atom groups that are residues 1 Choose Edit Group Atoms to display the Group Atoms dialog box Check Show Residues in the Group Atoms dialog box BioMedCAChe User Guide 7 29 Chapter 7 Manipulating Molecules The list of residues appears in the Defined Groups list Group Atoms _2 x m Define groups from the current selection Defined Groups M Show Residues E gt gt EUSI AA a E l lt lt Ungroup lt lt Eee ALAS Group Name ee ALA420 oOo 0 ALA455 Hee ALA462 xi m Combine the current selection S with group G to form a new selection only AN bot Song G bButnotg Sand S GutrGt Cancel The order of atoms in a residue is important You should not change the order of atoms in residues If yo
52. STANDARD set of MM2 A Parameter Data window is displayed Change any of the data in the window by selecting a value and overwriting with a new value When the modifications are complete choose File Save to save the modified parameter data set If you make any changes which are not satisfactory choose Edit Original Settings to revert to the system copy of the parameter data CAChe for Windows User Guide Creating a group procedure package Creating a group procedure package A package is a collection of different types of components that are used in the experiment environment Examples of these components include the property and the sample used in an experiment In the CAChe experiment environment there are three directories each of which can contain packages System This directory relates to the location of the CAChe executables and is shared by all users of the installation Group This directory contains packages that are available to a group of users This feature is available to both multiple user installations of CAChe and single user installations In the case of single users the group package s can be used to share CAChe experiments with other users User This directory contains packages available to a particular CAChe user You can create a new group procedure package for use by other users Packages can be created from the Organizer dialog box using the Create Package dialog box File Organ
53. Setup to display the Page Setup dialog box 12 40 BioMedCAChe User Guide Printing files Select Printer to display a further Page Setup dialog box To use a different printer from the one displayed in the Printer panel select the arrow button in the Name box and choose a printer from the drop down list The printer s status type and location are displayed in the Printer panel of the dialog box To change the properties of the printer select Properties to display a dialog box containing specific options for your printer type Select the Page Setup or Advanced tab to display and select the options relevant to your printer Select OK to close the dialog box of document properties and to return to the Page Setup dialog box Select OK in the Page Setup dialog box to save the selected printer and its properties and to close the Page Setup dialog box To change page orientation of a printout 1 2 Choose File Page Setup to display the Page Setup dialog box In the Orientation panel select one of the following a select the Portrait radio button to print portrait images where the paper is longer than it is wider a select the Landscape radio button to print landscape images where the paper is wider than it is longer Select OK to save the page orientation and to close the Page Setup dialog box To change paper size and source BioMedCAChe User Guide Choose File Page Setup to display the Page Setup dia
54. Text Color radio button in the Color Geometry Labels with section to enable it 5 Select OK to close the Geometry Label Attributes dialog box The geometry label you selected is displayed in the color assigned to standard text in the CAChe color palette lt t gt Refer to Editing the color palette p 6 38 for information on editing the CAChe color palette Deleting geometry labels Delete a geometry label in one of two ways e using the Delete key e using the Adjust menu options To delete a geometry label using the Delete key 1 Select the geometry label you want to delete by clicking on the label with the Select tool 2 Press Delete To delete a geometry label using the Adjust menu 1 Select the geometry label you want to delete by clicking on the label with the Select tool 2 Choose one of the following depending on the distance or angle that the label is representing o Adjust Atom Distance to display the Set Atom Distance 8 26 CAChe for Windows User Guide Working with geometry labels dialog box o Adjust Bond Angle to display the Set Bond Angle dialog box o Adjust Improper Torsion to display the Set Improper Torsion dialog box o Adjust Dihedral Angle to display the Set Dihedral Angle dialog box 3 Select the Define Geometry Label check box so that it is disabled 4 Select OK to close the Set Atom Distance Set Bond Angle Set Dihedral Angle or Set Improper Torsion
55. The files and folders that are installed depend on the particular CAChe product that you have purchased File name cache exe GenID exe MessageDirector exe PLWin exe ProcedureEditor exe Analysis idx SamplePart idx Space Groups het_dictionaryCIF txt Datadict cache chm cache2 chm cache cnt cache2 cnt cache hlp cache2 hlp cache _pe cnt ReleaseNotes pdf Tutorials pdf UserGuide pdf c CACHE APP B 2 errdll dll Crystal dll Description e CAChe applications e Property and procedure index e Space group transformations e HET group definitions from PDB e Data dictionary e CAChe Help files CAChe documentation e Various resource files and libraries used by cache exe PLWin exe and ProcedureEditor exe e Error code resource e Crystal code resource BioMedCAChe User Guide CAChe folders and files Folder File name Description c CACHE BIN CalcMgr exe CAChe Calculation Manager c CACHE BIN CONFLEX e Contains Conflex compute engine and Conflex manager c CACHE BIN DYNAMICS e Contains Dynamics compute engine and Dynamics manager c CACHE BIN MECHANICS e Contains Mechanics compute engine and Mechanics manager c CACHE BIN MOPAC e Contains MOPAC compute engines and MOPAC manager c CACHE BIN TABULATOR e Contains Tabulator compute engine and Tabulator manager c CACHE ExpEnvironment Data c CACHE ExpEnvironment Modules c CACHE ExpEnvironment Packages c CACHE Frag
56. The selected residue is added to the repository displayed in the Amino Acid list and available in the Residue Combo Box BioMedCAChe User Guide Extending the amino acid repository Creating and adding a nonstandard amino acid with the Workspace TIP BioMedCAChe User Guide 1 In the CAChe 3D Structure window build a nonstandard amino acid Amino acids in the repository are building blocks that appear in repeat units in the sequence For example the repository con tains the glycyl fragment not glycine Amino acids also must contain the N C C backbone Choose Beautify Valence Hydrogen atoms are added Choose Edit Group Atoms The Group Atoms dialog box appears Choose amino acid from the Group Type pull down and type In the group name into the Group Name text box and press the gt gt Group gt gt button Group Atoms 2 x r Define groups from the current selection Defined Groups M Show Residues Group Type amino acid ha Group Name MYG LYCYL Combine the current selection S with group G to form a new selection The group appears in the Defined Groups list Click OK The Group Atoms dialog box closes Choose Analyze Chemical Properties Spreadsheet and click the Groups tab The chemical properties workbook opens and the Groups page is at the front Check that 9 47 Chapter 9 Manipulating Biomolecules 9 48 10 11 o The group type is AA_GR
57. To build asymmetric atoms 1 2 Select the crystal structure using the Select Molecule Tool Choose Edit Crystal Shape to display the Crystal Shape dialog box In the Build panel select Asymmetric atoms only Select Apply to view the crystal structure in the workspace The asymmetric atoms are displayed and you can edit their positions Select OK to accept the changes and to close the Crystal Shape dialog box Building a molecular crystal 6 60 You can build a molecular crystal by first building one molecule from asymmetric atoms This enables you to adjust bond types in the molecule before you build the molecular crystal NS To build a molecule 1 Choose Edit Crystal Shape to display the Crystal Shape dialog box Define the space group and cell parameters in the Space Group panel and Angles panel respectively In the Build panel select Molecule Select the Fractional Coordinates tab In the Symbol column do one of the following o enter the atomic symbol for each atom o enter an alphanumeric label containing an atomic symbol and CAChe for Windows User Guide Building crystal structures any numeric tag to uniquely identify each asymmetric atom 6 Enter the coordinates in the X Y and Z columns by clicking the left uppermost cell using the left mouse button and use the Tab key to move between cells 7 Select Apply to view the crystal structure in the workspace The bond types and at
58. Translate in the positive y direction Increase scale 2 2 2 lt Assign a negative z direction to the current view adjustment mode Rotate about minus z axis Translate in the negative z direction Decrease scale Assign a positive z direction to the current view adjustment mode Rotate about positive z axis Translate in the positive z direction Increase scale A 5 Appendix A Keyboard and Toolbar Shortcuts Toolbar shortcuts The following diagram shows the menu commands that each toolbar button performs Bully a0edg mal JAPUI AD 9 jeg MAI Soul Mal Aluo seulq MAA UoHIsOd HPA MOPUIM UL MOI ansuayasdwo5 Ayyneag Jage7 Ajewoag uy q isnipy SWO Y JOBUUOD IPF UOEUUOJU JBAJBS MOUS JUaWLJedx3 sjuawuedxy p p uqns moys juewuedxy MON yu wadx4 dja aanisuas xa U05 x pul djeH Wd ld ased YPI do9 43 ND UPS aAeg alld uado alld MON la CAChe for Windows User Guide A 6 B CAChe File Management Overview This appendix contains details of e the files and folders added to your hard disk when you install CAChe from the installation CD ROM wn 8 Ss 3 lt Contents CAChe folders and files B 2 Appendix B CAChe File Management CAChe folders and files Folder c CACHE The table below lists the files and folders that are added to your computer when you install your CAChe product
59. User Guide Generating energy maps course of a reaction A series of reaction path structures are calculated between the transition state structure deformed structure to either the product or reactant molecule Potential_ Energy 2 96 to 4 50 kcal mole Ah Af ll ll j A UA f l l P ateps 1 00 to 479 00 steps Reaction path graph A A lt 4 gt Refer to Chapter 17 Investigating Reactions for more information on map reaction experiments Preparing your chemical sample file Before generating a rigid or optimized energy map or sequence of conformations you must first add search labels to the atom distances and bond angles that you want varied in your molecule to generate the series of conformations You do not have to add search labels to perform a dynamics trajectory or reaction path experiment CAChe steps the search labels a form of geometry label through the range of values that you specified when defining the search labels to form the conformations and measure the energy of each structure You can define search labels for atom distances bond angles improper torsion angles and dihedral angles lt t gt Refer to Chapter 8 Investigating Molecular Geometry for more information on adding search labels to a chemical sample CAChe for Windows User Guide 14 5 Chapter 14 Investigating Low energy Conformations Generating a rigid energy map NO
60. User Guide Understanding CONFLEX Stepwise rotation Optimization Pre check during optimization BioMedCAChe User Guide order to ensure smooth transformation of local structure by edge flip which is actually a much larger perturbation The acyclic part of a molecule is perturbed by stepwise rotation Typically a Csp Csp bond is given 120 and 120 rotations to produce a pair of new rotamers This method combined with the reservoir filling strategy for guiding the search direction searches low energy conformers for short side chains and linear molecules with up to six to ten rotatable acyclic bonds However it is not as effective for large molecules with multiple branching where unexpectedly high energy starting structures are produced a i i s N i D The time required to perform systematic perturbations on the initial structure comprises only a few percent of the total computing time while by far the most time consuming step is the geometry optimization Therefore the pre check is an effective way to increase the efficiency of the conformational space search In CONFLEX a structure that is being geometry optimized is frequently compared with all the stored conformers during the optimization and that calculation is stopped as soon as the candidate structure is identified as superimposable with one of the stored structures However if comparison is made too often the comparison ti
61. You do this by editing the sequence of the homologous 3D structure so that it matches the sequence of the unknown To build by homology 1 Open the known protein in the workspace 2 Choose Analyze Sequence to display the sequence in the Sequence View window 3 In the Sequence View window replace delete or add residues with ones from the new sequence When you replace a residue backbone atoms of both residues are superimposed and then the original residue is removed conserving the secondary structure When the unknown sequence has extra residues that are not in the known structure you will want to add them as loops 9 35 Chapter 9 Manipulating Biomolecules 9 36 To add loops without moving the other atoms in a chain you break the chain at the point of loop insertion then insert the residues forming the loop and finally rejoin the chain NS To insert a loop 1 In the Sequence View window click the name of the chemical sample to activate it for modification The sequence name is highlighted in yellow Use the Select tool to select the two residues where you want to insert the loop Select Edit Break Chain The chain is broken and an asterisk appears between the selected residues Use the Residue tool to add new residues to each chain in a loop As you add residues adjust the Psi and Phi angles so that new loop residues are added in the appropriate empty space and do not overlap existing
62. adds or removes hydrogen atoms and electrons to or from the selected atoms to satisfy the valence rules for each atom You can change the valence rules that you apply to a chemical sample using the Beautify menu options i e Beautify Valence and Beautify Comprehensive by changing valence options for each element in the periodic table CAChe for Windows User Guide Perfecting your molecule To change the valence rules for an element 1 Choose Options Periodic Table Settings to display the Periodic Table Settings dialog box Periodic Table Settings BE Charge Color Beautify C Carbon M Beautify Valence N Nitrogen 0 Oxygen Complete Shell H Hydrogen C Satisfy Configuration F Fluorine Cl Chlorine I Add Electrons Fe Iron Periodic Table OK Cancel Factory Settings for All 2 Do one of the following a Select an element from the element list by clicking on it a If the element you want is not shown double click on Periodic Table to display the Periodic Table dialog box Periodic Table 2 x lH He 1 ii Be B je IN fo F Ne 3 4 5 6 7 8 9 10 Na Mg as e is a a 11 12 13 14 15 16 17 18 K Ca Sc T MV Cr Mn Fe Co Ni Cu n Ga Ge As Se Br Kr 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Rb Sr Y Zz Nb Mo Tc Ru Rh Pd Ag Cd In Sn Sb Te i Xe 37 38 39 40 41 42 43 44 45 46 47 48 49
63. an arrow button 1 2 Position the cursor over the arrow button Press the left mouse button A drop down list is displayed Arrow buttons also indicate a text box in which you can enter a value or choose a value supplied by selecting either an up or down arrow button at the side of a text box 1 To enter a value into a text box using arrow buttons 1 Move the cursor over the up arrow button if you want to choose a value of 1 or more or over the down arrow button if you want to choose a value of 1 or less Press the left mouse button The value of 1 or 1 is displayed in the text box Increase or decrease the value further by selecting the arrow until the value you require is displayed Check boxes can be toggled on and off to enable or disable an option in the dialog box NS To enable a check box 1 2 Position the cursor over the blank check box Press the left mouse button A check mark is displayed in the check box to show that the option is enabled goeseesessscceessoesecoeseosos BioMedCAChe User Guide Using CAChe Radio buttons Radio buttons can also be toggled on and off to enable or disable an option in the dialog box bs To enable a radio button 1 Position the cursor over the blank radio button 2 Press the left mouse button A small black circle is displayed in the radio button to show that the option is enabled Element Directory buttons Directory button
64. and IUPAC IUB Commission on Biochemical Nomenclature Biochemistry 1970 9 3471 Structure Fully extended 135 113 Antiparallel beta sheet Parallel beta sheet 21 6 BioMedCAChe User Guide Understanding Dihedral Angles for Building Peptides Structure Phi Psi Right handed alpha helix 57 47 Left handed alpha helix 60 60 34 helix 49 26 pi helix 57 70 Predefined values for turns are from C M Wilmot and J M Thornton Analysis and Prediction of the Different Types of B Turn in Proteins J Mol Biol 1968 203 1 221 32 Turn Phit Psit Phi2 Psi2 Type 1 60 30 90 0 Type 1 60 30 90 0 Type 2 60 120 80 0 Type 2 60 120 80 0 BioMedCAChe User Guide D gt 5 i s 2 D i D 21 7 Chapter 21 CAChe BioComputations Understanding Sequence Property Predictions CAChe predicts sequence properties for e antigenicity e hydrophobicity e hydrophilicity e flexibility This section provides reference information about the way CAChe predicts sequence properties from the residue sequence using average parameters Sequence property concepts Regions of proteins can be described as antigenetic hydrophobic hydrophilic and or flexible CAChe uses established simple algorithms for predicting these properties The property for each residue depends on its type and the types of neighbor residues in the sequence The following for
65. and associated properties and objects which are represented by the corresponding color Define Colors x 1 lonic Bonds 2 Surface Labels l C l 3 Atom Distances Single Bonds Lancet 4 Double Bonds Set 5 Weak Bonds l pi s 6 Dihedral Angles i Help 7 Bond Angles Coordinate 8 Improper Torsion Triple Bonds Make Default 2 Click and drag the scroll bar to view all 14 colors in the color palette 6 40 CAChe for Windows User Guide Changing view settings Changing the color palette When you change a color in the color palette you can either e choose a pre defined color from a selection of basic Windows colors or custom colors e create a new color from any of 16 8 million colors by adjusting red green and blue values and hue saturation and luminosity values NS To change a color to a pre defined color 1 Select the color you want to change by clicking on it in the Define Color dialog box scrolling list A box is displayed around the list option to show that it is selected 2 Select Set to display the Color dialog box Basic colors Custom colors m En Define Custom Colors gt gt Cancel Help 3 Do one of the following lh BERET maa l i a o Select one of the 48 basic Windows colors by clicking on a color box in the Basic colors panel o Select a custom color by clicking on a color box in the Custom colors panel CAChe for Windows User
66. and reactivity including e similarities between potential structure activity drug molecules relationships QSAR e visualization of experimental e superimposition of lead structures e g PDB and molecules and quality of crystal structures superimposition drug receptor interactions bioavailability e g logP e molecular shape e electrostatic interactions e design of stereo specific e location of all low energy candidates conformations CONFLEX e automatic sequence e Crevice maps suggest alignment binding sites e location of binding sites e reactivity surfaces e design of ligands inside a e accessible surfaces binding site pocket e partial charges e IR spectra e transition states e H bond analysis e ribbon of proteins e Rule of 5 screening While many questions posed by biologists and medicinal chemists can be solved by using only one of these capabilities the availability of all these working together in CAChe is invaluable BioMedCAChe User Guide Overview of CAChe You can draw the atoms and bonds of a molecule using the CAChe tools copy a molecular structure from the fragment library of samples supplied with your CAChe product or you can copy and paste a sample structure from another application such as ChemDraw or Isis Draw You can manipulate this chemical sample on your computer screen then perform experiments on it CAChe provides the following tools lt Q 5 a 5 e b 5 i e
67. angle 8 14 strain 15 14 16 12 16 13 triple covalent 5 33 type 15 14 15 15 weak 5 33 Broken geometry locks 8 31 Bumps labeling 8 28 Buttons toolbar A 1 A 3 BioMedCAChe User Guide C CAChe overview 2 2 quitting 3 45 sequence view 9 20 user interface 3 3 workspace 3 8 Calculating atomic partial charge 16 2 bond order 16 4 bond properties 16 4 connectivity indexes 12 2 current energy 13 11 dipole vectors 12 2 RMS error 8 10 using classical mechanics 13 11 using quantum mechanics 13 11 Calibrating CAChe 2 9 Calibrations establishing 2 18 12 2 Calling a procedure 11 20 Center of rotation rotate tool 7 4 Centering objects 7 6 Changing atom or bond properties 3 42 Changing a bond 5 28 Changing atom and bond properties 5 19 Charge 16 7 changing 5 21 Charge box 3 9 3 11 Check boxes 3 24 Chemical sample files 4 2 opening existing 4 3 opening in ProjectLeader 12 12 opening new 4 2 preparing 10 4 Chemical samples creating 4 1 modifying 5 1 optimizing 13 1 properties 10 5 viewing 6 1 I 3 Index Chiral centers 8 1 8 2 inverting 8 3 labeling 8 2 viewing 8 2 Choosing options and items 3 17 Classical mechanics 2 4 13 3 rigid energy map 14 6 Clicking and dragging on objects 3 19 Clicking on objects 3 18 Cloning an experiment 11 27 Closing ProjectLeader 12 45 Color 15 14 15 15 16 11 atom 6 14 16 10 bond 15 14 changing bonds 6 25 default 15 13 define custom palette 6 42 elements 6 37
68. arrow buttons e directory buttons e tabs e workspace tools e toolbar buttons Choose Choose the following items in CAChe e menu options e drop down list options BioMedCAChe User Guide 3 17 Chapter 3 CAChe Basics Click Click on the following objects e document windows to make them active e in the workspace using the selection tools e in the workspace using the Atom Bond tool e hypertext links in the CAChe Help system To click on an object using the selection tools 1 Position the cursor over the workspace object you want to select 2 Press the left mouse button and release The selected object is highlighted and other workspace objects are grayed out 3 To select more objects hold down the Shift key 4 Position the cursor over the next object you want to select still holding down the Shift key 5 Press the left mouse button and release The second object you selected is highlighted along with the first while other workspace objects are grayed out 6 Continue to click on any further objects you want to select still holding down the Shift key To click on the workspace using the Atom Bond tool 1 Position the cursor anywhere over the workspace 2 Press the left mouse button and release An atom is displayed in the workspace BioMedCAChe User Guide Using CAChe Click and drag Click and drag on the following objects e scroll bars in dialog boxes e sliders in dia
69. cache folder For standalone users If you are using CAChe as a standalone program and cache localhost does not appear in the Experiment dialog box Server drop down list edit your tcpconf txt file in the following way NS To edit the tcpconf txt file to include a new server 1 Using a text editor open your tcpconf txt file located in the CAChe directory 2 Add the following to your tcpconf txt file to include the localhost server on which to run CAChe experiments locally a the keyword server a the server name of localhost a the login name of cache CAChe for Windows User Guide 10 33 Chapter 10 Performing Workspace Experiments a the keyword CACH a the keyword CalcManager The following shows an example tcpconf txt file with the server name localhost and login name cache added to the domain name server line tcpconf txt TCP configuration file Use these if the domain name server is available keyword server name login name pc _ ident unix process name server srvrl jillj CACH CalcManager server localhost cache CACH CalcManager 3 Save and close the tcpconf txt file 4 Quit and restart the CAChe application For users with access to GroupServer 10 34 For users who have access to CAChe GroupServer and the servers on which you wish to run experiments do not appear in the Experiment dialog box Server drop down list you need to add the following to your tcpconf txt file
70. can be useful Calculating all molecular orbital energies 15 8 This experiment calculates the shapes and energies of all of the molecular orbitals in your chemical sample Choose this experiment when the orbitals you are interested in lie outside the HOMO 5 to LUMO 4 range Do not use this experiment without careful consideration simply because it requires a significant amount of disk space to store all the orbitals for large molecules CAChe for Windows User Guide Viewing a surface Viewing a surface When you run an experiment that generates a surface for your molecule a surface file iso is created which contains information that CAChe uses to build a three dimensional molecular surface representing electronic properties You view this shaded surface superimposed on your molecule in the chemical sample file You do not open the isosurface file to view the surface NS To display a surface 1 Choose File Open to display the Open dialog box 2 Double click on the Cache folder to open it Select the arrow button in the Files of type box and choose Chemical sample csf from the drop down list 4 Click and drag on the scroll bar of the scrolling list to locate the relevant chemical sample file for which you generated the surface 5 Double click on the required chemical sample file to open it The chemical sample file opens 6 Choose Analyze Show Surfaces to display the Show Surfaces dialog box
71. changing the current selection The selected objects are highlighted CAChe for Windows User Guide 5 15 Chapter 5 Modifying Chemical Samples Selecting neighbors Using the Select tool in the workspace to select atoms or bonds adjacent to selected atoms in large molecules is tedious and error prone CAChe provides a single command that selects atoms and 5 16 bonds that neighbor selected atoms To select neighboring atoms 1 From the workspace choose Edit Select Neighbors The following dialog appears Select Neighbors 2x r Select Nearest Atoms E e S Number of Atoms a Number of Bonds oot 1 1 Cancel Choose the method to Select Nearest by Selection Radius e Number of Atoms Number of Bonds Type the radius number of atoms or number of bonds in the box adjacent to the chosen method Click OK to select the all neighboring atoms and add them to the current selection When selecting neighboring atoms by number of atoms CAChe creates a list of the atoms closest to the currently selected atoms and orders that list by distance from the selection CAChe then adds the nearest specified number of atoms to the current selection CAChe for Windows User Guide Selecting workspace objects When selecting by number of neighboring bonds CAChe selects all atoms that are closer than the specified number of bonds from the currently selected atoms To select neig
72. chemical sample file However the surface acs files remain in the iso folder You delete acs files with the Windows Explorer after they have been deleted from the chemical sample To display the ligand adjacent surface 1 With the Select Molecule Tool in the 3D Structure Window containing a ligand bound in a protein active site select the ligand NOTE The protein and ligand must have hydrogen atoms added first The ligand highlights and all other objects dim 2 Choose Analyze Adjacent Surface Pocket After a few seconds a progress dialog appears and then the BioMedCAChe User Guide 9 15 Chapter 9 Manipulating Biomolecules 1 9 16 surface of the protein adjacent to the ligand Choose View Hide Unselected The ligand and the surface remain visible All other objects disappear The surface that is drawn is one that is accessible to or touched by a 1 4A sphere rolling over that portion of the protein adjacent to the ligand This is the surface of the protein that interacts with the ligand and forms the pocket in which the ligand is docked The colors of the pocket indicate properties of an ideal ligand The mauve red areas indicate regions of the protein surface where hydrogen bond acceptors e g gt C O are needed in the ligand for optimal binding The blue areas map regions of the protein where nearby hydrogen bond donors e g OH or NH gt are needed for optimal binding in the lig
73. cursor to the workspace location where you want to put the selected object To scale the selected object use the Scale tool to zoom into or out from the selected object When you select the Scale tool by clicking on it in the tool palette a warning message is displayed informing you that scaling a portion of your chemical sample will affect atom distances Do one of the following o Select OK to proceed and select the Scale tool o Select Cancel to return to using the Rotate or Translate tool If you select OK click and drag the Scale tool to zoom into and out from the selected object Do one of the following to exit position mode o Select a selection tool or the Atom bond tool by clicking on BioMedCAChe User Guide Manipulating portions of your molecule BioMedCAChe User Guide the tool in the tool palette o Choose any menu option The check mark next to the Move Selected drop down list option disappears 7 11 Chapter 7 Manipulating Molecules Using faster motion mode Faster motion mode is helpful when viewing or manipulating large structures in the workspace When you make a change to your chemical sample or manipulate it in some way the chemical sample appears in a simplified form such as a line drawing This increases the speed at which CAChe can redraw the moving or changing molecule As soon as the simplified display of the molecule is complete CAChe reverts to the current display mode For
74. cyclic To create a turn 1 Inthe Sequence View window choose the Select tool 2 Select the two residues in the middle of the sequence where the turn is to be located If you are building oxytocin select residues 3 and 4 Ile and Gln 3 Choose Edit Make Turn Type I 4 Inthe workspace connect the sulfur atoms to make the cyclic peptide 5 Choose Beautify Valence 6 Fix the ends to NH3 and CO When the peptide is cyclic you close the cycle by creating bonds in the workspace To create a cyclic peptide CAChe for Windows User Guide 19 5 Chapter 19 Investigating Biomolecules 1 In the workspace choose the Select tool 2 Select the two sulfur atoms for the disulfide bond 3 Choose Edit Connect 4 With the two sulfur atoms selected choose Beautify Valence 5 Choose Beautify Hybridization A bond appears between the two sulfur atoms and the hydrogen atoms are removed You have finished building the peptide using standard templates for residues and standard bond angles and distances At this point your peptide may contain atoms that are too close together or bonds and angles that require refinement You clean up the geometry by optimizing the structure with molecular mechanics To refine the peptide 3D structure 1 To optimize the structure choose Experiment New 2 Select these options in the experiment window a Property of chemical sample a Property optimized geometry and a Us
75. density distribution and molecular orbital shape Refer to Chapter 10 Performing Workspace Experiments for a complete list of the properties computed by CAChe BioMedCAChe User Guide The advantages of CAChe Simulation of motion dynamic models Modeling reaction pathways Graphical displays make it easier to interpret the significance of a property and graphical comparisons are especially useful By making it relatively easy to obtain graphical displays of a variety of electronic properties CAChe can help you explore molecular properties and generate new ideas and draw conclusions i 2 5 S gt 3 b E Because molecules are not static it may be necessary to simulate motion to understand some problems This approach is most frequently used to model the changes in shape of macromolecules The key to the success of modeling a reaction is locating a low energy pathway from reactants to products CAChe models transition states to help clarify the choice between alternative pathways By comparing computed activation energies the selection of alternative modes of attack becomes apparent Animation of a molecule following a predicted pathway may reveal unexpected conformational or electronic changes Calculated versus measured properties Calibrating CAChe BioMedCAChe User Guide While computer aided chemistry is a tool that can help you in many ways like all tools it has some limitations CAChe
76. display area as shown in the following diagram E Workbook2 L OO x Chemical Atom Count Sample all atoms Tan Carboplatin va Tamoxifen Flutamide Footnote display area 2 By manual entry NS To add a footnote to a cell 1 Select the cell by clicking on it 2 Choose View Cell Information to display the Cell Information dialog box BioMedCAChe User Guide 12 37 Chapter 12 Using ProjectLeader 3 Click in the Footnote panel then enter the footnote that you want to add 4 Select OK to close the Cell Information dialog box The footnote is displayed in a scrolling window at the bottom of the worksheet To display or hide footnotes 1 Choose View Footnote to display or hide footnotes A check mark next to the menu option indicates whether footnotes are currently displayed Footnotes are displayed in a scrolling section below the worksheet 12 38 BioMedCAChe User Guide Viewing cell information Viewing cell information You can view the following information about a cell the property it displays the procedure used to calculate the property the date and time the information was last updated NS To view or edit cell information 1 Select the cell by clicking on it 2 Choose View Cell Information to display the Cell Information dialog box The Cell text text box displays the contents of the cell A scrolling list displays the chemical sample property t
77. electronic properties of molecules CAChe provides access to MOPAC methods through a Windows environment This section provides reference information about the kinds of computations possible using MOPAC theory and specific information about the CAChe computational application MOPAC Use MOPAC to compute bond orders e dipole moments e dynamics maps e ionization potentials molecular orbital energies optimum geometry e partial charges e potential energy maps D i i s N i D e intersystem crossings e reaction pathways e transition states vibrational frequencies and spectra structure and properties in solution The CAChe MOPAC Molecular Orbital Package application determines both an optimum geometry and the electronic properties of molecules by solving the Schr dinger equation using the semi empirical Hamiltonians AM1 PM3 and PMS developed by M J S Dewar and J J P Stewart respectively CAChe also supports the 20 11 Chapter 20 CAChe Computational Applications older parameter sets MNDO and MINDO 3 and the newer parameter set MNDO d In addition CAChe extends AM1 to AM1 d The molecular orbitals heat of formation and molecular geometry derivatives obtained are used to calculate vibrational spectra molecular geometries force constants and other properties of molecules radicals and ions These quantities are used to calculate reaction trajectori
78. file indicated by the suffix csf Use chemical sample files to e draw your molecule e view your molecule in different ways e launch experiments A lt t gt Refer to Chapter 4 Creating Chemical Samples for more information on chemical sample files The workspace title bar also contains the default Windows minimize maximize and close buttons The style bar The workspace style bar provides four items that enable you to change or create features of selected parts of your molecule as follows e element type e hybridization e charge e bond type BioMedCAChe User Guide 3 9 Chapter 3 CAChe Basics Element Type box Hybridization box Charge box Bond Type box Example style bar Use the style bar in conjunction with the workspace selection and drawing tools to e draw atoms of a specific element e draw bonds of a specific bond type e draw atoms with a specific hybridization and charge e change the element type of selected atoms e change the bond type of selected bonds e change the hybridization and charge of selected atoms The Element Type box The Element Type box lists the last seven elements for atoms you have drawn or selected and provides access to the Periodic Table dialog box from which you select any element in the Periodic Table Once you choose an element from the Element Type drop down list you can e draw an atom of that element e change a selected atom to tha
79. file and to close the Save As dialog box To save conformations in the conformational analysis window as chemical sample files 1 Select one or more conformations in a conformational analysis window by clicking on the conformations Choose File Save Selected Conformations As to display the Save As dialog box Click in the File name text box and type the name of the new chemical sample file The file name you enter will apply to all the files you are saving with each file name appended with the number that corresponds CAChe for Windows User Guide Viewing map files to that structure s place within the energy list For example chem005 csf would be the fifth lowest energy in the list 4 Select the arrow button in the Save as type box and choose Chemical Sample csf from the drop down list 5 Select Save to save the conformations in separate chemical sample files and to close the Save As dialog box CAChe for Windows User Guide 14 31 Chapter 14 Investigating Low energy Conformations 14 32 CAChe for Windows User Guide 1 5 Investigating Electron Distribution Overview This chapter describes the various types of experiments that CAChe offers to predict electron distribution in your chemical sample including experiments that generate e electron density surfaces e electrostatic potential surfaces e molecular orbital surfaces Contents Investigating electron density surfaces 15 2 Calculati
80. for the chemical samples Select the Load additional data radio button if you want to import any data from the SD file other than the structures Additional data will be loaded in the first unoccupied columns Select OK The structures are displayed in the Chemical Sample column Import an MDL SD File x Name the chemical samples by og e g 107 048721 T Load additional data Identifier e g demo 78 16 mol wt e g 105 151680 Ratio e g 0 982279 Response e g 107 048721 RegNum e g OXFD000001 00 il Description Select a field to name the CAChe chemical sample files once they have been translated from D Katrionaconf_oxford sd OK Cancel The name of each sample is saved with the worksheet cell CAChe works primarily with 3D structures Many corporate databases contain only 2D chemical structures The 2D structures must be converted to 3D before performing experiments that require 3D coordinates If your SD file appears to contain 2D coordinates instead of 3D coordinates you will 12 13 Chapter 12 Using ProjectLeader ProjectLeader Warning receive this informational message 7 of the 7 imported chemical samples may be 2D structures CAChe does not perform automatic 2D to 3D conversions and it is recommended that these structures be inspected in the Workspace and if necessary corrected before calculations are run on them Alternatively you may use a program such
81. geom Column Description Homo density m Type Internal Experiment Classes of ProjectLeader experiment Procedure MM AM1 H20_Geo Tab_Prop Browse C Manual Entry Extract From Chemical Sample Cancel Original Settings NOTE The Name text box cannot be edited unless the dialog box is displayed when creating a new experiment CAChe for Windows User Guide 11 15 Chapter 11 Using the Procedure Editor The following parameters can be set for different types of internal experiment Experiment type Parameters Atom Count Atomic number with available values in the range 0 to 102 Bond Count Bond order with available values of all single double or triple Connectivity Index Order with available values in the range 0 to 2 Normal or Polymer Group Count Group type with available values of aldehyde or thio Ring Count Ring size with available values of all rings small rings 5 membered 6 membered and large rings Aromatic or non aromatic Ring Size Ring size with available values of smallest or largest Shape Index Order with available values of 0 to 2 Normal or alpha weighted Valence Connectivity Order with available values of 0 to 2 Index Normal or Polymer The experiment types Elemental analysis Log P Molar Refractivity Molecular Formula Molecular Weight Net Charge and Structure Property Correlation have no additional controls Workspace experiment co
82. it is not checked 3 Select OK to close the Valence Settings dialog box and to save the view setting for hydrogen atoms This setting applies only when View Suppress Hydrogens is checked In that case all hydrogen atoms bonded to carbon are hidden and only those atoms attached to other elements are displayed If View Suppress Hydrogens is not checked all hydrogen atoms are displayed To display electrons attached to atoms with unsatisfied valence 1 Choose Options Valence Settings to display the Valence Settings dialog box 2 Select the Show electrons attached to atoms with unsatisfied valence check box so that it is enabled 3 Select OK to close the Valence Settings dialog box and to save the view setting for electrons To display a warning when saving files containing non standard hybridization or unsatisfied valence 1 Choose Options Valence Settings to display the Valence Settings dialog box 2 Select the When saving files display warning for any atoms with non standard hybridization or unsatisfied valence check box so that it is enabled 3 Select OK to close the Valence Settings dialog box When you attempt to save a chemical sample file containing atoms with non standard hybridization or unsatisfied valence an CAChe for Windows User Guide 6 49 Chapter 6 Viewing Chemical Samples alert box is displayed CAChe x gt This chemical sample contains atoms with non standard hybridiz
83. menu e automatically by generating dihedral angle search labels a type of geometry label using the CAChe Geometry Label Wizard lt t gt Refer to Working with search labels p 8 37 for information on creating and using search labels Defining geometry labels while viewing atom distance and bond length Add a geometry label while viewing or adjusting an atom distance or bond length value Toadda geometry label to a distance or angle 1 Select the required number of atoms for the distance or angle you want to label by clicking on the first atom with the Select tool then holding down the Shift key and clicking on the remaining atoms CAChe for Windows User Guide 8 19 Chapter 8 Investigating Molecular Geometry 8 20 For example select two atoms if you want to label atom distance three atoms if you want to label a bond angle or four atoms if you want to label an improper torsion or dihedral angle Choose one of the following menu options o Adjust Atom Distance o Adjust Bond Angle o Adjust Improper Torsion o Adjust Dihedral Angle The Set Atom Distance Set Bond Angle Set Dihedral Angle or Set Improper Torsion dialog box is displayed Select the Define Geometry Label check box so that it is enabled Select Apply to view the geometry label in the workspace A geometry label identifies the participating atoms and displays the value of the distance or angle in the workspace The followi
84. more information on experimental procedures that include solvation effects CAChe for Windows User Guide Optimizing chemical samples Classical or quantum mechanics Classical mechanical methods are much faster than using quantum mechanical calculations Also experiments tend to yield similar or more accurate optimized geometries when applying classical mechanics to discover a low energy structure However if your sample is in a state where electronic effects have a significant impact on the structure e g a transition state its geometry cannot be refined by a classical approach Similarly classical mechanical experiments do not yield any molecular orbital information Many CAChe procedures perform an optimization using classical mechanics first before refining the resulting structure using one of the quantum mechanics techniques This often reduces computation time while providing molecular orbital information Optimizing with classical mechanics CAChe examines bond angles and atom distances in your molecule and compares its geometry to the classical mechanical ideal value Deviations from the ideal accumulate a relative energy quantity known as steric or potential energy CAChe calculates these deviations from the ideal and optimizes a molecule by moving its atoms to lower the sum of the deviations and thus lower the steric energy until energy changes are negligible For example the deviation of a dihedral an
85. nf The Sequence View window Residues for each chemical sample are shown using 1 letter or 3 letter codes on a line that wraps at the window boundary An asterisk called the chain terminal marks the end of each protein chain The at symbol marks the terminus of a cyclic peptide Note that the chain terminal is not part of the structure and you cannot select the chain terminal Refer to Changing the sequence style p 9 25 for details about changing display options for sequences such as 1 and 3 letter codes The Sequence View the workspace and the Sample Property Windows work together That is selections or changes you make in one window are immediately reflected in the other two windows BioMedCAChe User Guide Working in the Sequence View window Residues shown as half intensity color are not selected On displays with only 256 colors residues that are not selected are gray Residues highlighted in bright full intensity colors have one or more atoms or bonds selected Residues with every atom selected are highlighted and surrounded by a black box Items copied in the Sequence View the 3D Structure window or a Sample Properties view can be pasted into another view Thus you can select a sequence in the Sequence View then switch to the 3D Structure window to paste the residue sequence and adjust its position in 3D space The style bar The Sequence View style bar provides three items that enable you to
86. one of the following a Format Left a Format Center a Format Right The alignment of the selected text changes To display text as a molecular formula 1 Select the cells containing the text you want to change 2 Choose Format Molecular Formula The selected text is displayed with the numbers as subscripts 3 Choose Format Normal Text to revert the display to normal text Changing the numerical display Select the cells containing the numbers you want to change and choose one of the following from the Format menu Scientific Notation to display numbers in scientific notation Standard Notation to display numbers in standard notation Digits after Decimal to set the number of decimal places to display 12 36 BioMedCAChe User Guide Changing workbook display options Hiding and displaying worksheet features To hide or display column or row buttons 1 Choose a View Column Labels to display or hide column labels a View Row Labels to display or hide row labels The menu option has a check mark next to it when the labels are displayed and no check mark when the labels are hidden Using worksheet footnotes ProjectLeader lets you add footnotes to a cell and choose whether to display them or not If a worksheet has a footnote a small icon is displayed in the worksheet cell When a cell is selected any footnotes associated with it are displayed underneath the ProjectLeader worksheet in the footnote
87. order type 0 0 60 Weak 0 61 1 60 Single 1 61 2 60 Double gt 2 60 Triple Ionic Coordination Electron density surfaces The following section describes how to interpret the appearance of the three dimensional surfaces that CAChe produces for different types of experiment Surface files that represent electron density properties are referred to as isosurface files depicting locations around your sample where the electron probability density is equal The electron density at the surface is 0 01 e A Although the electron density surface by itself is useful CAChe adds another property on top of it The electrostatic potential of your sample is calculated and added to the electron density surface as color CAChe for Windows User Guide 15 15 Chapter 15 Investigating Electron Distribution Along the electron isodensity surface different magnitudes of electrostatic potential are represented by different colors The colors displayed depend on the current colors assigned to each of the color indexes listed in the earlier color tables Susceptibility and frontier density Superdelocalizability 15 16 All three of the frontier density experiments nucleophilic electrophilic and radical generate an electron density surface similar to the electron density experiment However the surface colors represent reactivity based on active orbitals near the frontier orbitals HOMO and LUMO In the frontier density
88. path starts at the transition state conformation and proceeds toward either the reactant or the product animating a dynamics trajectory file shows you how long a sample remains in the same approximate conformation If a conformation has a long life span high energy barriers may exist that prevent the structure from changing Such a conformation might be a good starting structure for further analysis To animate a map file 14 26 Activate a graph window conformation window or conformational analysis window by clicking on the window 2 Choose one of the following a Edit Animate Along Axis if you activated a graph window to display the Animate Along Horizontal Axis dialog box a Edit Animate All Conformations if you activated a conformation window to display the Animate All Conformations dialog box a Edit Animate Analyzed Conformations if you activated a conformational analysis window to display the Animate Analyzed Conformations dialog box The Animate Along Horizontal Axis dialog box Animate All Conformations dialog box and Animate Analyzed CAChe for Windows User Guide Viewing map files m 4 CAChe for Windows User Guide Conformations dialog box function in an identical way The Animate All Conformations dialog box is shown below Animate All Conformations Contras e J Cancel Conformation fi _ of l 343 He Step by j conformations Select the forward button sh
89. reactions in which bonds are formed and broken BioMedCAChe User Guide Understanding MOPAC MOPAC calculates the heat of formation whereas the energy calculated in molecular mechanics is the steric energy Both MOPAC and Mechanics recognize locked geometry labels and atoms with locked workspace coordinates that you define in your chemical sample file Both MOPAC and Mechanics can use search labels to create energy maps You can use several search labels in Mechanics but MOPAC is limited to one or two search labels If you use one search label the result is a reaction coordinate search If you use two search labels the result is a grid search If you define more than two search labels MOPAC ignores the additional ones MOPAC maps are preferred for mapping bond breaking and bond formation Maps generated by Mechanics for bond breaking and bond formation are meaningless You can generate four different kinds of potential energy maps when using MOPAC If you use one search label you can choose to compute the heat of formation at each geometry defined by the search label without optimizing other internal coordinates or you can choose to optimize the internal coordinates for each geometry Similarly if you use two search labels you can compute the heat of formation at each geometry defined by the search labels with or without optimizing other internal coordinates a i i s N i D MOPAC
90. residues To view the sequence and 3D structure simultaneously select Window Tile to display the Sequence View window and the workspace side by side After all residues are added place the Residue tool to the right of the asterisk and press the backspace key The chains are rejoined and the asterisk disappears forming the loop and finally rejoin the chain NS To create a turn 1 In the Sequence View window click the name of the chemical sample to activate it for modification The sequence name is highlighted in yellow Use the Select tool to select the two residues where you want to place the turn Select Edit Make turn and choose one of the following o Typel o Type o Type II o Type ll BioMedCAChe User Guide Changing biomolecules The selected turn is created using angles in the selected residues Left Residue Right Residue Type Psi Phi Psi Phi I 60 30 90 0 r 60 30 90 0 II 60 120 80 0 I 60 120 80 0 Changing secondary structure You can change the secondary structure or protein conformation from the style bar in the Sequence View window To change secondary structure 1 Use the Select tool to select the residues you want to adjust Selected residues are highlighted If the workspace is open on this structure the atoms belonging to the selected residues are highlighted in the workspace Secondary structure patterns are created by more than one adjacent residue 2 Choose a second
91. scaled to 0 1A colored by atom color Atom colors are not changed To color selected atoms by element choose View Color by Element The following example shows a molecule displayed as a ball and cylinder model To view your chemical sample as a space filling CPK model 1 CAChe for Windows User Guide Select the portion of your molecule that you want displayed as a space filling model by clicking on objects with a selection tool The objects are highlighted to show that they are selected Choose View Space Filling Your molecule appears as a CPK Corey Pauling Kolton model with atoms displayed as shaded spheres with a van der Waals radius of 1A scaled to 1 0A Bonds are displayed as single cylinders scaled to 0 000A Atom colors are not changed To Chapter 6 Viewing Chemical Samples color selected atoms by element choose View Color by Element The following example shows a molecule displayed as a space filling model 4 To view your chemical sample by partial charge and calculated bond order 1 3 Run a partial charge experiment or a calculated bond order experiment on your chemical sample Select the portion of your molecule that you want displayed as by partial charge and calculated bond order by clicking on objects with a selection tool The objects are highlighted to show that they are selected Choose View Partial Chg and Calc Bond Order Atoms are displayed as shaded spheres
92. scientist to start to plan experiments You can use CAChe ProjectLeader to perform calculations on several chemical samples at one time or carry out statistical analyses on chemical samples including calculations based on customizable equations ProjectLeader is a separate application accessible from either the Windows Explorer or the Start menu on the Windows taskbar t gt Refer to Chapter 12 Using ProjectLeader for further details on starting ProjectLeader and ProjectLeader experiments and capabilities Use ProjectLeader to e perform an experiment on several chemical samples at once you can experiment on only one chemical sample at a time using the workspace BioMedCAChe User Guide 2 17 Chapter 2 Introduction to CAChe e perform statistical analyses on experimental results including multiple linear regression forward and reverse stepwise regressions and customizable algebraic equations view the values of experimental calculations for several chemical sample files at the same time e create scatter plots of the results of experiments and analyses to view trends in your data Viewing and analyzing columns of experimental data for several chemical samples at once enables you to establish mathematical relationships between one set of data and another thus aiding e the process of calibration by comparing the results of measurements on specific instruments and the known standard results the ca
93. search labels not currently displayed in the graph is the value at which those labels are held constant 5 Change the constant value for search labels not assigned an axis by selecting the up or down arrow button in the box displaying that label s current value The value jumps incrementally based on the step size you defined for the search label 6 Select OK to apply the changes to the graph and close the Graph Attributes dialog box Changing graph color You can choose to color the graph function by e relative energy where colors of the graph in the graph window represent the relative energies of graph locations and their equivalent conformations e constant color where the graph function is displayed in one color only In trajectory files produced by Dynamics experiments you can also choose to color a graph by total energy e kinetic energy e potential energy e temperature CAChe for Windows User Guide 14 17 Chapter 14 Investigating Low energy Conformations To change graph color 1 Activate the graph window of the map file by clicking on it 2 Choose View Graph Attributes to display the Graph Attributes dialog box 3 Select the arrow button in the Color By box to display a drop down list of color options Choose a color option from the drop down list Select OK to apply color options to the map file graph and to close the Graph Attributes dialog box Changing axis attributes Y
94. similar to susceptibility but is more sensitive to the relationship between the frontier orbital energies of your chemical sample versus any specific electrophilic nucleophilic or radical species that would be reacting with your sample In most cases susceptibility yields similar results without dependencies on reagent energies Superdelocalizability output is a three dimensional electron density isosurface with colors reflecting the relative differences in reactivity of the different parts of your sample Superdelocalizability experiments produce more accurate results in the following conditions e your sample s HOMO energy is less than the default energy of 8eV for electrophilic superdelocalizability 2eV for nucleophilic superdelocalizability and 5eV for radical superdelocalizability e your sample s LUMO energy is greater than the default energy of 8eV for electrophilic superdelocalizability 2eV for nucleophilic superdelocalizability and 5eV for radical superdelocalizability the energies of the attacking molecule s frontier orbitals are between the HOMO and LUMO energies of your sample Refer to Investigating molecular orbital energies p 15 7 for information on how to perform a frontier orbitals experiment to determine HOMO and LUMO energies for your chemical sample and the attacking reagent molecule CAChe for Windows User Guide 15 5 Chapter 15 Investigating Electron Distribution Generat
95. superimposed by clicking on the atom with the Select tool The atom is highlighted to show that it is selected Hold down the Shift key and select the corresponding atom in the second ring structure i e the other atom connected to the bond you want to fuse by clicking on it The atom is highlighted to show that it is selected The following example shows the order of atom selection in the two rings and the resulting structure when the bond in the second ring structure replaces the first When you fuse bonds the bond in the second ring structure will replace the bond in the first ring structure BioMedCAChe User Guide Fusing ring structures Fuse Bonds 6 Choose Edit Fuse Atoms The bond whose connecting atoms you selected in the first ring structure is replaced by the bond whose connecting atoms you selected in the second ring structure The second bond inherits all the connecting bonds and atoms from the first bond 7 Choose Beautify Comprehensive to correct the valence hybridization ring structure and molecular geometry of the resulting structure BioMedCAChe User Guide 7 23 Chapter 7 Manipulating Molecules Grouping atoms Defining a group 7 24 CAChe allows you to define and name a group of atoms select a named atom group in the workspace and then work with the group as a unit You can also ungroup previously grouped atoms NS To form an atom group 1 Select the atoms tha
96. surface locations in your chemical sample that are susceptible to attack nucleophilic electrophilic or free radical are identified by bright bull s eye patterns The remainder of the surface is colored to indicate the relative reactivity towards attack Use the Surface Legend dialog box accessed by choosing Analyze Surface Legend to determine the reactivity represented by each color The colors corresponding to larger values in the surface legend represent more reactive sites Each of the three superdelocalizability experiments electrophilic nucleophilic and radical generates an electron isodensity surface The surface colors represent reactivity based on active orbitals near the frontier orbitals HOMO and LUMO The nucleophilic experiment creates an electron density isosurface with colors reflecting the relative reactivity of your sample to a nucleophilic reagent Similarly the electrophilic and radical superdelocalizability routines build surfaces that show where an electrophile or a radical has the highest probability of initiating a reaction Use the Surface Legend dialog box accessed by choosing Analyze Surface Legend to determine the reactivity represented by each color The colors corresponding to larger values in the surface legend represent more reactive sites CAChe for Windows User Guide Viewing a surface Molecular orbitals Susceptibility frontier density and superdelocalizability are similar a
97. the Getting Started booklet or from the CAChe menu Help Online Books CAChe Getting Started The tutorials are worked examples that show how to use BioMedCAChe to perform structure guided drug discovery In the tutorials you learn how to clean a protein from the Protein Data Bank analyze protein and protein ligand interactions display proteins as ribbons visualize active sites align sequences and dock novel ligands into active sites i 2 o gt 3 b 5 For a guide to using CAChe on a task by task basis refer to Part 3 Using CAChe As you use CAChe you may find it useful to refer to Part 1 CAChe Basics for general details on how to use CAChe BioMedCAChe User Guide 1 3 Chapter I Introduction to the User Guide About this user guide Introduction CAChe Basics Using CAChe Understanding CAChe 1 4 This user guide describes how to use BioMedCAChe to build molecules and perform experiments on chemical samples It explains how to use the program and gives information necessary to understand the way the program works The user guide is divided into parts which are outlined below This Introduction describes how computer aided chemistry and CAChe can help you perform experiments on molecules It outlines the properties that you can investigate with CAChe and the procedures that you can apply to an experiment as well as an overview of the experimental process CAChe B
98. the corresponding ordered group in the other structure The selected groups should be in different molecules but the molecules can be in the same workspace or in different workspaces CAChe superimposes the atoms in the selected groups from both molecules so that they coincide with each other as much as possible You can then compare any differences in structural geometry indicated by the RMS value When superimposing atoms the atoms are superimposed in the order that they are defined in the group Before you can superimpose groups you must define the groups as described in Defining a group p 7 24 To superimpose two molecules by atom group CAChe for Windows User Guide 8 7 Chapter 8 Investigating Molecular Geometry 1 Choose Analyze Superimpose Groups The Superimpose dialog appears Superimpose 2 Click the plus symbol next to the groups name The ordered list of atoms appears Superimpose Atoms in the probe are superimposed on atoms in the target in order 3 Ifthe order needs to be changed drag the atoms so that each atom in the probe group corresponds in order to the atom you 8 8 CAChe for Windows User Guide Superimposing molecules want it superimposed on in the target group Alternatively drag the atoms in the target group The first atom in the probe group will be matched with the first atom in the target group for superposition and so forth until either all of the probe
99. the list of groups Choose OK Switch back to the Sequence View and continue selecting helices and creating groups until all seven groups TM1 TM7 are defined In the workspace choose Edit Select Backbone to select the backbone atoms Choose Edit Group Atoms Type the Group Name backbone Choose gt gt Group gt gt The group named backbone is added to the list of groups With the Group Atoms dialog still open choose group TM1 and then choose S or G The selection S now contains the atoms in both the backbone and TM1 Continue the choosing TM groups and choosing S or G until the selection contains the backbone atoms and all seven transmembrane helices Type locked backbone into the Group Name field choose gt gt Group gt gt The group named locked backbone is added to the list of groups Choose OK Choose Adjust Lock The backbone atoms in all the helices are locked Choose Beautify Valence and then Beautify Hybridization Choose Experiment New The Experiment dialog appears Choose a Property of chemical sample a Property optimized geometry and a Using MM geometry MM3 Choose Edit and change the procedure to use steepest descent for geometry optimization Refer to Modifying a procedure p 11 17 Choose the Choose Start The energy is minimized using steepest descent When the experiment completes start a new experiment Using MM geometry MM3 Choose Edit and change the proced
100. the locked state of a geometry label 1 Select the geometry label whose locked state you want to hide by clicking on the numeral portion of the label with the Select tool Choose View Geometry Label Attributes to display the Geometry Label Attributes dialog box Select the Label tab to display the Label geometry labels with panel Select the Lock State check box so that it is disabled Select OK to close the Geometry Label Attributes dialog box The geometry label you selected no longer displays an L if the geometry label is locked or an LB if the geometry label is locked and the lock has been broken or an LD if the geometry label lock is disabled To redisplay the locked state of a geometry label 1 Select the geometry label whose locked state you want to redisplay by clicking on the numeral portion of the label with the Select tool Choose View Geometry Label Attributes to display the Geometry Label Attributes dialog box Select the Label tab to display the Label geometry labels with panel Select the Lock State check box so that it is enabled Select OK to close the Geometry Label Attributes dialog box The geometry label you selected displays an L if the geometry label is locked or an LB if the geometry label is locked and the lock has been broken or an LD if the geometry label lock is disabled CAChe for Windows User Guide Working with geometry labels lt t gt Refer to Locking geometry label
101. the locks first Refer to Locking geometry labels p 8 29 and Locking atoms p 8 32 for details about disabling locks CAChe for Windows User Guide 8 5 Chapter 8 Investigating Molecular Geometry Superimposing molecules Superimposing by atoms 8 6 NOTE You can compare the molecular geometry of two structures by superimposing one or more atoms in one structure on corresponding atoms in the other structure You can select up to twenty five pairs of atoms one set of twenty five atoms from each structure CAChe superimposes the selected atoms from both molecules to coincide with each other as much as possible You can then compare any differences in structural geometry indicated by the RMS value When selecting atoms from two different structures to superimpose on each other you must select the atoms in a precise order Use one of the following two selection methods e select the same number of atoms from both molecules in the same order For example if you want two atoms from each molecule to coincide select two atoms from the first molecule and then select the corresponding two atoms from the second molecule select one atom in the first molecule and then select the corresponding atom in the second molecule then select another atom in the first structure and the corresponding atom in the second structure until you have selected the number of atoms that you want to coincide The
102. the molecule first using classical mechanics quantum mechanics or a combination of both You can combine all optimization procedures with generating electron density for your sample You cannot use procedures that involve MOPAC or ZINDO in Personal CAChe Calculating HOMO and LUMO energies A HOMO and LUMO experiment uses a quantum mechanical application to generate an electronic wavefunction and calculate the energies and shape of the highest occupied molecular orbital HOMO and lowest unoccupied molecular orbital LUMO of your chemical sample The energy of the HOMO is the energy required to remove an electron from the HOMO ionization energy and the energy of the LUMO is the energy added to the sample when an electron is added to the LUMO electron affinity CAChe for Windows User Guide 15 7 Chapter 15 Investigating Electron Distribution The following example shows calculated HOMO and LUMO energies for a furan molecule colored to show electrostatic potential which indicates furan s charge distribution HOMO energies LUMO energies Calculating HOMO 5 to LUMO 4 energies This experiment is similar to the HOMO and LUMO experiment described in the previous section The difference is that a total of nine molecular orbitals are generated ranging from HOMO 5 to LUMO 4 Often large molecules have several orbitals clustered near the HOMO and LUMO Viewing the shapes and energies of these orbitals
103. the plot 4 To change the title of the plot 1 Double click on the title of the plot to display the Graph Title dialog box 2 Edit the text box as required Select OK to update the title NOTE Deleting all of the text of the title is equivalent to removing the title To hide the title of the plot a Choose View Title to toggle off the display of the title The title of the plot is hidden Changing the legend of the plot To change the legend of the plot 1 Double click on the legend of the plot 2 Edit the legend as required To hide the legend of the plot a Choose View Legend to toggle off the display of the legend The legend of the plot is hidden Changing the axes labels NS To change the axes labels 1 Double click on an axis label 2 Edit the axis label as required 12 30 BioMedCAChe User Guide Using scatter plots Hiding the footer of the plot To hide the Footer of the plot a Choose View Footer to toggle off the display of the footer The footer of the plot is hidden Fitting a straight line Regression analysis gives a best fit straight line for one of the data sets and the regression equation between that data set and the data set plotted on the X axis The r value gives the correlation of the data To fita straight line 1 Select the data set to which you want to fit a line 2 Place the mouse cursor anywhere in the scatter plot and click the right mouse button
104. to the left or right of currently displayed objects BioMedCAChe User Guide The workspace lt t gt Refer to Using CAChe p 3 17 for a description of how to click and drag using the cursor Hiding the scroll bars You can choose to hide the scroll bars at the right and at the bottom of a CAChe document window NS To hide the scroll bars 1 When the scroll bars are visible choose Options Show Scroll Bars The scroll bars are no longer displayed at the right and at the bottom of the document window The check mark next to the Show Scroll Bars drop down list option is no longer displayed indicating that the scroll bars of the workspace are currently hidden NS To redisplay the scroll bars 1 When the scroll bars are hidden choose Options Show Scroll Bars Scroll bars are displayed at the right and bottom of the active workspace A check mark is displayed next to the Show Scroll Bars drop down list option indicating that the scroll bars of the workspace are currently visible Stereo 3D cursor If you have a stereo license the cursor may be drawn in 3D in the workspace To display the 3D cursor in the workspace 1 When the cursor exists in 2D in the workspace choose Options 3D Cursor The cursor is displayed in the workspace in 3D and a check BioMedCAChe User Guide 3 15 Chapter 3 CAChe Basics mark is displayed next to the 3D Cursor drop down list option NS To hide the 3D
105. transition states is to perform a grid search calculation in which the two internal coordinates varied are the principal deformations that occur in the course of the reaction The map that is produced may contain a pass on the energy surface that is a saddle point The molecular geometry at this point can be used as an estimate of the transition state geometry The geometry of the transition state is refined with an optimization method that can minimize the energy gradient without searching for a minimum energy geometry Once the stationary geometry has been found the transition state is characterized by calculating the vibrational frequencies for the molecule and verifying that there is one and only one frequency that corresponds to a negative force constant These frequencies are negative strictly speaking they are imaginary but they are reported as negative numbers as a matter of convenience Vibrational frequencies reported in the MOPAC output file contain six or five for linear molecules vibrational modes which correspond to translation and rotation of the molecule as a whole These vibrations have frequencies that are close to zero if the molecule is at a stationary point However they will not be identically zero because of the numerical approximations made in determining the stationary point geometry and in calculating the force matrix Dynamics calculations in MOPAC Two types of dynamics calculations are possible with MOPAC
106. uses search labels in the same way as Mechanics When you generate energy maps using MOPAC it is best for the geometry of the molecule to be at an extreme in the range of values used for the steps A map file map is produced just as in Mechanics Mechanics puts the molecule strain energy into map files whereas MOPAC adds heat of formation when you execute grid searches and reaction coordinate searches Mechanics calculations are simpler than quantum mechanical calculations Consequently Mechanics is much faster than MOPAC The time required for molecular mechanics increases as the square of the number of atoms whereas the time required for a MOPAC calculation increases as the cube of the number of atoms unless the linear scaling method for large molecules MOZYME is used BioMedCAChe User Guide 20 13 Chapter 20 CAChe Computational Applications Limitations of MOPAC MOPAC is a valence electron only program and cannot calculate properties that depend upon changes in the inner shell electrons The valence only nature of any semi empirical method can manifest itself in unexpected ways For example electron isodensity surfaces can have an unusual appearance Because valence only theories do not treat inner shell electrons the calculated electron density near the nuclei is very small Electron isodensity surfaces calculated at high density values may show no density around some atoms The absence of density around some atoms emp
107. values produced from quantum mechanical computations can be e directly compared e adjusted then compared to experimental heats of formation CAChe for Windows User Guide Optimizing chemical samples NOTE Optimization with quantum mechanics is not available with Personal CAChe CAChe for Windows User Guide 13 5 Chapter 13 Optimization and Energy Calculations Selective optimization You can optimize only selected portions of your molecule rather than the whole structure To do this you lock atom coordinates and specified geometry labels so that atoms remain in the same position and atom distances and bond angles remain at a constant value during an experiment All computational applications apart from ZINDO recognize locked atom coordinates and locked geometry labels Refer to Locking geometry labels p 8 29 and Locking atoms p 8 32 for information on applying locks There is no set procedure for selective optimization but the following sections describe situations where optimization of only one portion only of a chemical sample can be used Optimizing substituted portions of a molecule If you know the geometry of the structure for a sample closely related to your molecule you may want to explore the most likely geometry of sites where you made substitutions You can optimize the substituted portion of the sample while leaving the section for which data exists untouched wherea
108. view all the details of the experiment Save this information by clicking and dragging with the cursor to select all the text in the window and choosing Edit Copy You can now paste the text into any text editor or word processor document CAChe has also automatically saved this information in one or more log and output files located in an automatically generated input output io folder Refer to Viewing log files and output files p 10 40 for information on viewing log files 13 When you have finished viewing the experimental details select the Windows Close button in the upper right corner of the Experiment Status dialog box to close the dialog box You return to the Experiment dialog box 14 Do one of the following a Save the settings in the Experiment dialog box as described in the next section Saving an experiment file a Select the Windows Close button in the upper right corner of the Experiment dialog box to close the dialog box without saving its contents 10 22 CAChe for Windows User Guide Running an experiment Saving an experiment file You can save the settings in an Experiment dialog box as an experiment file exp so that you can reuse the same property and procedure settings without having to reselect any of the drop down list options The next time you want to run an experiment with the same settings open the exp file to display the Experiment dialog box with the settings y
109. was designed to help skilled experimental chemists explore questions that can be addressed by computational chemistry Your chemical intuition will help you compose the right questions and CAChe will help you interpret the answers Even though CAChe accurately solves mathematical equations to predict chemical properties the predicted properties do not always agree with measured properties The disagreements arise because the mathematical model is a simplification of the real world You can both gain confidence in the accuracy of CAChe predictions and improve the accuracy of your predictions by calibrating predicted results with known data Chapter 2 Introduction to CAChe Level of accuracy 2 10 The difference between calculated or measured values of a property and the true or exact value are referred to as error Errors in calculated results are not the same as experimental errors there is a fundamental difference Experimental errors generally fluctuate randomly about the true value The average of a large number of measurements gradually approaches the true value Errors in computational methods arise because the computational method is based on a generalized model of the real world Errors in a particular computational method are systematic not random Exploiting these systematic differences makes it possible to predict properties more accurately for particular classes of chemical samples by
110. where the potential energy of each conformation is measured and each conformation is either not optimized rigid map or optimized optimized map An optimized energy map energy map is also generated when you run a map reaction experiment Energy 0 34 to 9 63 kcal mole ihedral nglel 180 02 to 180 02 degree Bond amp nglet 100 15 to 130 12 degree Three dimensional rigid energy graph asequence of conformations seqsrch map where low energy conformations only are generated by finding a low energy value for a coordinate in the molecule and holding that coordinate at the low energy value while repeating the process for each specified coordinate in the molecule CAChe for Windows User Guide 14 3 Chapter 14 Investigating Low energy Conformations Potential_E 1 78 to 45 15 Keal mol g Sequence 1 50 to 20 00 step Sequence of conformations graph e adynamics trajectory dynamics map where kinetic energy is added to a molecule by randomly assigning velocities to atoms As the calculation proceeds kinetic energy is transformed into potential energy The potential energy of resulting conformations is plotted against time Potential_E Time 0 00 to 1 00 pe Dynamics trajectory graph e areaction path irc map irc 1 map drcl map drc 1 map where two internal coordinates of a chemical sample are varied to form the principal deformations occurring in the 14 4 CAChe for Windows
111. workspace Bond order determines the actual bond order of each bond in your chemical sample using semi empirical quantum mechanical methods Bond strain a purely classical mechanical quantity calculated every time a classical mechanical calculation is carried out A t gt Refer to Chapter 16 Investigating Atom and Bond Properties for further details BioMedCAChe User Guide 2 15 Chapter 2 Introduction to CAChe Chemical sample conformation experiments CAChe performs the following experiments on a chemical sample conformation from the workspace e Rigid map generates a potential energy map of conformations determined by geometry search labels in the sample for each structural element you want to vary with structures for each map point not optimized e Optimized map generates a potential energy map of conformations determined by geometry search labels in the sample for each structural element you want to vary with structures for each map point optimized Sequence of conformations generates a collection of low energy conformations by sequentially searching an unlimited number of geometry labels The resulting map file contains local energy minima but does not offer information about the energy barriers between them Dynamics trajectory generates a trajectory of a chemical sample in random thermal motion by randomly adding kinetic energy to each atom Motion is induced that ca
112. workspace are displayed Hiding text in geometry labels Hide and display the following text in a geometry label the value of the distance or angle that the geometry label represents the locked state of the geometry label lt t gt Refer to Locking geometry labels p 8 29 for further details To hide the geometry label value 1 Select the geometry label whose value you want to hide by clicking on the numeral portion of the label with the Select tool Choose View Geometry Label Attributes to display the Geometry Label Attributes dialog box XN 3 Select the Label tab to display the Label geometry labels with panel 4 Select the Value check box so that it is disabled 5 Select OK to close the Geometry Label Attributes dialog box The geometry label you selected no longer displays the value it represents To redisplay the geometry label value 1 Select the geometry label whose value you want to display by clicking on the label with the Select tool 2 Choose View Geometry Label Attributes to display the Geometry Label Attributes dialog box 3 Select the Label tab to display the Label geometry labels with panel CAChe for Windows User Guide 8 23 Chapter 8 Investigating Molecular Geometry 8 24 Select the Value check box so that it is enabled Select OK to close the Geometry Label Attributes dialog box The geometry label you selected displays the value it represents To hide
113. you are using CAChe as a standalone program the list displays just cache localhost 2 Select the server for which you want to view submitted experiments from the list and select OK The Experiments Submitted dialog box is displayed listing experiments running on that server E Experiments Submitted on cache localhost BBE Experiment Mol User Alison Peake Executing CAChe for Windows User Guide 10 29 Chapter 10 Performing Workspace Experiments 10 30 To stop an experiment select the experiment in the list and choose Stop The Stop an Experiment dialog box is displayed Stop immediately and discard output files Stop immediately and return output files Cancel Stop when convenient and return output files Help Select the required radio button as described in the section Stopping an experiment p 10 24 Select OK to close the Stop an Experiment dialog box and stop the experiment Select Close to close the Experiments Submitted dialog box CAChe for Windows User Guide Size and element limitations Size and element limitations The size of your molecule might limit the experimental procedures that you can successfully execute Procedures that use MOPAC for example those that include AM1 PM3 or PMS calculations are limited by the amount of memory on your system In practice this means that MOPAC calculations are limited to molecules with 20 000 30 000 atoms or less Pro
114. you from evaluating the cells in the property of sample component column 12 26 BioMedCAChe User Guide Using scatter plots Using scatter plots Scatter plots enable you to view trends in data columns To plot a scatter plot 1 2 Select the data columns that you want to plot as a scatter plot Choose View Scatter Plot to display a dialog box that prompts you to choose the columns for each axis of the scatter plot You can have one column of data plotted along the horizontal axis and multiple columns along the vertical axis By default the first column that you chose from a ProjectLeader worksheet is assigned to the horizontal axis and the other columns are assigned to the vertical axis If only one column is selected it is assigned to the vertical axis Specify the columns that you want to plot on each axis Select OK to plot the scatter plot The scatter plot is displayed so that it is the same size as the worksheet from which it was plotted Click and drag a corner of the scatter plot window to resize it Title Predicted and actual atom counts G 6 60955 B 1 88 821 rCV 2 0 267911 r 2 0 26213 100 Selected point Label Regression line 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 conformation minimum energy kcal mole Legend Selected data set BioMedCAChe User Guide 12 27 Chapter 12 Using Projec
115. you want to change by clicking on the atoms with a selection tool The atom or group of atoms are highlighted to show that they are selected Select the arrow button in the Hybridization box A drop down list is displayed listing a number of hybridization options Choose the hybridization you require from the drop down list The hybridization is displayed in the Hybridization box and the selected atom changes to the chosen hybridization value CAChe for Windows User Guide Changing atom and bond properties To change the charge of an atom using the style bar 1 Select the atom or group of atoms whose charge you want to change by clicking on the atoms with a selection tool The atom or group of atoms are highlighted to show that they are selected Select the up or down arrow button in the Charge text box to display the positive or negative value you require or enter the value you require by clicking in the text box The charge of the selected atom changes to the positive or negative value that you selected or entered into the Charge text box Changing an atom using the Atom Attributes dialog box You can also change the element type hybridization and charge of an atom using the Atom Attributes dialog box The dialog box also provides access to display options that you can apply to one or more selected atoms lt t gt Refer to Chapter 6 Viewing Chemical Samples for details about changing the appearanc
116. 0 8 Reactions investigating 17 1 Reactive sites investigating on enzyme surface 13 8 Refine transition experiment 17 1 Refine transition state 2 17 10 9 Regression forward stepwise regression 12 3 multiple linear regression 12 3 reverse stepwise regression 12 3 Index Repairing broken geometry locks 8 31 Residue tool 9 25 Residue type box 9 21 9 22 Reverse stepwise regression 12 3 Reversing a coordinate bond 5 31 RGB values 15 14 Rigid energy map 14 6 Rigid map 10 8 Ring count 12 3 size 12 3 Ring geometry correcting 4 13 Ring structures fusing 7 21 Rotate tool 3 14 3 30 3 32 3 38 7 2 7 3 Rotating objects 7 4 Rotation defining center for rotate tool 7 4 Rotation settings dialog box 7 5 Rules for the selection tools 5 4 Running a procedure 11 21 experiments simultaneously 10 26 ProjectLeader experiments 12 20 S Saddle points 20 17 Sample properties copying 12 18 editing 12 18 Sample Properties table 12 17 viewing 12 17 Sample Properties table 12 17 Sample io folder 10 37 Sample iso folder 10 37 Save as dialog box 4 17 Saving experiment files 10 23 files 4 17 4 19 map files 14 30 settings 6 51 Scale tool 3 14 3 30 3 33 3 39 7 2 7 8 Scaling a scatter plot 12 28 bond radius 16 12 objects 7 7 Scatter plots exporting 12 31 labeling points 12 29 plotting 12 27 printing 12 32 scaling 12 28 selecting data points 12 28 straight line fitting 12 31 title 12 30 translating 12 28 viewing 12 27
117. 05 CHNO 2 442 QSAR 1 descr 4 94 Eg Nitrofuran 3 5 300 0 571 CHNO 2167 5 02 Nirtrofuran 4 5 400 0 466 CHNO 1 759 5 43 5 NITROFURAN S 5 600 2 394 CHNO 3 215 5 63 6 000 0 874 CHNO 2 169 6 09 0 09 7 000 0 694 CHAO 2 770 6 40 0 60 8 Nitrofuran 8 6 000 2 012 OHANO 3 106 5 50 0 50 z Nitrofuran 9 6 600 3 938 CHO 4 184 660 0 00 NITROFURAN 10 5600 4 308 CHO 1 551 se 0 22 Nitrofuran 11 5 500 1 560 CHNO 3 008 6 08 0 58 Nitrofuran 12 5 000 0 525 CHAN Os 3 089 54 0 40 Nitrofurans QSAR 2 B 15 58 D 797 r 2 0 73 rCV 2 0 65 2 6 BioMedCAChe User Guide Introduction to computer aided chemistry Introduction to computer aided chemistry Computer aided chemistry enables you to create a model of a molecular structure on a computer screen You can move the model around the x y and z axes of the computer screen and view the structure from many different angles and perspectives You can display the molecule as a simple line drawing as three dimensional spheres and cylinders or as a combination of many different modeling styles Use computer aided chemistry to measure the geometry of a structure precisely and lock atom distances and bond angles at any value you require i 2 o gt 3 b 5 You can then perform experiments on the molecule where exp
118. 2 18 6 19 3 19 14 19 20 20 2 20 7 20 11 20 22 20 23 20 34 21 2 21 4 21 6 21 8 A 2 A 6 B 2 BioMedCAChe User Guide Support and further information For support and further information about other products available from Fujitsu Limited please contact your local Fujitsu office telephone and e mail information is listed below Japan contact Fujitsu Limited Life Science amp Material Science Division 9 3 Nakase 1 Chome Mihama ku Chiba City Chiba 261 8588 Japan North America contact CAChe Group Fujitsu America Inc Europe contact FQS Poland Sp z 0 0 Palac Pugetow ul StarowisIna 13 15 31 038 Krakow Poland BioMedCAChe User Guide Tel 81 43 299 3681 Fax 81 43 299 3019 e mail cache ssd se fujitsu co jp http www CACheSoftware com Tel 1 503 531 3600 Fax 1 503 531 9966 e mail support cACheSoftware com http www CACheSoftware com Tel 48 12 429 43 45 Fax 48 12 429 61 24 e mail support fgspl com pl http www fgspl com pl vii Vili BioMedCAChe User Guide 3 Q S 3 OH d ABLSIWAHIOL Introduction to CAChe i e S gt cS o i The following chapters introduce you to the structure of this user guide and provide an overview of BioMedCAChe Chapter 1 Introduction to the User Guide describes the conventions used in this user guide and outlines the content of each user guide part Chapter 2 Introduction to CAC
119. 2 limitations 20 14 Motion Dynamic Models Simulation 2 9 Motion vectors displaying 18 2 Mouse actions 3 17 choose 3 17 click 3 18 click and drag 3 19 double click 3 20 select 3 17 Moving objects 7 6 7 7 in the workspace 5 5 Multiple pass search 14 9 20 6 Multiple windows 6 32 Mutual orientations 13 8 BioMedCAChe User Guide N Navigator window 11 4 New geometry labels 8 37 New users important information 1 2 Non scrolling lists 3 28 windows 3 29 Notes icon 1 6 O Objects copying 7 14 cutting 7 18 deleting 7 19 duplicating 7 13 moving 7 6 rotating 7 4 scaling 7 7 zooming in and out 7 8 Octanol water partitition coefficient 12 3 One pass search 14 9 Online Help 3 43 context sensitive Help 3 43 the Help system 3 44 Open dialog box 4 3 Opening a ProjectLeader project 12 11 chemical samples in ProjectLeader 12 12 saved files 4 20 Optimization selective 13 6 Optimized geometry 2 14 12 3 Optimized map 2 16 10 8 Optimized structures viewing 13 10 Optimizing chemical samples 13 1 13 2 energy maps 14 7 geometry 10 5 1 9 Index molecule portions 13 6 quantum mechanics 13 4 using classical mechanics 13 3 Optimum geometry 20 3 20 11 Orbital energies 15 7 Orbital surfaces displaying 18 6 Orbitals 15 17 Original Settings command 11 36 Output files 10 21 generation 10 32 P m coordination bond 5 34 Packages loading new packages 11 33 Page orientation 4 24 Paper size 4 25 source 4 25
120. 4 Deleting hydrogens 4 15 Using the Atom Bond tool 4 4 Saving files 4 17 Drawing an atom 4 5 Saving a new file 4 17 Drawing a bond 4 6 Saving an existing file 4 19 Completing your molecule 4 9 Opening a saved file 4 20 Perfecting your molecule 4 10 Printing files 4 22 Correcting valence 4 10 P reviewing a printout 4 22 Defining valence rules 4 10 Choosing print options 4 23 Correcting hybridization 4 13 Printing a CAChe window 4 25 Correcting ring geometry 4 13 Chapter 4 Creating Chemical Samples Working with chemical sample files You create a molecular structure by drawing atoms and bonds in a document window The document in which you draw edit and save your molecular model is called a chemical sample file and this is the default file type in CAChe You use chemical sample files to e draw and perfect your molecule e view your molecule in different ways e perform experiments on your molecule This chapter describes how to draw edit view and save your chemical sample lt t gt Refer to Chapter 10 Performing Workspace Experiments for details about launching experiments from a chemical sample file Opening a new chemical sample file When you first start CAChe a document window entitled ChemicalSample1 is opened ChemicalSamp1lel1 is a blank chemical sample file When you create a molecule in the document window and save the data the chemical sample file suffix csf appears in the title bar of the docum
121. 50 51 52 53 54 Cs Ba La Hf Ta 55 56 57 72 73 fr Ra Ac 87 88 83 lg W Re Os Ir Pt Au Hg Tl Pb Bi Po At Rn 74 75 76 77 78 79 80 81 82 83 84 85 86 Pr Nd Pm Sm Eu Gd b Dy Ho Er m Yb lu e 58 59 60 61 62 63 64 e5 6 87 68 69 70 71 ele Np Pu Am Cm Bk Cf Es Fm Md No ir 3 31 92 93 94 95 96 97 98 99 100 101 102 103 Cancel CAChe for Windows User Guide 4 11 Chapter 4 Creating Chemical Samples NOTE 4 12 Select the element whose valence rules you want to change by clicking on it Select OK to close the Periodic Table dialog box Select the Beautify tab in the Periodic Table Settings dialog box to display a list of valence options Select the Beautify Valence check box so that it is enabled You can now apply valence rules by using the menu options Beautify Valence and Beautify Comprehensive Do one of the following a Select the Complete Shell radio button so that it is enabled You can now fill the valence shell to satisfy atom hybridization by using the menu options Beautify Valence and Beautify Comprehensive a Select the Satisfy Configuration radio button so that it is enabled You can now fill the orbitals of the element s atoms to satisfy atom hybridization by using the menu options Beautify Valence and Beautify Comprehensive Select the Add Electrons check box so that
122. 500 1 065 Default 7 7 19 19 19 Window size w a Hopp T P and Woods K R Proc Natl Acad Sci USA 1981 78 3824 3828 b Parker J M Guo D Hodges R S Biochemistry 1986 25 5425 5432 BioMedCAChe User Guide 21 9 D E i s N i D Chapter 21 CAChe BioComputations c Welling G W Weijer W J van der Zee R Welling Wester S FEBS Lett 1985 188 215 218 d Kyte J and Doolittle R F J Mol Biol 1982 157 105 132 e Sweet R M and Eisenberg D J Mol Biol 1983 171 479 488 cy Hydrophilicity 1 letter Hydrophobicity ee Hydrophobicity Goldman code Janin ep Manvalan Engelman Pliska od Steitz A 0 300 0 31 12 97 1 600 B 0 550 0 68 11 13 7 000 C 0 900 1 54 14 63 2 000 D 0 600 0 77 10 85 9 200 E 0 700 0 64 11 89 8 200 F 0 500 1 79 14 3 700 G 0 300 0 12 43 1 000 H 0 100 0 13 12 16 3 000 I 0 700 1 8 15 67 3 100 K 1 800 0 99 11 36 8 800 L 0 500 1 7 14 9 2 800 M 0 400 1 23 14 39 3 400 N 0 500 0 6 11 42 4 800 P 0 300 0 72 11 37 0 200 Q 0 700 0 22 11 76 4 100 R 1 400 1 01 11 72 12 300 S 0 100 0 04 11 23 0 600 T 0 200 0 26 11 69 1 200 V 0 600 1 22 15 71 2 600 WwW 0 300 2 25 13 93 1 900 X 0 000 0 000 0 0 000 Y 0 400 0 96 13 42 0 700 Z 0 700 0 43 11 82 6 150 Default 19 19 19 19 Window size w 21 10 BioMedCAChe User Guide Understanding Sequence
123. 6 BioMedCAChe User Guide The application window A check mark is displayed next to the Show Status Line drop down list option indicating that the status bar is currently visible BioMedCAChe User Guide 3 7 Chapter 3 CAChe Basics The workspace The active document window is referred to in CAChe as the workspace While you can have many document windows open at any one time there can only be one active document window Any menu bar or toolbar commands you choose affect the active document window To activate a window click on it The main components of the workspace are e atitle bar that displays the name of the document e astyle bar with drop down lists that enable you to change the element type bond type charge and hybridization of selected parts of your molecule e atool palette that provides selection tools a drawing tool and manipulation tools Title bar Style bar g y oo EE 4 Tool palette Scroll bars A blank workspace 3 8 BioMedCAChe User Guide The workspace The title bar The workspace title bar displays the name of the document G ChemicalS ample1 Oy x The workspace that appears when you start CAChe has the default name ChemicalSample1 To change this name save the file Once you save a file a three letter suffix appears in the document name which describes the file type of the document The main document file type for CAChe is the chemical sample
124. 8 parameter data 11 30 procedures 11 17 sample properties 12 18 settings of a compute engine 11 23 Electron affinity 12 3 15 7 Electron density 2 14 10 6 15 13 15 15 colored by electrostatic potential 15 3 Electron density surface 15 2 colored by superdelocalizability 15 5 colored by susceptibility 15 4 Electron distribution 15 1 Electronic properties 2 8 spectra 18 6 Electrons displaying 6 16 hiding 6 16 view settings 6 48 I 5 Index Electrostatic potential 10 7 15 3 15 18 Electrostatic potential surface 15 6 Element and size limitations 10 31 Element color changing 6 37 Element type box 3 9 3 10 4 5 Energy 10 6 calculating 13 11 molecular mechanics 20 2 Energy maps creating with mechanics 20 5 generating 14 2 optimizing 14 7 rigid 14 6 Enzymes 13 8 Exit See Quitting Experiment dialog box 10 23 Experiment environment managing the 11 8 refreshing the 11 35 Experiment status dialog box 10 27 Experiments 10 2 atom 2 15 bond 2 15 chemical sample 2 14 chemical sample conformation 2 15 cloning 11 27 creating 11 25 displaying details 10 35 displaying servers 10 33 importing 11 28 performing 2 12 10 1 reaction 2 16 running 10 18 running a ProjectLeader experiment 12 20 running simultaneously 10 26 saving files 10 23 setting up 10 4 stopping 10 24 troubleshooting 10 32 viewing 10 27 workspace 2 13 Experiments submitted dialog box 10 25 10 29 1 6 Exporting experiment components 11 37 ProjectLe
125. 8 41 Delete geometry labels 8 26 hydrogens 4 15 molecule portions 7 18 objects 7 19 BioMedCAChe User Guide Density 15 16 Deselecting more than one object 5 6 one object 5 5 similar atoms 5 11 Details buttons 3 26 DGauss 2 22 Dialog boxes using 3 22 Dielectric energy 12 3 Dihedral angle specifying 8 15 Dihedral search labels 8 41 Dipole moments 12 3 20 11 Dipole vectors calculating 12 2 x y and z 12 3 Directory buttons 3 25 Display options 6 2 ball and cylinder 6 3 lines 6 2 lines only 6 2 partial charge and calculated bond order 6 3 space filling 6 3 surfaces 15 18 Displaying bonds 6 28 electrons 6 16 experimental details 10 35 sample properties 12 17 servers 10 33 Workspace from ProjectLeader 12 14 Distance changing the workspace distance 6 44 specifying within molecules 8 12 Distribution of electrons 15 1 Docking ligands into proteins 19 22 Document windows arranging 3 16 Documentation set 1 2 Double covalent bonds 5 32 Double clicking items 3 20 BioMedCAChe User Guide Draw atom bond tool 3 30 Drawing a bond with an atom 4 8 atoms 4 5 bonds 4 6 bonds between two existing atoms 4 7 molecules 4 4 Drawing settings 6 43 Drawing settings dialog box 6 43 Drawing tools 2 3 Drop down lists 3 27 Duplicating molecules 7 13 objects 7 13 Dynamic reaction coordinate 17 4 20 19 Dynamics 20 7 generating trajectories 20 9 trajectory 2 16 10 8 14 10 Dynamics application 2 21 E Edit color palette 6 3
126. A range of default values and steps between those values are displayed in the text boxes beneath the Search radio button If you want to change the default values do one or all of the following o Click in the between text box and enter a new value for the start of the value range o Click in the and text box and enter a new value for the completion of the value range o Click in the using text box and enter a new value for the number of steps throughout which you want the range of values to be varied Select OK to close the relevant dialog box and to define the search label with the specified value range and number of steps A search label displays the value of the distance or angle in the workspace and an S to indicate that the label is a search label CAChe for Windows User Guide Working with search labels Defining search labels automatically NOTE A lt t gt Vv You can use the CAChe Geometry Label Wizard to automatically generate dihedral angle search labels for selected bonds in your molecule When defining labels the Geometry Label Wizard excludes the following e ring structures e locations that conflict with locked geometry labels e locked atom coordinates e any other search labels already present in your sample In addition you can specify the following to be excluded from the automatic generation of dihedral angle search labels one or more bond types e terminal groups such as CH3 CCl3
127. AChe User Guide Using CAChe drop down list sp3 tetrahedron z s line sp line sp2 trigonal plane sp3 tetrahedron sd3 tetrahedron d2sp3 octahedron dzsp3 trigonal pyramid dxysp3 square pyramid p3 trigonal pyramid dsp3 square plane Unconfigured 3 Click in the Charge text box and type the charge for the atom that you want to draw in the Charge text box or select the up arrow button or down arrow button to display charge values in increasing or decreasing order respectively 4 S 4 Select the arrow button in the Bond Type box and choose the bond type for the bond that you want to draw from the drop down list Single Coordinate 5 Use the Atom Bond tool to draw the atoms and bonds you require Refer to Chapter 4 Creating Chemical Samples for information on using the Atom Bond tool Using the style bar with the selection tools Select atoms and bonds with the selection tools to e view current atom and bond properties using the style bar boxes BioMedCAChe User Guide 3 4 Chapter 3 CAChe Basics 3 42 e change atom and bond properties using the style bar boxes To view current atom and bond properties 1 Use the Select tool to select the atom or bond whose properties you want to view The current atom or bond properties are displayed in the relevant style bar boxes If you select more than one object and the objects you select possess diff
128. AChe for Windows User Guide 4 5 Chapter 4 Creating Chemical Samples Drawing a bond JH Hydrogen sp3 tetrahedron Single x s line sp line sp2 trigonal plane isp3 tetrahedron sd3 tetrahedron d2sp3 octahedron dzsp3 trigonal pyramid dxysp3 square pyramid p3 trigonal pyramid dsp3 square plane Unconfigured 4 Choose a hybridization from the drop down list The atom you are going to draw will possess hybridization of the chosen value 5 Do one of the following a Select the up or down arrow button in the Charge text box in the style bar until the positive or negative charge value you require is displayed a Click in the text box and type the charge value you require H Hydrogen x sp3 tetrahedron ma Single 6 Click in the workspace with the Atom Bond tool An atom of the chosen element type hybridization and charge is displayed similar to the example shown to the left When drawing bonds you can either e click and drag between two existing atoms to create a bond between the two atoms e click and drag from an existing atom to a blank part of the workspace to create a bond with an atom attached CAChe for Windows User Guide Drawing a molecule in the workspace Drawing a bond between two existing atoms Drawing a bond between existing atoms involves 1 Choosing a bond type from the style bar Bond Type drop down list 2
129. ALA Arginine R ARG Asparagine N ASN Aspartic acid D ASP Cysteine C CYS Glutamine Q GLN Glutamic acid E GLU Glycine G GLY Histidine H HIS Isoleucine I ILE Leucine L LEU Lysine K LYS Methionine M MET Phenylalanine F PHE Proline P PRO Serine S SER Threonine T THR Tryptophan W TRP Tyrosine Y TYR Valine V VAL Computing and viewing secondary structure To view secondary structure 1 Choose View Secondary Structure to display icons below each residue that show the secondary structure that is contained 9 26 BioMedCAChe User Guide Working in the Sequence View window in the PDB file The secondary structure is displayed in 1 letter codes defined in Defining secondary structure p 21 4 If you delete replace or insert residues you change the secondary structure and you must update the secondary structure information To compute secondary structure 1 Choose Edit Analyze Secondary Structure to compute the secondary structure and display icons below each residue that show the secondary structure The secondary structure is computed by the PDB standard Kabsch and Sander algorithm see Defining secondary structure p 21 4 Numbering sequences You can number sequences by the number assigned to residues within the original PDB file or from one to n using a ruler NS To number sequences 1 Do one of the following o View Residue numbers PDB to display the PDB number above each residue Th
130. BIOMEDCAChe 6 0 WINDOWS i J 08 FUJITSU Copyright statement ii 2000 2003 Fujitsu Limited All rights reserved 1989 2000 Oxford Molecular Limited All rights reserved This document may not be used sold transferred copied or reproduced in any manner or form or in any medium to any person other than with the prior written consent of Fujitsu Limited Published by Fujitsu Limited All possible care has been taken in the preparation of this publication but neither Fujitsu Limited nor Oxford Molecular Limited accepts any liability for any inaccuracies that may be found Fujitsu Limited reserves the right to make changes without notice both to this publication and to the product it describes This version of the User Guide was published in January 2003 FJ1290 04 BioMedCAChe User Guide Contents Support and further information iv Introduction to the User Guide 1 1 The BioMedCAChe documentation set 1 2 New users 1 3 About this user guide 1 4 Conventions in this user guide 1 6 Navigation aids 1 8 Introduction to CAChe 2 1 Overview of CAChe 2 2 Introduction to computer aided chemistry 2 7 The advantages of CAChe 2 8 Performing experiments with CAChe 2 12 Computational chemistry and CAChe 2 20 CAChe Basics 3 1 Starting the CAChe workspace 3 2 The CAChe interface 3 3 The application window 3 4 The workspace 3 7 Using CAChe 3 16 Using CAChe Help 3 42 Quitting CAChe 3 44 Creating Chemical Samples 4 1 Wo
131. CAChe and BioCAChe CAChe for Windows User Guide Investigating transition state structures Before running a search for saddle experiment Because the reactant and product molecules must have all the same atoms and each atom must have the same atom number the best way to prepare the two chemical sample files is to 1 Save a copy of the reactant molecule 2 Change the atom and bond positions to create the product molecule 3 Save the file and use it as the product molecule It is sometimes useful to specify a molecule structure for the product that is very close to the expected transition state structure Viewing transition state structures TIP The transition state structure resulting from a search for saddle experiment is saved in the chemical sample file of the reactant product For this reason it is important to save a copy of the reactant chemical sample file before proceeding with a search for saddle experiment The contents of the product input file are untouched The resulting transition state structure from a refine transition state experiment is saved automatically in the chemical sample file on which the experiment was performed The resulting transition state structure from a verify transition state experiment is also saved automatically in the chemical sample file It is important to use the same parameter set and solvent effects when generating refining and verifying a transition state structu
132. Che However it is possible to view the UV visible and vibrational spectra in Personal CAChe and BioCAChe that have been created in other versions of CAChe Viewing infrared spectra S 18 2 To view infrared spectra 1 Open a chemical sample file for which you have infrared CAChe for Windows User Guide Investigating infrared spectra vibrational spectra data Choose Analyze IR Transitions to display the IR Transitions window If you have more than one chemical sample file open with infrared spectra data choose Analyze IR Transitions for each file to display the associated spectrum in the IR Transitions window Additional spectra are indicated by a legend which is automatically displayed The following shows an example of an IR Transitions window Ti IR Transitions Biel Es E Transmittance a Ql 2000 Wavenumber cm 1 H NS To view motion vectors 1 CAChe for Windows User Guide Using the Select tool click a transition in the graph function which is indicated by a triangle The selected transition is highlighted in red to show that it is selected Motion vectors indicating the direction of movement for each atom in motion appear in the workspace Hold down Shift and click repeatedly on triangles in the graph function to select several transitions The selected transitions are highlighted in red and motion vectors belonging to all the selected transitions are displayed f
133. Computational Applications Understanding Mechanics Mechanics concepts 20 2 This section provides reference information about the kinds of computations possible using molecular mechanics methods and specific information about the CAChe computational application Mechanics The term molecular mechanics refers to methods of determining molecular geometries using equations from classical Newtonian physics These methods describe the forces acting on atoms in molecules using empirically derived equations Currently several different molecular mechanics force fields are widely used You may also hear molecular mechanics methods called force field methods or Westheimer methods Most molecular mechanics force fields include terms describing bond stretching angle bending torsional and nonbonded interactions such as van der Waals and hydrogen bond interactions The sum of all these terms constitutes the steric energy of the molecule Steric energy is a type of potential energy and here the terms steric energy and potential energy are used interchangeably Mechanics computes the net force acting on each atom in your molecule as the sum of the following energy terms bond stretch bond angle e dihedral angle improper torsion e van der Waals e electrostatics MM2 MM3 dipoles or partial charges e hydrogen bond torsion stretch MM3 only bend bend interactions MM3 only BioMedCAChe User Guide Understandin
134. Create new blank file Open an existing file Undo or redo last operation Save active file Quit application Print active window Scale and center a chemical sample Copy selected items to clipboard Cut selected items to clipboard Paste selected items into active workspace Delete selected items Duplicate selected items Add a label to selected items Connect two selected atoms with a bond Menu option File New File Open Edit Undo File Save File Exit File Print View Fit in Window Edit Copy Edit Cut Edit Paste Edit Delete Edit Duplicate Adjust Define Geometry Label Edit Connect Atoms Toolbar a 5 AC A 2 2 2 lt Appendix A Keyboard and Toolbar Shortcuts Keys Action Toolbar button Menu option CtrlA Select all Edit Select All Ctrl I Invert chiral carbon Edit Invert Chirality Miscellaneous keyboard commands The following keyboard commands are available for miscellaneous functions Keys norN space ior aorA Action Exit all keyboard modes keys no longer manipulate your chemical sample or Increase the rate of change for keyboard view adjustments like rotating translating and scaling Decrease the rate of change for keyboard view adjustments like rotating translating and scaling Toggle the autorepeat flag When on autorepeat continues a
135. E Molecules 1A9T _pdb 2 Iof x A B c Do E F Pe a l 2 Atom List ID Formal X Coordinate Y Coordinate Z Coordinate Partial Name Temperature Charge angstrom angstrom angstrom Charge Factor charge_au charge_au 1 1 14 163 64 880 73 555 0 000 N 66 570 2 0 12 834 64 648 72 928 0 000 CA 67 120 3 a 12 529 65 859 72 050 0 000 E 65 110 4 a 12 807 66 994 72 444 0 000 0 64 630 5 0 11 760 64 508 74 015 0 000 CB 70 190 6 0 10 428 63 926 73 544 0 000 CG 72 790 7 0 10 505 62 143 73 213 0 000 SD 75 680 8 0 10 339 62 114 71 423 0 000 CE 74 100 9 0 12 022 65 606 70 845 0 000 N 63 230 10 0 11 675 66 672 69 907 0 000 CA 58 960 11 0 10 408 67 380 70 400 0 000 E 56 120 12 0 10 007 67 193 71 552 0 000 0 56 350 13 0 11 471 66 098 68 505 0 000 CB 59 060 14 0 9 765 68 155 69 528 0 000 N 52 410 4 gt fi Atoms Bonds Crystals Groups Notes a Note that the sample properties for a PDB molecule contain several worksheets e Atoms contains atoms and their properties Bonds contains bonds and their properties e Groups contains residues and their properties Electrons worksheet keeps track of nonbonded electron pairs so that the valence can be checked Electrons are added when you beautify a structure and do not appear when the PDB file is first opened e Notes contains PDB REMARK NOTE SOURCE COMPND and HEADER records information When a PDB file is opened in CAChe some new information is automatically calculated and ad
136. Generates the energies and shapes of a total of 11 molecular orbitals ranging from HOMO 5 to LUMO 4 All molecular orbitals Generates the shapes and energies of all of the molecular orbitals MOs in your chemical sample CAChe for Windows User Guide Setting up a workspace experiment Atom properties Bond properties Electrostatic isopotential Generates an electrostatic potential isosurface that shows both the polarity of the potential and where in space the potential equals 0 03 a u 18 kcal mol 75 kJ mol Susceptibility electrophilic nucleophilic or radical Creates a three dimensional surface superimposed over your chemical sample which indicates areas that are vulnerable to an attack by either electrophiles nucleophiles or radicals Superdelocalizability electrophilic nucleophilic or radical Creates a three dimensional electron density isosurface with colors reflecting the relative differences in reactivity of the different parts of your sample Choose the following property for an atom Atomic partial charge Calculates atomic partial charges for every atom in your chemical sample Choose from the following properties for a bond Calculated bond order Determines the computed bond order of every bond in your chemical sample using semi empirical quantum mechanical methods Calculated bond strain Determines the computed bond strain of every bond in your chemical sample using classical me
137. Heat 24 16353 Cycle 2 Time Time left 863996 3 Grad 34 454 Heat 24 11354 Scroll Cycle 3 Time 7 Time left 863995 7 Grad 18 378 Heat 23 85615 gt i bar Cycle 4 Time 6 Time left 863995 0 Grad 13 147 Heat 23 74013 Cycle SLs 1 1 Time left 863994 0 Grad 10 932 Heat 23 68709 Cycle 6 Time Sel Tine Left ieee Rak Grad oo Neut 23 66336 Cycle 7 Tine 4 Time left 863992 7 Grad 15 116 Heat 23 62363 Cycle 8 Time 7 Time left 863992 0 Grad 11 059 Heat 23 57669 If a window does not display scroll bars all the information present in that window is currently displayed on screen NS To scroll a window Move the cursor over the square in the scroll bar 2 Hold down the left mouse button and drag the cursor upwards or downwards to view the window contents above and below the currently displayed information or objects Using the workspace selection tools This section introduces the palette of workspace tools which is displayed at the left of the workspace window and consists of e four selection tools the Select default Select Molecule Select Similar and Select Group tool e a drawing tool the Atom Bond tool three manipulation tools the Rotate Translate and Scale tool This section also describes in detail how to use the default Select tool to do the following select or deselect individual atoms and bonds in the workspace select or deselect several atoms and bonds
138. NDO or MOPAC can also result in slightly altered values for locked coordinates Broken locks are labeled with LB in the workspace to indicate that a broken lock is present The following example shows a broken geometry label lock Repairing broken locks If the coordinates of a locked geometry label change you can return the value of a broken geometry label lock to its locked value To repair a broken geometry label lock 1 Select the geometry label with a broken lock by clicking on the numeral portion of the label with the Select tool 2 Choose Adjust Repair Locked Geometry Labels The spatial relationship that the geometry label represents returns to the locked value CAChe for Windows User Guide 8 31 Chapter 8 Investigating Molecular Geometry Locking atoms You can freeze the location of an atom by locking its x y and z coordinates in the workspace When you perform an experiment on a chemical sample with locked atoms locks are enforced even if the lock is currently disabled Locking atoms is useful to e perform calculations that require some atoms to remain at a fixed position while others are free to move For example you could lock the structural bulk of an enzyme to optimize the surface of an enzyme and its substrate To study the effect of a zeolite cage on the deformation of a molecule that passes through it you could lock the atoms in the zeolite and optimize the molecule in various positio
139. OPAC will override any attempt to use cartesian coordinates Transition states in MOPAC BioMedCAChe User Guide Saddle points are stationary geometries for which the energy increases when atoms are displaced in all directions except one This means that only one of the force constants of a molecule at a transition state geometry is negative and all the rest are positive or zero The vibrational frequency of the normal mode with the negative force constant is negative On an energy map a saddle point is at the top of the pass that connects two minimum energy geometries with each other Chemically this geometry is a transition state The reaction coordinate is the direction of greatest energy decrease from the saddle point The reaction pathway is the minimum energy path from reactants to transition state to products 20 17 D lt s i s N i D Chapter 20 CAChe Computational Applications MOPAC has a method designed for locating transition states called a SADDLE calculation Both the reactant and product molecules are specified and MOPAC attempts to locate a stationary point that corresponds to the transition state for the reaction The geometry generated from a saddle calculation can be some distance away from the transition state However refining this structure through a minimize gradient calculation usually leads to a structure closer to the transition state Another method for locating
140. OUP o the group name is as you typed it o and the group PDB Name is the first 3 letters of the group name Close the Sample Properties Window In the 3D Structure window select Analyze Sequence The Sequence View comes to the front with the sequence of the chemical sample Choose Options Amino Acids Repository The Amino Acids Repository dialog appears Amino Acid Repository 27 x Repository Standard Amino Acids User Defined Delete Assign Key View Replace lt lt Less In the Amino Acids Repository dialog press the New button The New Amino Acids dialog appears Select the available item that contains the name of the new amino acid group that you created and click Add The selected residue is added to the repository and the dialog closes The new amino acid is displayed in the Amino Acid list and available in the Residue Combo Box BioMedCAChe User Guide 1 0 Performing Workspace Experiments Overview This chapter describes experiments in the CAChe workspace including e an overview of the experimental properties and procedures available in CAChe and the computational applications involved in each experiment e adetailed description of how to perform a CAChe experiment in the workspace e an overview of all experiment files that CAChe creates their file names and file locations 4 gt Refer to Chapter 11 Using the Procedure Editor for details about creating ne
141. Optimized 3 Optimized None Optimized 3 1 Optimized Stored At the beginning no input structure exists in the conformation storage Generation of starting structure BioMedCAChe User Guide The lowest energy structure of the unused stored conformers is chosen as the initial structure a structure is considered to be unused if it has never been perturbed to generate a starting structure This strategy is important to search through the region in the conformational space in the most efficient way towards a lower 20 25 Chapter 20 CAChe Computational Applications Variable search limit 20 26 energy area This is similar to a stream filling an empty reservoir by finding the the lowest point Limit 2 Limit 1 gt Conformers found when the search has been conducted below Limit gt Low energy conformers found only after search is extended ta Limit 2 The strategy is illustrated schematically here for a conformational space search by the reservoir filling algorithm e The initial structures are sampled in the numbered order given to the conformers ellipses A pair of conformers connected by a line comprise an initial structure and a conformer generated from that initial structure through perturbation and geometry optimization e When the search limit is set to the level of Limit 1 the search is complete after the initial structures 1 through 17 have been processed Then the search l
142. PAC AM1_H20_Geo using Sample1 Steps involved in the procedure L Call Tab_EDens_EP using Samplet Description Description of the procedur Use the five buttons in the Procedure Steps section to modify the existing procedure In addition you can use the menu options in the Procedure window to modify the procedure This dialog box is displayed from the Navigator window when you double click on a procedure object in the tree view lt t gt Refer to Modifying a procedure p 11 17 for details about modifying procedures using this dialog box 11 6 CAChe for Windows User Guide The Procedure Editor interface The Parameter Data window The Parameter Data window lets you modify a parameter data set The title bar contains the name of the data set displayed within the window fm Data MM2 STANDARD i n GONDANA UN WOnwWmnN Woe 0 600 0 000 n acn n ann 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 a Edit the figures in the window to change the parameter data set If any unsaved changes have been made to the data set the title bar displays an asterisk symbol This window is displayed from the Navigator window when you double click on a data set object in the tree view lt t Refer to Expert modification p 11 30 for details about editing parameter data sets using this window CAChe for Windows User Guide 11 7 Chapter 11 Using the Procedure Editor Managing the exper
143. Property Predictions Janin J Nature 1979 277 491 Fauchere J L and Pliska V Eur J Med Chem Chim Ther 1983 18 No 4 369 375 Manvalan P and Ponnuswamy P K Nature 1978 275 673 Karplus P A and Schulz G E Naturwissenschaften 1978 72 212 213 anoo D i i s N i D BioMedCAChe User Guide 21 11 Chapter 21 CAChe BioComputations Understanding Sequence Alignment Alignment concepts CAChe aligns two sequences by performing a pairwise global alignment using the Needleman Wunsch algorithm with a BLOSUM5SO substitution matrix When sequences from two proteins are placed in adjacent rows it is Sequence Yiew of x ALA Other phif180 Psi 18 PDB Number Test2 Sequences before alignment likely that some residues in one sequence will be identical to the residues at the same position in the other sequence In some cases the adjacent residues will be similar in properties and function and frequently substituted during evolution In other cases the number 1 Needleman S B and Wunsch C D J of Mol Bio 1970 48 443 453 A general method applicable to the search for similarities in the amino acid sequence of two proteins 21 12 BioMedCAChe User Guide Understanding Sequence Alignment of matching residues can be increased by inserting gaps in the sequence that account for evolutionary insertions and deleti
144. SESLGKGHSDGGCYEQLFVSPEVFVTLGVISLLENILVIVAAIKNKNLHSPMYFFI 083 OPSD_BOVIN LNLAVADLFMVFGGFTTTLYTSLHGYFVFGPTGCNLEGFFATLGGEIALWSLVVLAIERY 136 MC4R_ MOUSE CSLAVADMLVSVSNGSETIVITLLN STDTDAQSFTVNIDNVIDSVICSSLLASICSLLS 142 OPSD_BOVIN VVVCKPMSNFRFGENHAIMGVAFTWVMALACAAPPLVGWSRYIPEGMQCSCGIDYYTPHE 196 MC4R_MOUSE IAVDRYFTIFYALQYHNIMTVRRVGIIISCIWAACTV SGVLFIIYSDSS 191 OPSD_BOVIN E TNNESFVIYMFVVHFIIPLIVIFFCYG QLVFTVKEAAAQQQESATTQKA 246 MC4R_MOUSE A VIICLISMFFTMLVLMASLYVHMFLMA RLHIKRIAVLPGTG TIRQGT 239 OPSD_BOVIN EKEVTRMVIIMVIAFLICWLPYAGVAFYIFTHQGSDFGPIFMTIP AFFAKTSAVYNP 303 MC4R_ MOUSE NMKGAITLTILIGVFVVCWAPFFLHLLFYISCPONPYCVCFMSHFNLYLILIMCNAVIDP 299 OPSD_BOVIN VIYIMMNKQFRNCMVTTLCCGKNPLG DDEA STTVSKTET SQVAPA 348 MC4R_ MOUSE LIYALRSQELRKTFKEIICFYPLGGICELSGRY 332 NS To change the helices 1 Chose File Open and open the bovine rhodopsin csf file CAChe for Windows User Guide 19 17 Chapter 19 Investigating Biomolecules that you created in Viewing bovine rhodopsin p 19 16 2 Choose File Save As and rename this file MC4R csf Choose Analyze Sequence Refer to Working in the Sequence View window p 9 18 for information on using the Sequence View 4 Check View Residue Numbers PDB A Sequence No line appears in the Sequence View window containing the residue numbers from the PDB file 5 Delete residues fro
145. Scroll bars 3 14 Scrolling lists 3 28 windows 3 29 Search for saddle 2 17 10 8 experiment 17 1 Search labels 8 37 8 40 animating 8 44 for potential energy maps 20 5 Secondary structure 21 4 Secondary Structure box 9 22 Secondary structure box 9 21 Select 3 17 groups 7 25 groups of atoms 7 26 more than one object 5 5 non grouped atoms 7 27 one object 5 5 Select a server dialog box 10 29 Select all visible 3 31 Select Columns dialog box 12 18 Select conserved 9 41 Select Group tool 3 30 3 32 5 4 5 12 Select Molecule tool 3 30 3 31 5 4 Select molecule tool 5 6 BioMedCAChe User Guide Select Molecule chain tool 9 24 Select Similar residue tool 9 24 Select similar settings dialog box 5 12 Select Similar tool 3 30 3 31 5 4 Select similar tool 5 9 Select tool 3 30 3 31 5 4 9 24 how to use 3 33 using 5 6 Selecting cells in ProjectLeader 12 24 defining similarity 5 11 items and options 3 17 similar atoms 5 10 Selection tools 3 13 9 24 Selective optimization 13 6 Sequence of conformations 2 16 10 8 14 9 Sequence view style bar 9 21 Tool palette 9 23 sequence view 9 20 Sequence view window 19 3 Sequential search generating with mechanics 20 5 in mechanics 20 6 Servers 10 17 displaying 10 33 in ProjectLeader 12 24 viewing information 10 29 Set atom distance dialog box 8 13 Set bond angle dialog box 8 14 Set dihedral angle dialog box 8 16 8 27 Set improper torsion dialog box 8 18 Setting up experiments 10 4 S
146. Shift key 1 Position the Select tool over the first object you want to select 2 Press the left mouse button to select the object The object is highlighted to show that it is selected Position the Select tool over the second object you want to select 4 Hold down the Shift key and select the second object by clicking on it The second object you selected is highlighted to show that it is selected 5 Position the Select tool over the third object you want to select 6 Hold down the Shift key and select the third object by clicking on it The third object you selected is highlighted to show it is selected 7 Continue to hold down the Shift key and click on objects until you have selected everything you want Using the Select tool to deselect objects Use the Select tool to deselect objects that are currently selected by e clicking on objects in the workspace while holding down the Shift key e clicking and dragging around objects in the workspace while holding down the Shift key The object is grayed out to show that it is deselected Deselecting more than one object Clicking and dragging around a group of selected objects while holding down the Shift key is also a useful way of deselecting more than one object when the objects are close to each other You can BioMedCAChe User Guide 3 35 Chapter 3 CAChe Basics 3 36 also deselect more than one object by clicking on each object and holding down the Shi
147. Solid ribbon backbone of 1A9T colored by secondary structure NSS To redisplay all atoms 1 Choose View Backbone Ribbon None All objects are displayed Displaying surfaces With CAChe you can display the accessible surface of 1 a protein accessible to a probe sphere of 1 4A radius colored by hydrophobicity and hydrophilicity 2 an active site adjacent pocket colored by the hydrophobic and hydrophilic properties required in a ligand for good binding 3 a protein colored by the depth of the crevices in the surface 1 Carson M J of Mol Graphics 1985 5 103 106 BioMedCAChe User Guide 9 11 Chapter 9 Manipulating Biomolecules 9 12 4 To display the protein accessible surface With the Select Molecule Tool in the 3D Structure Window select the protein NOTE The protein must have hydrogen atoms added first The protein highlights and all other objects dim Choose View Hide Unselected The protein remains visible all other objects disappear Choose Analyze Accessible surface After a few seconds a progress dialog appears and then the surface is drawn on the protein The surface that is drawn is one that would be accessible to or touched by a 1 4A sphere rolling over the protein Since water is approximately 1 4A in size this surface is sometimes called the solvent accessible surface The mauve red areas indicate regions of the protein surface where there are hydrogen bond ac
148. TE A lt t gt Y CAChe steps the search labels through their defined range of values and computes the energies of each resulting conformation For example if you define two search labels each with 10 steps your energy map will contain 121 conformations 1 1 because 10 steps results in 11 conformations and each one is tested in combination with all other possibilities CAChe provides procedures that use one of the following e classical mechanics which generates a potential energy rigid map e quantum mechanics which generates a heat of formation rigid map You cannot generate a rigid energy map using quantum mechanics with Personal CAChe or BioCAChe A rigid energy map calculation keeps the structure rigid at the defined search label values The unoptimized conformational energy is plotted as a function of the position of any two of the structural elements to create the rigid map An optimized map optimizes each conformation resulting from the search label values Both rigid and optimized maps are useful for investigating how energy changes as a function of specific geometry attributes in your molecule Refer to Generating an optimized energy map p 14 7 for more information Generating a rigid energy map with classical mechanics 14 6 Classical mechanical procedures measure the potential energy of each conformation of a molecule formed by varying the search labels The labeled bond angles and atom di
149. To change page orientation of a printout 1 Choose File Print Setup to display the Print Setup dialog box 2 Select the Portrait radio button in the Orientation panel to print portrait images where the paper is longer than it is wider 4 24 CAChe for Windows User Guide Printing files 3 Select the Landscape radio button in the Orientation panel to print landscape images where the paper is wider than it is longer 4 Select OK to save the page orientation and to close the Print Setup dialog box To change paper size and source 1 Choose File Print Setup to display the Print Setup dialog box 2 Select the arrow button in the Size box located in the Paper panel and choose a paper size from the drop down list 3 Select the arrow button in the Source box located in the Paper panel and choose a paper source from the drop down list 4 Select OK to save the paper size and source settings and to close the Print Setup dialog box Printing a CAChe window You can print the contents of all CAChe document windows regardless of file type When printing the contents of a document window are scaled so that all currently visible objects are printed Prints are made as a bitmap at the resolution of your printer CAChe also gives you the option of printing the contents of a document window to a file as well as to a printer To print a CAChe document window to a printer 1 Activate the document window whose content
150. View Adjust Beautify Analyze Options Experiment Window Help lt t gt Refer to Using the menu bar p 3 20 for details on how to use the CAChe menu 3 4 BioMedCAChe User Guide The application window The toolbar The toolbar contains a collection of buttons that provide a shortcut to some of the menu options The following diagram shows the toolbar and the corresponding menu options that each button performs Hil Laite Sali tgi zia fe eles gt co sa xaa He o p c Se o d a5 L aeu EJS 62 5 EL 5656 8 Sz 26o S EI Zog swe SR y SEE Zo Ee Z 4A G6 o ON Be gt E lt Sa ele amp b _w oo L2 v o Ozz QL 2 z 3O BSS a is L Oo oO nan o Z 00 G amp G E we wo L 7 S E w a o Q Io ELU L g E E5 22 po o E 626 2 gt a ggz 686 5 gt x lt o ar paesc 3 5 sas S amp 2 S z gt 8 5 gt u 2 2 2 o 5 O 8 gt o B a oe 3 5 5 z z D E 3 5 WH 2 x lt Lu A lt t gt Refer to Using the toolbar p 3 21 for details on how to use the CAChe toolbar and a list of toolbar buttons and their equivalent menu options Hiding the toolbar You can choose to hide the CAChe toolbar To hide the CAChe toolbar 1 When the toolbar is visible choose Options Show Toolbar The toolbar is no longer displayed in the CAChe application window The check mark next to the Show Toolbar drop down list option is no longer d
151. a angle in degrees beta angle in degrees gamma angle in degrees scale multiplier converting x y z coordinates to range 0 1 Repeat cell number of times to repeat the unit cell along a b and c axes Space Group international space group symbol Descriptor none or enter the descriptor as found on the third line of the International Tables for Crystallography Temperature Factor must be UIJ BIJ or BETA This line is optional Z xyzT11 T22 T33 T12 T13 T23 Z the atomic symbol or atom label x y z frac tional coordinates separated by tabs or white space T optional thermal tensor data separated by tabs or white space Parentheses can be used to include additional com ments data enclosed in parentheses are ignored Note the following The CrystalStructure file can have any name but the first line in the file must include the word CrystalStructure spelled exactly as shown Three comment lines must follow The keywords are case sensitive and should be spelled exactly as shown e Thermal tensor data is optional If only the first element of the tensor is entered then the atom is considered isotropic To build a crystal structure using a CrystalStructure file 1 2 Choose File Open to display the Open dialog box From the Files of type drop down list select Crystal Structure xsf Select the file From the scrolling list locate the file and click on it to select it
152. a click the right mouse button to display a popup menu and choose View Sample Properties 3 Select the tabs at the bottom of the workbook to view information about the different components BioMedCAChe User Guide 12 17 Chapter 12 Using ProjectLeader A t gt Refer to Running a ProjectLeader experiment p 12 20 for details of performing experiments in the Sample Properties workbook Editing sample properties By default the Sample Properties workbook is locked against editing However it is possible to unlock it and to edit the values in the workbook NOTE Care should be taken when editing sample properties because ProjectLeader does not check the validity of any changes made to chemical samples To edit a sample property 1 Choose Edit Edit Property Values The lock icon is removed from the Sample Properties workbook 2 Edit the cells that you want to change Cells that have been edited automatically have a footnote added to them warning you that the cell has been edited 3 Choose Edit Lock Property Values to lock the sample properties again This avoids the risk of editing properties accidently Copying sample properties Sample properties can be copied to the ProjectLeader workbook and displayed in the same row as the chemical sample to which they relate Experiments can then be performed on the sample properties in the ProjectLeader workbook To copy sample properties to the Projec
153. a color from the drop down list 6 Inthe Color Label With panel select the radio button next to the color option you want to apply to the label of each selected atom ensuring that the relevant radio button is enabled 7 Select OK to close the Atom Attributes dialog box The selected atoms and their atom labels are displayed in the colors you chose Hiding and displaying electrons CAChe can add representations of non bonded valence electrons to your chemical sample You can display or hide electrons in the chemical sample When you hide electrons they remain part of the chemical sample Hiding electrons has no effect on calculations run on the chemical sample during an experiment The following example shows electrons displayed in the workspace __ Electrons H es To display electrons 1 When electrons are hidden choose View Show Electrons A check mark is displayed next to the drop down list option to indicate that electrons are visible All of the electrons in the 6 16 CAChe for Windows User Guide Changing the appearance of atoms workspace are displayed NS To hide electrons 1 When electrons are visible choose View Show Electrons The check mark next to the drop down list option disappears to indicate that electrons are hidden All of the electrons in the workspace are hidden CAChe for Windows User Guide 6 17 Chapter 6 Viewing Chemical Samples Hiding atoms You may wan
154. a few seconds the CAChe application window opens containing an empty document window referred to as the workspace 3 2 BioMedCAChe User Guide The CAChe interface The CAChe interface The CAChe user interface shown below consists of e an application window containing a menu bar and toolbar e adocument window which contains tools and drop down lists to help you draw and manipulate your chemical sample When the active document is a chemical sample file the document window is referred to as the workspace Chemical sample files are used to create edit and experiment on molecules Refer to Chapter 4 Creating Chemical Samples for a description of chemical sample files E CAChe ChemicalSample2 File Edit View Adjust Beautify Options Experiment Window Help olele elel Sl eine al eed ele eee D aagi gt ChemicalSample2 Application window H H Fl l H Document window workspace BioMedCAChe User Guide 3 3 Chapter 3 CAChe Basics The application window The CAChe application window contains standard Windows features such as e amenu bar with a selection of menu options e atoolbar containing buttons that provide a shortcut to some of the menu options e astatus bar at the bottom of the window The menu bar The menu bar displays options that give access to drop down lists of menu options The menu that is visible when you first start CAChe is as follows File Edit
155. a the keyword server a the name of the server or its IP address a your login name on the server a the keyword CACH a the keyword CalcManager The following shows an example tcpconf txt file with the servers srvr1 and srvr2 added to the domain name server line CAChe for Windows User Guide Troubleshooting experiments tcpconf txt TCP configuration file Use these if the domain name server is available keyword server name login _name pc_ident unix process name server localhost cache CACH CalcManager server srvrl jillj CACH CalcManager server srvr2 markp CACH CalcManager 5 Save and close the tcpconf txt file 6 Quit and restart the CAChe application Displaying experimental details If you exit CAChe by mistake while an experiment is running or if you accidentally close the Experiment Status dialog box while an experiment is in progress you can redisplay experimental details To redisplay experimental details 1 Choose Experiment Show Submitted Experiments to display a list of experiments in progress 2 Select the experiment in progress whose details you want to view by clicking on it in the list 3 Select Details The Experiment Status dialog box is displayed informing you of the experiment s progress CAChe for Windows User Guide 10 35 Chapter 10 Performing Workspace Experiments Viewing experimental results 10 36 When you run an experiment in CAChe a number of fil
156. a2 Aba 14 amb I4 amd Fmm2 Fmm 14 acd I4 acd CAChe for Windows User Guide Building crystal structures CAChe Fdd2 P3 P34 P 3 P312 P321 P3 12 P3 21 P3512 P3521 P3m1 P31m P3c1 P31c P 31m P 31c P 3m1 P 3cl P6 P6 P64 P 6 P6 m P63 m Defining cell parameters Alternative Fdd C3 C3 C3 C 3 C312 C32 C3 12 C3 2 C3512 C352 C3m C3lm C3c C31c C 31m C 31c C 3m C 3c C6 C6 C65 C6 C64 C6 C 6 C6 m C63 m CAChe P622 P6 22 P6522 P6522 P6422 P6322 P6mm P6cc P63cm P63mc P 6m2 P 6c2 P 62m P 62c P6 mmm P6 mcc P63 mcem P63 mme P432 P4 32 F432 F4 32 1432 P4332 P4 32 14 32 Alternative C62 C62 C652 C652 C642 C632 Comm C6cc C63cm C63mc C 6m C 6c C 62m C 62c C6 mmm C6 mcc C6 mcm C6 mme P43 P4 3 F43 F4 3 143 P433 P4 3 14 3 Cell parameters define the unit cell for the space group The cell parameters a b and c specify the lengths of the edges of the unit cell and the cell parameters B and y specify the angles between the edges of the unit cell CAChe for Windows User Guide 6 57 Chapter 6 Viewing Chemical Samples NSS To define cell parameters 1 Select the crystal structure using the Select Molecule Tool 2 Choose Edit Crystal Shape to display the Crystal Shape dialog box 3 Inthe Angles panel enter values by editing the a b c and a B y text boxes If the crystal system to which the space group belongs places re
157. able 12 17 scatter plots 12 27 starting 12 5 ProjectLeader workbook 12 7 adding a chemical sample 12 12 adding a property sample component analysis or comment 12 21 adding footnotes 12 37 components of 12 7 copying objects from ChemDraw ISIS Draw or Kekule 12 15 displaying chemical samples as line drawings 12 33 exporting as an sdf file 12 43 hiding column or row buttons 12 37 selecting a server 12 24 selecting cells 12 24 sorting rows 12 34 viewing cell details 12 39 Properties atom 10 7 available properties 11 14 bond 10 7 conformation 10 8 matching to procedures 10 15 Sample properties 12 17 showing properties 11 13 Property class choosing 10 5 Protein accessible surface 9 13 adjacent surface pocket 9 15 backbone N C C trace 9 10 selecting 9 9 coloring residues 9 8 crevice surface 9 13 docking 19 22 ribbons 9 10 Protein Data Bank 21 5 Proteins BioMedCAChe User Guide docking ligandsDocking ligands into proteins 19 22 Q QSAR relationships establishing 2 18 12 2 QSPR relationships establishing 2 18 12 2 Quantum mechanics 13 3 optimized energy map 14 8 optimizing molecules 13 4 rigid energy map 14 7 Quitting CAChe 3 45 Procedure Editor 11 38 ProjectLeader 12 45 R Radio buttons 3 25 Radius bond 16 12 Ramachandran 21 6 Reaction path 10 9 structures 17 4 structures that conserve kinetic energy 17 4 structures without kinetic energy 17 4 Reaction pathways 2 9 20 11 Reaction properties 10 5 1
158. ader supports the statistical analyses of chemical samples such as multiple linear regression forward and reverse stepwise regression and calculations based on customizable equations BioMedCAChe User Guide 12 3 Chapter 12 Using ProjectLeader ProjectLeader experiments use the same set of computational applications as Workspace experiments lt t gt Refer to Chapter 20 CAChe Computational Applications for further details 12 4 BioMedCAChe User Guide Starting ProjectLeader Starting ProjectLeader NS To start ProjectLeader 1 Do one of the following a Choose Start Programs CAChe ProjectLeader from the Windows taskbar a In Windows Explorer double click the plwin exe icon in the CAChe folder The splashscreen is displayed After a few seconds an empty ProjectLeader workbook Untitled1l is opened E Workbook2 olx Worksheet button z Column button emical Name Atom Count all atoms Row button Carboplatin 237 Tamoxifen 57 Flutamide 30 Sheet tab Footnote display area __ By manual entry Column row and worksheet buttons Each column has a lettered column button and each row has a numbered row button Click on these to select a whole column or row respectively Click on the worksheet button to select the whole worksheet BioMedCAChe User Guide 12 5 Chapter 12 Using ProjectLeader Sheet tab Footnotes Each worksheet in a workbook has a s
159. ader worksheet 12 43 scatter plots 12 31 F Faster motion mode 7 12 File management B 1 Files B 1 B 2 experimental 10 36 generation of output files 10 32 log 10 40 opening saved files 4 20 output 10 40 printing 4 22 saving 4 17 saving experiments 10 23 Find reaction paths 2 17 experiment 17 1 Folders B 1 B 2 sample io 10 37 sample iso 10 37 Footnotes 12 37 Forward stepwise regression 12 3 Frontier density 2 14 15 16 orbitals 10 6 Fuse atoms 7 21 bonds 7 22 ring structures 7 21 G Generating energy maps 14 2 rigid 14 6 Geometry broken locks 8 31 correcting 4 14 BioMedCAChe User Guide disabling locks 8 35 investigating molecular 8 1 label wizard 8 41 labels 8 40 optimization 2 8 repairing broken locks 8 31 Geometry label attributes dialog box 8 22 8 25 Geometry label wizard dialog box 8 42 Geometry labels 8 19 8 24 changing 8 21 changing color 8 25 deleting 8 26 hiding 8 22 hiding text 8 23 locking 8 29 Graph attributes 14 20 changing color 14 17 Graph attributes dialog box 14 16 Group packages 11 31 Grouping atoms 7 24 Groups defining 7 24 selecting 7 25 7 28 7 29 GroupServer 10 34 H H bond labeling 8 27 Heat of formation 2 14 10 5 12 3 20 13 HELIX 21 5 het_dictionaryCIF txt 9 3 Hiding atoms 6 18 bonds 6 28 electrons 6 16 surfaces 15 10 text in geometry label 8 23 HOMO 10 6 12 3 18 7 HOMO 5 to LUMO 4 energies calculating 15 8 BioMedCAChe User Guide
160. ailable as an optional add on to CAChe 2 22 BioMedCAChe User Guide aUu1dIpauU 3 2 OH d 30 A LS IW3IH CAChe Basics The following chapter describes the basics of CAChe for Windows Chapter 3 CAChe Basics introduces the components of the workspace 3 CAChe Basics Overview This chapter introduces the basics of using CAChe including how to e start and quit CAChe use the components of the workspace access CAChe on line Help Contents Starting the CAChe workspace 3 2 Using CAChe 3 17 The CAChe interface 3 3 Using the mouse 3 17 The application window 3 4 Using the menu bar 3 20 The menu bar 3 4 Using the toolbar 3 21 The toolbar 3 5 Using dialog boxes 3 22 The status bar 3 6 Using the workspace selection tools 3 29 The workspace 3 8 Using the Select tool 3 33 The title bar 3 9 Using the workspace style bar 3 40 The style bar 3 9 Using CAChe Help 3 43 The tool palette 3 13 Viewing context sensitive Help 3 43 The scroll bars 3 14 Viewing the CAChe Help system 3 44 Stereo 3D cursor 3 15 Quitting CAChe 3 45 Manipulating document windows 3 16 Chapter 3 CAChe Basics Starting the CAChe workspace CAChe runs in a Windows Me Windows 98 Windows NT 4 0 and Windows 2000 environment To start the CAChe workspace 1 Choose Start Programs CAChe Workspace from the Windows taskbar An initializing CAChe splash screen containing CAChe version details is displayed After
161. al considerations that you should be aware of For simple particles the temperature of a system is related to the average kinetic energy as translational energy for the molecules present KE 3K For polyatomic molecules additional energy is found as rotational motion of the molecule and vibrational motion of the atoms KE KE KE KEy For anything but a linear molecule KE kT kT NKT where N is the number of degrees of vibrational freedom For nonlinear molecules N 3 x number of atoms 6 Thus the total kinetic energy of a large molecule is larger than that of a small molecule at the same temperature In the CAChe Dynamics simulation the molecule remains centered with no rotation that is with no net translational or rotational momenta The motions you observe are only vibrational stretching bending and internal rotation motions of the atoms where their average velocities are determined from the relationships E dm v NKT and v kT i m The velocity of each atom is determined using random selection from a Gaussian distribution of velocities around its average velocity The amplitude of motion varies with the square root of the temperature This relationship is true for molecules of all sizes although the collective motions possible in large molecules may create an illusion of more vigorous motion Relating temperatures and the motions of molecules in dynamics to our theoretical understanding requires
162. al sample file in which you want to paste the copied object o If the chemical sample file in which you want to paste the copied object is already open click on its workspace to make it active Do one of the following o Choose Edit Paste o Press Ctrl V o Select the toolbar button shown to the left A copy of the selected object is pasted in the center of the active workspace The copy is highlighted in the workspace to show that it is selected while all other workspace objects are grayed out Do one of the following o Click and drag in the workspace with a selection tool to move the selected copy to the location you want o Use the Translate tool to click and drag across the workspace to the location where you want to place the copied object The pasted copy moves to the location where you dragged it 7 15 Chapter 7 Manipulating Molecules The copied object remains on the Windows Clipboard until you copy or cut another object or quit CAChe so you can continue to paste copies of the object until you have the required number of copies To copy and paste an object to another Windows app 1 2 3 4 5 7 16 lication Select the object that you want to copy by clicking on it with a selection tool The object is highlighted to show that it is selected Do one of the following o Choose Edit Copy o Press Ctrl C o Select the toolbar button shown to the left Open or maximize the a
163. and The cream areas indicate where the ligand should have hydrophobic groups e g gt CH You can use this wire pocket to design new ligands with improved binding affinity by 1 filling empty space in the pocket with functional groups that bind to the protein and 2 trimming protruding groups As a guide carbonyl oxygens gt C O should touch the red mesh hydrogens that hydrogen bond to the protein should stick through the blue mesh and hydrophilic groups should be inside and away from the mesh Bohacek R and McMartin C J Med Chem 1992 35 1671 1684 BioMedCAChe User Guide Viewing biomolecules To hide the adjacent surface pocket 1 Choose Analyze Show Surfaces The Show Surfaces dialog appears Show Surfaces 2 x Displayed surfaces wv adjacentl aas Cancel 2 Uncheck the aas surface and choose OK The dialog closes and the surface disappears To delete the protein adjacent surface pocket 1 With the protein adjacent surface displayed click on the aas surface label Both the surface label and the surface highlight all other objects dim 2 Choose Edit Delete The surface and its label disappear from the screen and are removed from the chemical sample file However the surface aas files remain in the iso folder You delete aas files with the Windows Explorer after they have been deleted from the chemical sample BioMedCAChe User Guide 9 17 Chapter 9
164. and LUMO calculates the energies and shapes of the HOMO and LUMO of your chemical sample using a quantum mechanical application All molecular orbitals generates the shapes and energies of all of the Molecular Orbitals MOs in your chemical sample Susceptibility electrophilic nucleophilic and radical creates a three dimensional surface superimposed over your chemical sample that indicates areas that are vulnerable to an attack by electrophiles nucleophiles or radicals BioMedCAChe User Guide Performing experiments with CAChe A lt 4 Refer to Chapter 13 Optimization and Energy Calculations for further details about optimized geometry Refer to Chapter 15 Investigating Electron Distribution for further details about the other chemical sample experiments in the preceding list Refer to Chapter 18 Investigating Spectra for further details on infrared and UV visible spectra experiments i 2 S gt 3 b 5 Atom experiment CAChe performs the following experiment on an atom from the workspace e Atomic partial charge calculates atomic partial charges for every atom in your chemical sample whenever you run an experiment that includes a semi empirical quantum mechanical procedure t gt Refer to Chapter 16 Investigating Atom and Bond Properties for further details Bond experiments CAChe performs the following experiments on a bond from the
165. and conformation displayed by the map file windows is not one of the conformations listed in the conformational analysis window Do one of the following to view a conformation from a different perspective Double click on a conformation listed in the conformational analysis window to display a larger conformation window Use this second conformation window to view the same conformation as appears in the first smaller conformation window from a different angle or from a different perspective Choose Window New Conformation Window or Window New Graph Window to display as many map file windows as you want When you have finished viewing the list of conformations select the Windows close button at the upper right corner of the conformational analysis window to close the window When you have finished viewing the graph or a conformation 14 23 Chapter 14 Investigating Low energy Conformations from a different perspective select the Windows close button at the upper right corner of extra copies of the graph or conformation window to close the window Specifying analysis criteria You can change analysis settings to view selected portions only of the energy and conformational data in a map file Control display of variable values in the following ways e display a percentage only of a range of values e display only those conformations with a specified energy value e display a specified number only of the lowest energ
166. and dragging 1 Position the Select Molecule tool to one side of a molecule you want to select 2 Click and drag the Select Molecule tool to form a selection box around the molecules you want to select The molecules you encompassed in the selection box are highlighted to show that they are selected Using the Select Molecule tool to deselect a molecule NS To deselect a selected molecule 1 Position the Select Molecule tool over the selected molecule you want to deselect 2 Press the left mouse button to deselect the molecule The molecule is grayed out to show that it is deselected Using the Select Molecule tool to deselect more than one molecule Use the Select Molecule tool to deselect more than one molecule by e holding down either the Shift or Ctrl key while clicking on the selected molecules e holding down either the Shift or Ctrl key and clicking and dragging around the selected molecules in the workspace 5 8 CAChe for Windows User Guide Selecting workspace objects To deselect more than one molecule by clicking 1 Position the Select Molecule tool over the selected molecule you want to deselect and hold down either the Shift or Ctrl key 2 Press the left mouse button to deselect the molecule while holding down either the Shift or Ctrl key The molecule is grayed out to show that it is deselected 3 Position the Select Molecule tool over the second molecule you want to select 4 Continue to
167. and the MechanicsManager both of which are located in the Mechanics folder in cache bin Optimizing with Mechanics Mechanics can be used in a variety of ways to help you find low energy conformations of your structure When you use the fastest procedure or MM geometry procedures Mechanics starts with the molecular structure in your chemical sample file After calculating the structure s potential energy Mechanics adjusts the atomic positions and calculates the potential energy of the new structure 1 N J BioMedCAChe User Guide Allinger N L and others J Am Chem Soc 1977 99 8127 Allinger L Yuh Y H Lii J H J Am Chem Soc 1989 111 8551 8566 Bowen P and Shim J Y J Comp Chem 1998 19 1370 1386 20 3 D i s n i D Chapter 20 CAChe Computational Applications Mechanics then moves the atoms and calculates the energy until the energy reaches a minimum and moving the atoms no longer decreases the energy Mechanics continues optimizing until the energy change between iterations is within a specified limit or until reaching the specified number of iterations The direction and distance that atoms move between iterations depends on the slope of the potential energy surface Normally optimizing is the next step after you create a molecule in the workspace and before proceeding to other computations Most CAChe experimental procedures begin with opt
168. angle Because bump labeling is based on a distance criterion labels may appear in unexpected locations if your structure is poorly refined A large number of bump labels can indicate a structure requiring further refinement CAChe for Windows User Guide Locking geometry labels Locking geometry labels Locking geometry labels allows you to freeze an atom distance bond angle dihedral angle or improper torsion angle at a specified value ensuring that the locked portions of your chemical sample do not change during an experiment Lock geometry labels in one of two ways e lock a label while defining the geometry label using the Set Atom Distance Set Bond Angle or Set Improper Torsion dialog box e lock an existing geometry label directly from the Adjust menu To lock a geometry label while defining it 1 Select the required number of atoms for the distance or angle you want to label by clicking on the first atom with the Select tool then holding down the Shift key and clicking on the remaining atoms For example select two atoms if you want to create and lock a label for an atom distance three atoms if you want to create and lock a label for a bond angle or four atoms if you want to create and lock a label for an improper torsion or dihedral angle 2 Choose one of the following menu options o Adjust Atom Distance o Adjust Bond Angle o Adjust Improper Torsion o Adjust Dihedral Angle The Set Ato
169. anine In the gas phase MOPAC predicts that neutral alanine H2N CH2 CH2 COOH is more stable than the zwitterionic form H3N CH2 CH2 COO When COSMO is used to model the solvent effects the zwitterion is correctly predicted to be more stable Because COSMO includes solvent effects for energy gradients as well as energy it is applicable to all types of MOPAC calculations However because COSMO requires a considerable amount of computation it should not be used unless solvent effects are important Because of extra memory usage calculations that use COSMO cannot handle as many atoms as those that do not use it The practical limit depends upon computer speed and memory but for most computers the practical limit is approximately 200 atoms MOPAC contains a patented method called MOZYME that alters the way in which the electronic structure is calculated As a result calculations on large chemical systems require on a small fraction of the memory needed for a conventional calculation and run very much faster MOZYME can be used for simple geometric calculations such as geometry optimization and transition state location and for the calculation of polarizability There are limitations when this option is used e Only closed shell RHF calculations are allowed Thus large molecule calculations are limited to chemical samples in their ground state Radicals electronic excited states cannot be run The results are not so precise F
170. ap from the following experiments e rigid energy map energy map e optimized energy map energy map sequence of conformations seqsrch map e dynamics trajectory dynamics map e reaction path ircl map irc 1 map drcl map drc 1 map Refer to Chapter 17 Investigating Reactions for details about reaction paths Map files are also called assemblage files because they are an assemblage of structure energy pairs Map files enable you to visualize the relationships between sample conformations and their energy plotted in a two or three dimensional graph Energy maps are generated by varying specified coordinates of your molecule to create a series of conformations The energy of each conformation is plotted in a two or three dimensional graph so that you can easily locate low energy conformations separated by high energy barriers This makes it possible to locate a global rather than a local energy minimum for the molecule CAChe allows you to e view and manipulate each conformation of your molecule beside the energy graph CAChe for Windows User Guide Generating energy maps e view the corresponding conformation for any point on the graph and vice versa e animate the conformations so that you can view each structure generated while the energy map displays the graph location of each conformation CAChe generates the following types of energy maps e rigid or optimized energy maps energy map
171. appears in a yellow ToolTip and a line of help appears in the lower left border of the window CAChe for Windows User Guide 5 3 Chapter 5 Modifying Chemical Samples When you select a tool the mouse cursor in the workspace changes shape to indicate which tool is currently selected Alternatively you may choose the tool from the popup menu that appears when you press right mouse button in the 3D Structure Window Select Molecule Select Similar Select Group Drawing Pencil Clicking the right mouse button in the Workspace pops up this menu Rotate Move Magnify Fit Beautify Comprehensive Move Selected The table below displays the selection tools as they appear in the tool palette and their corresponding cursors Selection tool Tool palette icon Mouse cursor the Select tool default N the Select Molecule tool e the Select Similar tool e the Select Group tool General rules for the selection tools Mm p RE Re The following methods of selecting and deselecting workspace objects apply to all four selection tools 5 4 CAChe for Windows User Guide Selecting workspace objects Selecting one object e clicking on an object selects it For example click on an atom with the Select tool to select the atom or click on a molecule with the Select Molecule tool to select the molecule Selecting an atom with the Select Molecule tool will select all the atoms in the mo
172. are the fastest and usually give good results You can optimize a molecule to discover low energy structures e transition state structures which can also be determined by investigating reaction properties Heat of formation Calculates the energy of a chemical sample at a geometry optimized energy minimum CAChe for Windows User Guide 10 5 Chapter 10 Performing Workspace Experiments 10 6 NOTE IR transitions Generates an infrared IR spectra for a molecule created by coordinated motions of the atoms as electromagnetic radiation in the infrared region is absorbed by the molecule UV visible transitions Generates a UV visible spectrum for a molecule created by electron transition between molecular orbitals as electromagnetic radiation in the visible and ultraviolet UV visible region is absorbed by the molecule UV visible spectra can be generated only if you have the optional VAMP add on Current energy Calculates the energy of the chemical sample at its existing geometry The geometry of the sample is not changed by this experiment Electron density Generates an electron density isosurface for an electron probability density of 0 01 e A gt The surface is colored to reflect the electrostatic potential at every point on the surface HOMO and LUMO Calculates the energies and shapes of the HOMO and LUMO of your chemical sample using a quantum mechanical application HOMO S to LUMO 4
173. arge as long as you have run a partial charge experiment on your chemical sample first e atom number displays the CAChe atom number CAChe assigns a unique number to each atom and numbering is in the same order that you added the atoms to the workspace 6 8 CAChe for Windows User Guide Changing the appearance of atoms If you delete an atom from your chemical sample the associated atom number is also deleted creating a gap in the sequential order of atom numbers The deleted atom s number is assigned to the next atom you add to the workspace e chirality for asym carbons indicates which asymmetric carbon atoms are chiral centers e g R or S e locked state indicates whether the atom is locked L and whether the lock is broken LB The following example shows a molecule s atoms displaying atom symbol hybridization and atom number labels H 8 H s 10 H 9 5 faa a 2 H 9 H 6 H7 CAChe for Windows User Guide 6 9 Chapter 6 Viewing Chemical Samples 4 To change atom labeling 1 Select the atoms for which you want to display labels by clicking on the atoms with a selection tool Choose View Atom Attributes to display the Atom Attributes dialog box Atom Attributes 2x Type Color Shape Label I Atomic Symbol T Hybridization M Charge J Partial Charge M Ate I Chirality for Asymmetric Carbons I Locked State I Alphanumeric Label T Name I
174. ary structure option from the secondary structure drop down in the style bar at the top of the Sequence View window The Phi and Psi angles are set to the values for the secondary structure and the residue geometry is changed to the new values To adjust Phi and Psi angles 1 Use the Select tool to select the residue you want to adjust k The selected residue is highlighted If the workspace is open on this structure the atoms belonging to the selected residue are highlighted in the workspace 2 Type the new angles into the Phi or Psi boxes in the style bar at the top of the Sequence View window The residue geometry is changed BioMedCAChe User Guide 9 37 Chapter 9 Manipulating Biomolecules NOTE When you change the Psi and Phi angles of a residue there can be large global effects on the protein 9 38 BioMedCAChe User Guide Comparing biomolecules Comparing biomolecules Aligning sequences You can compare sequences to discover similarities in their structure and thus their function To do so you can align sequences by placing gaps in the sequences To align a sequence automatically 1 Open the sequences of two or more chemical samples as described in Viewing sequence residues p 9 18 2 From the Sequence View window choose Edit Align The Align Sequence dialog appears Align Sequence 21x m Select Two Sequences Sequencel Sequence2 1A9T MEO Cancel
175. as Cony2d3d exe available from CAChe Concord or Corina to convert the 2D file into a 3D file before importing it into CAChe When a Chemical Sample file is added to a worksheet you have the option to display it either as a line drawing or by name Line drawings are displayed by default and have the advantage that you can enlarge them in order to view the details more clearly lt t gt Refer to Changing workbook display options p 12 33 for details of changing the chemical sample display Using the CAChe Workspace from a worksheet ProjectLeader allows you to view a chemical sample in the CAChe Workspace by selecting the sample from a ProjectLeader worksheet You can also open the Workspace and create a new Chemical Sample file Displaying the CAChe Workspace 12 14 To open an existing Chemical Sample file in the Workspace 1 2 Hold down Shift and click on a chemical sample in the ProjectLeader worksheet The Workspace is opened displaying the selected Chemical Sample file The selected worksheet cell in ProjectLeader is colored pink to indicate that the corresponding Chemical Sample file is currently displayed in the Workspace Edit the chemical sample in the Workspace and save the file The changes are displayed in the worksheet cell in BioMedCAChe User Guide Adding chemical samples ProjectLeader To add a new Chemical Sample file to a ProjectLeader worksheet 1 Hold down Shift and clic
176. asics introduces the CAChe interface and describes how to use interface components such as menu options toolbar buttons and dialog boxes This part also describes the tools in the CAChe workspace which you use to build and manipulate a molecule Using CAChe describes in detail how to use CAChe to draw and manipulate a molecule display a molecule in different ways measure molecular geometry and perform experiments on a sample to investigate low energy or transition state structures and to discover various electronic properties Understanding CAChe contains a detailed explanation of the computational applications in CAChe and the difference between these applications in their approach to experiments on chemical samples BioMedCAChe User Guide About this user guide Appendices The appendices list keyboard shortcuts toolbar button functions and the files that are added to your computer when you install your BioMedCAChe product S Index E gei 2 There is a fully comprehensive index of the BioMedCAChe User Guide at the end of the manual BioMedCAChe User Guide Chapter I Introduction to the User Guide Conventions in this user guide Text styles Icons NOTE TIP A lt gt 1 6 Before using this user guide you should be familiar with the following Different text styles are used throughout this user guide in order to emphasize the following Items on the interface that you need to select such as bu
177. ate Select Server to display the Select Server dialog box 2 Select a server by clicking on it then select OK You can find out which server is currently selected by choosing Evaluate Show Server To select cells 1 Select one or more cells to include in the experiment where the row of the cell corresponds to the chemical sample on which you want to experiment and the column of the cell corresponds to the property or analysis that you want to investigate or perform Use one of the following to select the cells a To select a group of adjacent cells click and drag the mouse over the cells a To select one or more non adjacent cells hold down the Ctrl key and click on the cells BioMedCAChe User Guide Running a ProjectLeader experiment a To select a whole column click on the relevant lettered column button a To select a whole row click on the relevant numbered row button a To select the whole worksheet click on the worksheet button or choose Edit Select All The cells are highlighted in black to show that they are selected Evaluating the cells To evaluate the selected cells 1 To evaluate selected cells do one of the following a choose Evaluate Cell a press the right mouse button and choose Evaluate Cell from the popup menu Individual cells display the status of the calculations being performed then the results as calculations are completed TIP You can stop a lengthy evalu
178. ation x Using all atoms is The number of atoms of all elements present in the chemical a sample x Example of an Experiment dialog box The currently selected procedure is displayed in the Using box and a description of the procedure is displayed in the box underneath Select the down arrow to scroll to the bottom of the description where a number is displayed The last two digits of the four digit number display the procedure number for the selected procedure For example the procedure number of the example shown in the example dialog box earlier is 12 Refer to Running an experiment p 10 18 for details about how to use the Experiment dialog box The following table lists the different procedures and the computational applications involved in each procedure The fastest quantum mechanical procedure for chemical sample atom and bond properties is usually procedure 3 CAChe for Windows User Guide Setting up a workspace experiment CAChe for Windows User Guide The most accurate quantum mechanical procedure for chemical sample atom and bond properties is usually procedure 8 although depending on your sample 7 or 9 may yield better results To model your sample in water choose procedures 4 5 10 11 14 15 18 or 19 To model transition state geometries choose procedures 16 17 18 or 19 To generate additional surfaces for a chemical sample when an experiment that uses one of the p
179. ation by choosing Evaluate Stop Cell Evaluation Parallel cell evaluation Where two or more columns of cells are to be evaluated ProjectLeader checks to see whether the individual cell evaluations correspond to the same named procedure running on the same chemical sample If so the experiment is run only once so that analyses are calculated on the same chemical state of the chemical sample BioMedCAChe User Guide 12 25 Chapter 12 Using ProjectLeader Editing data You can cut copy and paste selected data in ProjectLeader and you can insert or delete selected columns or rows The following actions can be chosen from the Edit menu Cut Copy Paste Clear Delete Insert to remove selected cells from the worksheet to copy selected cells to the Windows Clipboard to insert copied data into selected cells Any existing data in the cells is overwritten to clear the data in selected cells to delete selected columns or rows from the worksheet Any adjacent columns or rows in the worksheet move correspondingly to insert columns or rows before the selected column or row Any adjacent columns or rows move correspondingly NOTE If you attempt to delete cells in a ProjectLeader worksheet that provide the source of information for other cells a warning will be displayed For example deleting a sample component column in a worksheet where a property of sample component column exists will disallow
180. ation or unsatisfied valence Do you want to highlight them instead of saving 4 Do one of the following o Select Yes to highlight atoms with non standard hybridization or unsatisfied valence o Select No to save the chemical sample file without highlighting atoms with non standard hybridization or unsatisfied valence o Select Cancel to close the alert box 6 50 CAChe for Windows User Guide Saving settings Saving settings When you change the display styles for atoms and bonds the changes only apply to selected objects in the active workspace unless you specify that you want to make that display style a default setting Once you have made a display style the default any new atoms or bonds added to an existing chemical sample file or to anew chemical sample file will be displayed in the new default style NOTE When you change default settings those default settings will not apply to display styles for atoms and bonds in chemical sample files that you have already saved Default settings only apply to atoms and bonds you draw after changing the default settings Changing settings using menu options The following settings become default settings as soon as you change them e View Suppress Hydrogens e View Show Electrons A en 4 gt Refer to Hiding atoms p 6 18 and Changing the appearance of atoms p 6 8 for information on these View menu options e Options Use Faster Motion
181. atoms are matched or all of the target atoms are matched The number of atoms in the probe group and the target group can be different Left over atoms at the end are not included in the superposition 4 Select one group from each molecule Superimpose 2 x r Select Probe and Target Probe Atom Group Target Atom Group CHEMICALSAMPLE2 CHEMICALSAMPLE2 E e Probe Eee Probe e C380 CA Ele C360 CA e C3198 CA e C336 CA e C2116 CA ee Target C2100 CA I Show Residues r Superposition options Supetimpose Probe onto Target Replace Target with Probe Superimpose Target and Probe in New Window OK Cancel 5 Choose the Superimpose Option and press OK The molecule that contains the probe group moves to overlap the target group in the other molecule The selected atoms are highlighted to show that they are still selected An RMS error is displayed which indicates the error in molecular geometry between the two structures 6 Do one of the following to move the molecules apart again o Choose Edit Undo There is no undo if molecules were superimposed in a new window o Press Ctrl Z o Select one molecule by clicking on it with the Select Molecule tool and click and drag to move the selected molecule to one side CAChe for Windows User Guide 8 9 Chapter 8 Investigating Molecular Geometry TIP To superimpose multiple molecules in a single window repeatedly superimpose new probes aga
182. aximum of three or four search labels to one molecule Generating an optimized energy map with quantum mechanics 14 8 NOTE Quantum mechanical procedures measure the heat of formation of each conformation of a molecule formed by varying the search labels Each conformation is then optimized by measuring the presence and positions of electrons based on the Schr dinger equation The heat of formation of each optimized conformation is then plotted in an energy graph You are limited to a maximum of two search labels in your molecule If you use one search label the result is a reaction coordinate search If you use two search labels the result is a grid search Energy maps generated using quantum mechanics are useful for mapping bond breaking and bond formation in a molecule You cannot generate an optimized energy map using quantum mechanics in Personal CAChe or BioCAChe CAChe for Windows User Guide Generating energy maps Investigating water solvent effects You can include water solvent effects in rigid or optimized energy map experiments and map reaction experiments lt t gt Refer to Modeling solvent effects with COSMO p 20 19 for more information on experimental procedures that include solvation effects Generating a sequence of conformations A sequence of conformations or sequential search is similar to an optimized map but offers a faster method to arrive at purely low energy conformations
183. bel 1 From two molecules in the workspace select a corresponding atom from each both of which are defined within a group 2 Choose Analyze Calculate RMS Error to display an RMS error label 3 Use the Select Group tool to select the RMS error label The atoms in the groups used for the calculation are selected Finding workspace objects Select chemical sample atoms bonds and groups by property using the Find menu item To find objects with specific properties 1 From either the workspace or the Sample Properties view choose Edit Find to display the Find dialog box Seah ioe hms o Equals b I Look in selection only Add to selection r Display options I Show selection only J Zoom to selection Cancel 2 Choose the atoms bonds or groups from the Search for drop down menu 3 Choose the property from the Where drop down menu The properties listed are those available in the chemical sample for the chosen object They are listed in alphabetic order Different molecules may have different properties available for searching 5 14 CAChe for Windows User Guide Selecting workspace objects 4 Choose the search criteria The criteria in the list depend upon the type of property Criteria available for strings names integers and real numbers are different Strings Is Is not Contains Does not contain Names Zs Is not Integers Equals Not equals Is less than
184. cal Samples Chapter 6 Viewing Chemical Samples Chapter 7 Manipulating Molecules Chapter 8 Investigating Molecular Geometry Chapter 9 Manipulating Biomolecules Chapter 10 Performing Workspace Experiments Chapter 11 Using the Procedure Editor Chapter 12 Using ProjectLeader The following chapters describe details of the different experiments in CAChe Chapter 13 Optimization and Energy Calculations Chapter 14 Investigating Low energy Conformations Chapter 15 Investigating Electron Distribution Chapter 16 Investigating Atom and Bond Properties Chapter 17 Investigating Reactions Chapter 18 Investigating Spectra Chapter 19 Investigating Biomolecules 4 Creating Chemical Samples Overview This chapter explains how to create a molecule using the tools and menu options of the CAChe workspace This chapter describes how to e draw the atoms and bonds of your molecule in the workspace correct the geometry valence and hybridization of the resulting structure e save all CAChe files e print CAChe files and set up print options for CAChe Contents Working with chemical sample files 4 2 Correcting geometry 4 14 Opening a new chemical sample file 4 2 Correcting hydrogen bond geometry 4 14 Opening an existing chemical sample file 4 3 The Comprehensive command 4 15 Drawing a molecule in the workspace 4
185. cal data first a select Text only to sort only textual data 8 If required do one of the following in the Text Handling panel a select Case sensitive to sort textual data so that capitals have a higher priority a select Case insensitive to sort textual data regardless of case 9 Select OK to accept the changes and to close the Sort dialog box The data in the column is sorted according to your preferences TIP Press the right mouse button and select Sort Ascending to sort rows from A to Z or in numeric order Press the right mouse button and select Sort Descending to sort rows from Z to A or in reverse numeric order Changing the grid line display To change the grid line display Choose one of the following a View Grid Line None a View Grid Line Dotted a View Grid Line Gray a View Grid Line Solid The grid lines in the worksheet change to the selected style BioMedCAChe User Guide 12 35 Chapter 12 Using ProjectLeader Changing the text display To display text in a different font size or type 1 Select the cells containing the text you want to change 2 Choose Format Font to display the Font dialog box 3 Select the Font Font style and Size from the scrolling lists or edit the text box directly 4 Select OK to apply the changes and to close the Font dialog box NS To change text alignment 1 Select the cells containing the text you want to change then choose
186. ce Protocol 3 Choose the Method lt t gt Method details are explained in Chapter Understanding Y ape Sequence Property Predictions The method window specifies the number of adjacent residues that are grouped together for analysis For example a window of 17 will result in the sequence being analyzed in blocks of 17 9 28 BioMedCAChe User Guide Working in the Sequence View window residues to determine properties such as the antigenicity or hydropathy A coloring legend showing the resulting color scheme displays in the bottom half of the dialog box For example if you color by sequence protocol you see this dialog Residue Colors Scheme Residue Type CGF Sequence Protocol None Antigenicity Hopp and Woods Hydrophilicity Index Color Codes Color Band 4 Click Apply to color all residues in the sequence view without closing the dialog Click OK to color all residues and close the dialog For some residues and some types of properties the property value cannot be determined because the sequence may be too short Residues for which the property cannot be determined are colored white To display the property legend 1 Inthe Sequence View window choose View Property Legend The Property Legend is available when residues are colored by sequence protocol and the residues have different colors Wrapping and hiding sequences To wrap sequences 1 Check Format Wrap Lin
187. cedures that include INDO 1 calculations are limited to 200 atoms and 700 basis functions where a basis function is equivalent to a valence atomic orbital For example carbon has four basis functions one 2s and three 2p All other procedures are simply limited by the availability of memory The elements contained within your chemical sample file may limit your choice of procedures Procedures that use the computational applications ExtHiickel or Mechanics accept all elements NOTE Procedures that use AM1 PM3 PM5 or INDO 1 parameters are not available with Personal CAChe or BioCAChe CAChe for Windows User Guide 10 31 Chapter 10 Performing Workspace Experiments Troubleshooting experiments This section outlines problems that you may encounter while trying to run CAChe experiments Reattempting output file generation 10 32 Occasionally when an experiment is returning output files your disk may fill up and the experiment will report an error because the output files cannot be saved CAChe enables you to make more disk space available and then continue to generate and save the output files You can reattempt to generate output files from the following dialog boxes e the Experiment Status dialog box displayed automatically while an experiment is running e the Experiments Submitted dialog box displayed by choosing Experiment Show Submitted Experiments To reattempt output file generation from the Ex
188. ceptors e g gt C O within 3 0A The blue areas map regions of the protein where there are hydrogen bond donors e g OH or NH gt more than 3 0A from a carbonyl oxygen and less than 2 6A from a hetero hydrogen XH The rest of the surface is colored cream and that indicates hydrophobic regions of the protein BioMedCAChe User Guide Viewing biomolecules To hide the protein accessible surface 1 Choose Analyze Show Surfaces The Show Surfaces dialog appears Show Surfaces 2 x Displayed surfaces wv accessiblel ast Cancel 2 Uncheck the asf surface and choose OK The dialog closes and the surface disappears To delete the protein accessible surface 1 With the protein accessible surface displayed click on the asf surface label Both the surface label and the surface highlight all other objects dim 2 Choose Edit Delete The surface and its label disappear from the screen and are removed from the chemical sample file However the surface asf files remain in the iso folder You delete asf files with the Windows Explorer after they have been deleted from the chemical sample To display the crevice surface 1 With the Select Molecule Tool in the 3D Structure Window select the protein NOTE The protein must have hydrogen atoms added first The protein highlights and all other objects dim BioMedCAChe User Guide 9 13 Chapter 9 Manipulating Biomolecules
189. ces 15 18 You can choose whether to display surfaces as shaded three dimensional surfaces e dotted three dimensional surfaces wireframe three dimensional surfaces e labeled or unlabeled CAChe for Windows User Guide Viewing a surface Viewing shaded surfaces When viewing surfaces as shaded and solid you have the option of viewing the front of the surface only which displays the portion of the surface facing you the back of the surface only which displays the back of the surface as a shell in which the molecule is floating Displaying surfaces as shaded is the default view option To display shaded surfaces 1 Select a surface by clicking on its label with the Select tool 2 Choose Analyze Surface Attributes to display the Surface Attributes dialog box Surface Attributes 24x Shaded gt t Wireframe M Show Front I lt 7 Plane T Show Back ennes l V YZ Plane Cancel ME Dotted l WF XZ Plane Jot Intensity 110 Make Default T Display Surfaces IV Show Label 3 Select the Shaded radio button so that it is enabled 4 Do one of the following a To display the front of the surface select the Show Front check box so that it is enabled a To display the back of the surface select the Show Back check box so that it is enabled 5 Select OK to view the selected surface as the front or back of a solid shaded surface and to close the Surface Attributes dialog box CAChe f
190. ces dialog box The selected surface is no longer displayed in the workspace NS To hide all surfaces 1 Choose Analyze Surface Attributes to display the Surface Attributes dialog box Surface Attributes 21x i m C Wireframe M Show Front r Re I Show Back J VM Yz Plan Cancel C Dotted j M ZPre Sariater p 4 Make Defaut Joe n I Display Surfaces IV Show Label 2 Select the Display Surfaces check box so that it is disabled 3 Select OK to hide all surfaces in the chemical sample file and to close the Surface Attributes dialog box Surfaces are no longer displayed in the workspace Interpreting surface color Electron density susceptibility and superdelocalizability experiments all generate electron density isosurfaces with colors representing a second chemical property The transition from one color to another occurs at a threshold value You can view the actual value associated with each color transition for a surface as described in the next section Viewing color threshold values The use of color in other surface experiments such as investigating electrostatic potential and generating molecular orbitals is explained in the section CAChe color tables p 15 13 CAChe for Windows User Guide 15 11 Chapter 15 Investigating Electron Distribution Viewing color threshold values NS To view values associated with surface color thresholds 1 Select a surface by clicking on its label wi
191. ch and Christian Sander Dictionary of Protein Secondary Structure Pattern Recognition of Hydrogen Bonded and Geometrical Features Biopolymers 1983 22 2577 2637 21 4 BioMedCAChe User Guide Understanding Protein Secondary Structure Definition This method is the standard method used by the Protein Data Bank for automatic verification and validation of HELIX and SHEET records Secondary structure is displayed with 1 letter codes shown in the following table Secondary Structrue Codes Description H Residue is in 4 helix B Residue is in isolated beta bridge E Residue is in extended strand or participates in beta ladder G Residue is in 3 helix I Residue is in 5 helix T H bonded turn BioMedCAChe User Guide D gt 5 i s 2 D i D Chapter 21 CAChe BioComputations Understanding Dihedral Angles for Building Peptides This section provides reference information about the way CAChe builds peptides 3D structure concepts The shape of proteins and peptides is determined largely by the dihedral angles of the backbone The backbone is defined by PDB atom names For proteins the backbone consists of atoms named N CA and C Predefined dihedral angles for regular polypeptide conformations CAChe uses predefined dihedral angles for protein conformations The angles are from G N Ramachandran and V Sasisekharan Adv Protein Chem 1968 23 283
192. chanical methods CAChe for Windows User Guide 10 7 Chapter 10 Performing Workspace Experiments Chemical sample conformation properties Choose from the following properties for a chemical sample conformation Rigid map Generates a potential energy map of conformations determined by geometry search labels in the sample for each structural element you want to vary with structures for each map point not optimized Optimized map Generates a potential energy map of conformations determined by geometry search labels in the sample for each structural element you want to vary with structures for each map point optimized Sequence of conformations Generates a collection of low energy conformations by sequentially searching an unlimited number of geometry labels The resulting map file contains local energy minima but does not offer information about the energy barriers between them Dynamics trajectory Generates a trajectory of a chemical sample in random thermal motion by randomly adding kinetic energy to each atom Motion is induced that can overcome small barriers to lower energy structures Reaction and transition state properties 10 8 Map reaction Creates a transition state structure from a reactant and a product molecule of a chemical reaction Search for saddle Locates a stationary point between the reactant and product that corresponds to the transition state for the reaction CAChe for Windows Use
193. ck the outer shell of oxygen atoms The outer most atoms are locked To display the locked state choose View Atom Attributes and check Locked State on the Label tab In the workspace choose Edit Select All and then choose Beautify Comprehensive to add hydrogen atoms and set the hybridization You now have a sphere of 515 water molecules 1545 atoms all oriented in the same direction Choose Beautify H Bonds CAChe for Windows User Guide Investigating peptide conformations 20 21 The hydrogen atoms are rotated so that the local hydrogen bonding is maximized This is a partial optimization of the hydrogen bonding To further optimize the hydrogen bonding you use Mechanics Since you will be using this droplet to solvate molecules it will be convenient to have the atoms grouped into a single group Choose Edit Select All and then Edit Group Atoms Type a name for the group such as 11A water drop and choose Group and then OK All water molecules are now part of the same group named 11A water drop To optimize the structure choose Experiment New save the file and then choose a Property of chemical sample a Property optimized geometry and a Using MM geometry MM3 Choose Start The water droplet is optimized within the sphere of frozen oxygen atoms You can use this droplet to add water molecules to your peptide To solvate the peptide 1 CAChe for Windows User Gui
194. ctory for the component Select the Save button to export the component and to close the dialog box A lt t gt Refer to Importing a CAChe experiment p 11 28 for details about importing environment components CAChe for Windows User Guide 11 37 Chapter 11 Using the Procedure Editor Quitting the Procedure Editor 11 38 NS To quit the Procedure Editor 1 Choose File Exit If you have any unsaved changes in the displayed experiment environment an alert box asks if you would like to save changes Do one of the following a Select Yes to save the changes and exit the Procedure Editor a Select No to exit the Procedure Editor without saving the changes a Select Cancel to keep the Procedure Editor running CAChe for Windows User Guide 12 Using ProjectLeader ProjectLeader is a component of CAChe that is used to automate the calculation of properties and to perform analyses on multiple chemical This chapter describes how you can use ProjectLeader to e perform experiments on chemical samples or on components of chemical samples such as atoms and bonds e carry out statistical analyses and evaluate equations e plot scatter plots of the results of experiments and analyses Refer to Chapter 10 Performing Workspace Experiments for an overview of performing experiments in the CAChe workspace and Workspace versus ProjectLeader p 2 21 for a comparison Overvie
195. cts an entire molecule or sequence chain in a protein e the Select Similar tool which selects all residues of a similar type Choose a tool by clicking on it in the tool palette When you choose a tool the mouse cursor in the workspace changes shape to indicate which tool is currently selected The table below displays the selection tools as they appear in the tool palette and their corresponding cursors Selection tool Tool palette icon Mouse cursor the Select tool default N the Select Molecule Chain tool h e the Select Similar tool N 9 24 BioMedCAChe User Guide Working in the Sequence View window The Residue tool Use the residue tool to edit residue sequences in the sequence window Editing Tool Tool palette icon Mouse cursor e the Residue tool TR Ir R With the residue tool you may type residues in a sequence You must specify secondary structure type and Phi and Psi angles first before typing a residue Changing the sequence style NS To view 3 letter codes 1 Choose View 3 letter Code to display 3 letter codes for all sequences The 3 letter Code menu item is checked NS To view 1 letter codes 1 Choose View 1 letter Code to display 1 letter codes for all sequences The 1 letter Code menu item is checked BioMedCAChe User Guide 9 25 Chapter 9 Manipulating Biomolecules The codes for the residues are listed in the table Residue 1 letter 3 letter code Alanine A
196. ctures are sampled and the vertical axis represents the energy of the resulting conformation CAChe for Windows User Guide Generating energy maps Low energy structures in a trajectory map are not truly energy minima These structures are good starting points for a geometry optimization which leads to a more accurate minimum energy geometry NOTE You cannot generate a dynamics trajectory in Personal CAChe CAChe for Windows User Guide 14 11 Chapter 14 Investigating Low energy Conformations Viewing map files When you open a map file two windows open side by side as shown in the following example Graph window Conformation window Pe Sea Se ee La EGG TESS eee eee _ Oo x a Tool ag a q palette Parameter Ki bar DinedratAnalet x jaooo degree To open a map file Choose File Open to display the Open dialog box 2 Double click on the Cache folder to open it Click and drag on the scroll bar of the scrolling list to locate the map folder belonging to the relevant chemical sample file and double click on the map folder to open it 4 Select the arrow button in the Files of type box and choose Map map from the drop down list 5 Double click on the required map file to open it Map file windows The structure displayed in the right window the conformation window is the lowest energy conformation of all the structures generated by the experiment Its energy value is disp
197. cursor in the workspace 1 When the cursor exists in 3D in the workspace choose Options 3D Cursor The cursor is displayed in 2D in the workspace and the check mark next to the 3D Cursor drop down list option is no longer displayed Manipulating document windows View all open CAChe document windows at the same time using the Windows Tile and Cascade options You can also arrange minimized windows using the Windows Arrange Icons option To arrange windows to overlap in a cascading pattern 1 Choose Window Cascade All open CAChe document windows are opened in a cascading pattern so that you can view the title bar of each window To arrange windows side by side 1 Choose Window Tile All open CAChe document windows are arranged side by side so that you can view the title bar and a portion of the contents of each window S To arrange minimized windows 1 Choose Window Arrange Icons All minimized CAChe windows those made into an icon are arranged along the bottom of the main CAChe application window 3 16 BioMedCAChe User Guide Using CAChe Using CAChe The following section explains terms used throughout this User Guide and provides instructions on using the components of the CAChe interface Using the mouse The following terms are used in this User Guide to describe mouse actions Select Select the following items in CAChe e dialog box buttons check boxes e radio buttons e
198. dard amino acid in a PDB file 9 26 Creating and adding a nonstandard amino Numbering sequences 9 27 acid with the Workspace Coloring sequences by properties 9 28 9 29 9 31 9 31 9 32 9 33 9 33 9 34 9 34 9 35 9 37 9 39 9 39 9 40 9 41 9 42 9 44 9 45 9 45 9 47 Chapter 9 Manipulating Biomolecules Viewing biomolecules 9 2 To view biomolecules contained in CAChe chemical sample files simply open them as you would any other molecule In addition to viewing biomolecules that are contained in chemical sample files CAChe can view biomolecules from structural databases like the Protein Data Bank maintained by the Research Collaboratory for Structural Bioinformatics RCSB The structures of proteins and other biomolecules can be downloaded from http www rcsb org pdb as PDB files PDB files have an extension of pdb or ent To view the 3D structure contained in a PDB file you simply open it in the CAChe workspace To open a PDB file 1 Choose File Open to display the Open dialog box Open Look in ja CAChe cl Ea i App 28 phenol Bin FragmentLibrary Procs A Xlators 2 benzenet 2 isoprene Fiename Files of type Chemical Sample csf Cancel I Open as read only Help 2 Select the arrow button in the Look in drop down box to display a drop down list of o folders in the directory structure above the currently open folder o available driv
199. de With both the water droplet and peptide open choose Edit Copy from the peptide workspace In the water droplet workspace choose Edit Paste The peptide appears in the center of the water droplet To reorient the peptide to a different position choose Edit Move Selected and rotate or drag to peptide to the position you prefer Notice that some water molecules overlap the structure You need to remove them To remove overlapping water molecules use the Select Molecule tool to select the peptide Then choose Edit Select Neighbors and Select Nearest Residues waters HETs within 2 angstroms 19 13 Chapter 19 Investigating Biomolecules 19 14 10 All waters residues and HET groups within 2 angstroms of the selected peptide atoms are selected Using the Select Molecule tool hold down the shift key while clicking on the peptide to deselect the peptide The peptide dims and all water atoms near the peptide remain highlighted Choose Edit Delete Water molecules that overlap the peptide are deleted Choose File Save As to save the model using a different name To complete the model you optimize the solvated peptide Choose Experiment New The Experiment dialog appears Choose a Property of chemical sample a Property optimized geometry and a Using MM Geometry MM3 Choose Start A calculation that optimizes the geometry of the peptide within the water sphere of 11 angstrom radi
200. ded However the information required for molecular modeling must still be added for example hydrogen atoms and atom hybridization To prepare a PDB molecule for molecular modeling BioMedCAChe User Guide 9 5 Chapter 9 Manipulating Biomolecules Saving a PDB molecule 1 Choose Edit Select All 2 Choose Beautify Valence Hydrogen atoms and electrons are added If atoms do not have hybridization or electrons then hybridization and electrons are added Only the geometry of hydrogen atoms and the hybridization and electrons around atoms that do not have hybridization already assigned are changed with these commands As you work with this chemical sample you may add additional information that you want to save NS To save a PDB molecule Displaying proteins 1 Select File Save When you save this workspace you can chose to save it as a chemical sample file cs a PDB file or other file type Save the workspace as a chemical sample file cs to preserve all of the information you have added Otherwise information such as rendering style and computed atom properties will be lost You can display 3D structures from PDB files using the display options described in Chapter 6 Refer to Chapter 6 Viewing Chemical Samples for details about display options for chemical samples In addition you can e view PDB atom names highlight residues color the protein by residue property e d
201. default with up to nine digits after a decimal point e footnotes column buttons and row buttons can be displayed or hidden Changing the chemical sample display By default the ProjectLeader workbook displays chemical samples as line drawings However you can choose to display the names of the chemical samples instead Individual line drawings can be scaled in the workbook so that you can view the molecular structure more clearly To display or hide a chemical sample 1 Select a chemical sample by clicking on it in the Chemical Sample column The cell is highlighted in black to show that it is selected 2 Choose Format Structure to enable or disable the structure view A check mark is displayed next to the menu option if it is enabled When it is enabled the chemical samples are displayed as line drawings When it is disabled the chemical samples are BioMedCAChe User Guide 12 33 Chapter 12 Using ProjectLeader displayed as names NS To scale a structure line drawing in a worksheet 1 Position the cursor at the bottom of the row button adjacent to the line drawing that you want to scale The cursor changes into a crosshair shape 2 Click and drag downwards to increase the depth of the row The adjacent molecular line drawing increases in size in proportion to the row button 3 Position the cursor to the right of the column button A The cursor changes into a crosshair shape 4 Click and drag t
202. dialog box The geometry label you selected is no longer displayed in the workspace Labeling H Bonds To label hydrogen bonds within a selection and between the selected atoms and the set of visible and unselected atoms do the following To label all hydrogen bonds 1 Select the atoms whose hydrogen bonds you wish to label with the Selection tool the Select molecule tool or the Select Group tool 2 Choose Analyze Label H Bonds Blue hydrogen bond labels are created between any selected hydrogen bonded atom and any visible atom it is hydrogen bonded to In this analysis hydrogen bonds are formed between any hydrogen atom attached to O N S or F and all O N or S hydrogen acceptors that are within 2 2 A Because H bond labeling is based on a distance criterion H bond labels may appear in unexpected locations if your structure is poorly refined CAChe for Windows User Guide 8 27 Chapter 8 Investigating Molecular Geometry Labeling Bumps 8 28 To label unselected atoms that are too close to the selected atoms do the following To label all bumps 1 Select the atoms that you wish to analyze for bumps with the Selection tool the Select molecule tool or the Select Group tool Choose Analyze Label Bumps Orange bump labels are created between any selected atom and any visible unselected atom that is within 0 87 times the sum of their van der Waals radii and that is not bonded or in the same bond
203. dialog box displayed by choosing one of the following a Experiment Show Submitted Experiments a Experiment Show Server Information To stop an experiment from the Experiment Status dialog box 1 Select Stop to display the Stop an Experiment dialog box Stop an Experiment x Stop immediately and discard output files Stop immediately and return output files Cancel Stop when convenient and return output files Help 2 Select one of the following Select the Stop immediately and discard output files radio button to stop the experiment immediately without returning any computational results Your chemical sample input file is not altered Any files that would have been overwritten by the calculation such as map documents tabulated orbital information or computational output files are untouched Select the Stop immediately and return output files radio button to return whatever results the experiment has generated up to that point This option is not recommended because it does not allow the experiment time to clean up before returning results Consequently the data returned may not be valid CAChe for Windows User Guide Running an experiment Select the Stop when convenient and return output files radio button to stop the experiment at a logical point in the calculations and save the output files This returns files just as if the experiment had completed 3 Select OK to close the S
204. disabled The parameter bar in the active window is no longer displayed Changing the variables plotted along an axis In a two dimensional graph energy is plotted on the y axis Ina three dimensional graph energy is plotted on the z axis You can change the variables plotted along any axis This is useful for displaying combinations of search label values if you generated a map with more than two search labels To change the variable plotted along any axis 1 Activate the graph window of the map file by clicking on it 2 Choose View Graph Attributes to display the Graph Attributes dialog box Analysis Settings 21x Variable Energy 7 Range E s1 72 to 47 4561 kcal mole Show minima in the lowest 50 of the range Show all minima with Value less than fi 0 kcal mole I Coalesce minima which C Show 10 incest are separated by value minima barriers smaller than fo Make Default kcal mole Cancel pE 14 16 CAChe for Windows User Guide Viewing map files 3 Select the arrow button in the X Y or Z boxes to display a drop down list of variables which you can plot along that axis 4 Choose the variable that you want to plot along the relevant axis from the X Y or Z drop down lists The drop down lists include any search labels that are not currently assigned to a graph axis These search labels are also listed at the left side of the Graph Attributes dialog box The value shown for
205. diting of cells is enabled 2 Click in a cell and type the new value When you click out of the cell the value is updated and all open workspace and sequence views are also immediately updated NOTE Editing the value of geometry labels does not alter the geometry CAChe for Windows User Guide 6 35 Chapter 6 Viewing Chemical Samples To copy cut paste and delete chemical sample properties 1 In the Chemical Properties workbook choose Edit Edit Property Values Editing of cells is enabled 2 Select a cell or information in a cell Choose one o Edit Copy o Edit Cut o Edit Paste o Edit Delete The chosen operation is performed on the selection Entire rows are selected by clicking on the row number Note that you can copy and paste between sample property worksheets between chemical samples and to and from external applications like word processors and spreadsheets 6 36 CAChe for Windows User Guide Changing view settings Changing view settings CAChe allows you to customize display attributes for workspace objects such as the color assigned to elements the color assigned to atom and bond properties workspace labeling and text and background color text and line width for general workspace labeling the perspective from which you view your chemical sample You can also specify display criteria for showing and hiding hydrogen atoms and electrons in the workspace
206. ditor and how to use it to e create a new experiment e modify the settings of an experiment e clone an existing experiment e share experiments with other CAChe users lt gt Refer to Chapter 10 Performing Workspace Experiments for an Y overview of performing experiments in the CAChe workspace Contents The Procedure Editor 11 2 Calling a procedure 11 20 Starting the Procedure Editor 11 3 Running a procedure 11 21 The Procedure Editor interface 11 4 Editing the settings of a compute engine The Navigator window 11 4 11 23 The Procedure window 11 6 Creating experiments 11 25 The Parameter Data window 11 7 Creating a new experiment 11 25 Managing the experiment environment Cloning an existing experiment 11 27 11 8 Importing a CAChe experiment 11 28 Using the tree view 11 8 Expert modification 11 30 Using the list view 11 11 Creating a group procedure package Showing properties of a component 11 13 Available properties 11 14 Modifying a procedure 11 17 Adding a step 11 19 Deleting a step 11 19 Moving a step 11 19 Viewing the settings of a step 11 20 11 31 Loading new packages 11 33 Refreshing the experiment environment 11 35 Returning to original settings 11 36 Exporting environment components 11 37 Quitting the Procedure Editor 11 38 Chapter 11 Using the Procedure Editor The Procedure Editor The Procedure Editor allows you to customize the procedure environment of the Workspace and Projec
207. dows Clipboard into another CAChe file or if the file is already open activate it by clicking on its workspace o If you want to paste the object into another Windows application open or maximize the application and open or activate the file into which you want to paste the cut object 7 18 BioMedCAChe User Guide Deleting portions of your molecule 4 Do one of the following o Choose Edit Paste o Press Ctrl V o Select the toolbar button shown to the left if you are pasting into a CAChe file The cut object is pasted into the new document 5 Continue to paste copies of the object until you have the required number of copies Deleting workspace objects To delete workspace objects 1 Select the object that you want to delete by clicking on it witha selection tool The object is highlighted to show that it is selected 2 Do one of the following o Choose Edit Delete o Press Delete The selected object disappears from the workspace and is not copied to the Windows Clipboard The undo command You can undo most editing actions performed on CAChe files For example if you delete part of your molecule by mistake you can undo the delete action to retrieve the deleted object You can also reapply an editing action that you have undone by choosing the Redo menu option as long as you have not performed another editing action since choosing Undo BioMedCAChe User Guide 7 19 Chapter 7 Manipu
208. drawing tools to create your molecule s atoms and bonds e manipulation tools to rotate scale and move a chemical sample in three dimensions e selection tools to modify all or part of a structure after it has been built You can apply a selection of modeling styles to your sample to view its structure in many different ways The following example shows two different ways that you can view the same molecule in CAChe BioMedCAChe User Guide Ball amp cylinder model Space filling model You can rotate enlarge and move a chemical sample around the workspace to view a molecule more closely both before and after experimenting CAChe shows most experimental results graphically CAChe can quickly and easily correct the geometry valency and hybridization of your chemical sample 2 3 Chapter 2 Introduction to CAChe The following illustration shows a molecule before and after a CAChe optimization experiment to lower the steric energy of the molecule using calculations from classical mechanics Relaxed bond angle Strained bond angle Steric energy 13 3 kcal mol Steric energy 1 5 kcal mol You can use CAChe to superimpose one molecule on another to highlight structural differences The following example shows the capoten molecular structure transparent superimposed on the x ray derived capoten structure solid 2 4 BioMedCAChe User Guide Overview of CAChe CAChe can measure the potent
209. e change selected bonds to another bond type lt t gt Refer to the next section for details about correcting the structure geometry and chemistry of your chemical sample Refer to Chapter 5 Modifying Chemical Samples for details about using the selection tools to change atom and bond properties on a molecule you have already drawn CAChe for Windows User Guide 4 9 Chapter 4 Creating Chemical Samples Perfecting your molecule NOTE Correcting valence Once you have drawn all the constituent atoms and bonds of your molecule you can correct its valence hybridization and geometry by choosing drop down list items from the Beautify menu Do not use the Beautify menu options on any portion of a molecule that has been optimized previously by running an Optimize Geometry experiment This is because the geometry achieved by running an optimization experiment is superior to the geometry resulting from the Beautify menu options Refer to Chapter 13 Optimization and Energy Calculations for information on performing optimization experiments NS To correct valence Defining valence rules 4 10 1 Select a workspace selection tool by clicking on it in the tool palette Using the selection tool select the portion of your molecule or the entire molecule for which you want to correct valence The objects you have selected are highlighted in the workspace Choose Beautify Valence CAChe
210. e Description binary electron density surface colored by electrostatic potential binary electron density surface colored by nucleophilic susceptibility frontier density 10 37 Chapter 10 Performing Workspace Experiments File name EF DENS ISO RF DENS ISO NS DENS ISO ES DENS ISO RS DENS ISO ELEC ISO M0123 ISO 10 38 Location SAMPLE SAMPLE SAMPLE SAMPLE SAMPLE SAMPLE SAMPLE ISO ISO ISO ISO ISO ISO ISO Creator Tabulator Tabulator Tabulator Tabulator Tabulator Tabulator Tabulator Type Description binary electron density surface colored by electrophilic susceptibility frontier density binary electron density surface colored by radical susceptibility frontier density binary electron density surface colored by nucleophilic superdelocalizability binary electron density surface colored by electrophilic superdelocalizability binary electron density surface colored by radical superdelocalizability binary electrostatic potential isosurface binary molecular orbital isosurface orbital 123 CAChe for Windows User Guide Viewing experimental results Sample map folder File name ENERGY MAP DYNAMICS MAP SEQSRCH MAP IRC1 MAP IRC 1 MAP DRC1 MAP DRC 1 MAP CAChe for Windows User Guide Location SAMPLE MAP SAMPLE MAP SAMPLE MAP SAMPLE MAP
211. e with the second atom positioned at the fulcrum of the angle The following example shows a labeled bond angle with the atoms labeled in the order of selection To measure and adjust bond angle 1 Select the three atoms between which you want to measure bond angle by clicking on the first atom with the Select tool then holding down the Shift key and clicking on the second and third atom If you are adjusting the bond angle ensure that the first atom you select is the atom that you want to move Choose Adjust Bond Angle to display the Set Bond Angle dialog box The current bond angle value in degrees is displayed in the Angle text box CAChe for Windows User Guide Specifying angles and distances Set Bond Angle Angle 41906000 4 degree Cancel Apply I Define Geometry Label using fe steps of 5 000000 degree 3 Do one of the following o Click in the Angle text box and type the new bond angle value that you require o Select the Angle text box arrow buttons to increase or decrease the current bond angle value to the value that you require 4 Select Apply to view the results of the new bond angle value in the workspace The first atom that you selected moves to increase or decrease the bond angle to the value that you specified in the Angle text box 5 Select OK to accept the new bond angle value and close the Set Bond Angle dialog box Specifying dihedral angle V
212. e you can gain a new perspective and view your sample from every conceivable angle with unmatched precision You can zoom in on a tiny portion of your molecule or view it from a distance Three dimensional ball and stick models space filling models and shaded surfaces are standard CAChe modeling tools Chemists who use x ray data for structure analysis want to simulate manipulating the models in space Superimposing related samples helps compare the structural differences Docking one sample to another can help you see steric interactions hydrogen bond possibilities or molecular orbital overlap CAChe provides all these modeling tools Experimental results are often saved in graphical form either superimposed on the image of the original molecule or displayed next to the molecule as a three dimensional graph or series of structures that you can animate If you need to analyze a structure of unknown geometry the best place to start is with an exploration of low energy conformations of the chemical sample Reactions usually proceed from the lowest energy conformation or sometimes from any of several low energy conformations with low barriers for interconversion CAChe makes it easy to generate and analyze any number of low energy geometries Sometimes the characteristics of a molecule can be predicted on the basis of some of its physical properties Important properties estimated by CAChe include partial charges bond order electron
213. e Multiplier box and choose a value from the drop down list The multiplier divides the entered coordinates to give the fractional coordinates In the Symbol column do one of the following o enter the atomic symbol for each atom o enter an alphanumeric label containing an atomic symbol and any numeric tag to uniquely identify each asymmetric atom Each atom in the crystal is assigned a unique number that is displayed in the Atom column Enter the coordinates in the X Y and Z columns by clicking the left uppermost cell using the left mouse button and use the Tab key to move between cells Select Redefine All Atoms as Asymmetric to identify additional atoms as asymmetric Select Apply to view the crystal structure in the workspace Select OK to accept the structure and to close the Crystal Shape dialog box The fractional coordinates are altered when you use CAChe computational methods or use commands in the workspace Beautify menu on the crystal structure You can transfer data between tables on the Fractional Coordinates tab using Edit Copy and Edit Paste CAChe for Windows User Guide 6 59 Chapter 6 Viewing Chemical Samples Building asymmetric atoms You may want to build only the asymmetric atoms This option can be used after building a molecular crystal or infinite lattice as a way to start again This option deletes all bonds and all atoms except asymmetric atoms from the molecule file NS
214. e Save As dialog box 2 Do one of the following as required a Click in the File name text box and type the new file name a Select the arrow button in the Save as type box and choose the new file type from the drop down list a Select the arrow button in the Save in box and choose from the drop down list the new drive or folder where you want to save the file a Click and drag the scroll bar in the scrolling list to locate the folder in which you want to save the file and double click on the folder to open it 3 Select Save to close the Save As dialog box and to save the file with the new file name as the different file type in another folder or on another drive CAChe for Windows User Guide 4 19 Chapter 4 Creating Chemical Samples Opening a saved file 4 20 To open a saved file 1 Choose File Open to display the Open dialog box Open ixi Look in fa CAChe cl jE App Bin FragmentLibrary Procs A xlators 2 benzenel 2 isoprene File name Files of type Chemical Sample csf Cancel I Open as read only Help 2 Select the arrow button in the Look in box to display a drop down list of a folders in the directory structure above the currently open folder a available drives on which you can save the file 3 Choose the folder or drive where the file is located from the drop down list 4 Do one of the following a To move up a level of folders to locate t
215. e experiments You can use the the CAChe workspace to build and view your molecule and its properties and investigate molecular geometry When you perform an experiment from the workspace you can choose to investigate the properties of the following e achemical sample e an atom e a bond BioMedCAChe User Guide 2 13 Chapter 2 Introduction to CAChe Chemical sample experiments 2 14 a chemical sample conformation a chemical reaction CAChe can perform a variety of experiments on a chemical sample from the workspace including Optimized geometry optimizes the geometry of your chemical sample using procedures from either classical molecular mechanics or semi empirical quantum mechanics Procedures that use classical methods are the fastest and usually give good results UV visible transitions generates a UV visible spectra for a molecule created by electron transition between molecular orbitals as electromagnetic radiation in the visible and ultraviolet UV visible region is absorbed by the molecule Heat of formation calculates the energy of a chemical sample at a geometry optimized energy minimum Current energy calculates the energy of a chemical sample at its current geometry Electron density generates an electron density isosurface for an electron probability density of 0 01 e A gt The surface is colored to reflect the electrostatic potential at every point on the surface HOMO
216. e hidden choose View Suppress Hydrogens The check mark that is displayed next to the drop down list option disappears to indicate that hydrogens are visible All the hydrogen atoms in the workspace are visible Exceptions to hiding hydrogen atoms 6 20 You cannot hide hydrogen atoms that are attached to a locked atom or hide locked hydrogen atoms Refer to Chapter 8 Investigating Molecular Geometry for details about locked atoms You also cannot hide hydrogen atoms that are attached to an atom that has not had its valence checked by choosing Beautify Valence or Beautify Comprehensive Refer to Chapter 5 Modifying Chemical Samples for details about the Beautify menu options You can also choose to keep hydrogens displayed if they are attached to atoms with valence exceptions by choosing Options Valence Settings You can also choose to keep hydrogens displayed if they are attached to atoms other than carbon by choosing Options Valence Settings Refer to Changing view settings for valence p 6 48 for details about the Options Valence Settings menu option CAChe for Windows User Guide Changing the appearance of bonds Changing the appearance of bonds CAChe allows you to change the shape and color of a bond s appearance As with changing the appearance of atoms choosing another display style for bonds has no impact on a chemical sample s structure or on any experiments you run using t
217. e number displayed is the number obtained from the PDB file Sequences do not necessarily start numbering from one and residues may have the same PDB number but differ in PDB insertion code The PDB numbers always define the order in the sequence o View Residue numbers Ruler to display the sequence ruler above each residue Sequence rulers always start from 1 and end with the number of the chain termini in the sequence The ruler counts residues gaps and chain termini During editing the PDB number assigned to a residue may no longer reflect its position in the sequence For example editing the residue with PDB number 10 might appear after the residue with PDB BioMedCAChe User Guide 9 27 Chapter 9 Manipulating Biomolecules number 24 Or there can be many residues with the same PDB number but different insertion codes To renumber sequences 1 Choose Edit Resequence PDB numbers to display the PDB number above each residue Renumbering replaces all PDB numbers in the sequence with the current numbers in the sequence ruler Coloring sequences by properties NS To color a sequence 1 Choose View Residue Colors The Residue Colors dialog appears Residue Colors 2 x r Scheme q p Method Ex i ox Residue Type CGF Chemical Type es Sequence Protocol Chemical lop C None Chemical type Color Codes Hydroxyl containing 2 Choose the color Scheme e Residue Type e Sequen
218. e of an atom To change an atom s element type hybridization and charge using the Atom Attributes dialog box 1 CAChe for Windows User Guide Select the atom or group of atoms whose element type hybridization or charge you want to change by clicking on the atoms with a selection tool The atom or group of atoms are highlighted to show that they are selected Choose View Atom Attributes to display the Atom Attributes dialog box 5 21 Chapter 5 Modifying Chemical Samples Atom Attributes ix Type Color Shape Label Element Ic Carbon Hybridization sp2 trigonal plane Charge fo a M Display Atoms Cancel Make Defaut Help 3 Select the Type tab to display the Element Hybridization and Charge boxes 4 Select the arrow button in the Element box to display a drop down list which is identical to the Element Type drop down list in the style bar 5 Select the element you require from the drop down list if the element is displayed 6 Ifthe element you require is not displayed choose Periodic Table from the drop down list to display the Periodic Table dialog box 5 22 CAChe for Windows User Guide Changing atom and bond properties Periodic Table BEI H He 1 I Be Bie NDF Ne 3 4 5 6 7 8 3 10 Na Mg as PP f a a 11 12 13 14 15 16 17 18 l ta S f i r Mn fe Co Ni Cu in Ga Ge As Se Br Kr 19 20 21 22 23 24 25
219. e specified bond type Coordinate lt t gt Refer to Using the workspace style bar p 3 40 for information on using the Bond Type drop down list Hiding the style bar You can choose to hide the workspace style bar To hide the workspace style bar 1 When the style bar is visible choose Options Show Ribbon The style bar boxes are no longer displayed at the top of the workspace The check mark next to the Show Ribbon drop down list option is no longer displayed indicating that the style bar is currently hidden To redisplay the workspace style bar 1 When the style bar is hidden choose Options Show Ribbon The style bar is displayed at the top of the workspace A check mark is displayed next to the Show Ribbon drop down list option indicating that the style bar is currently visible 3 12 BioMedCAChe User Guide The workspace The tool palette The workspace tool palette provides three types of tools selection tools e adrawing tool e manipulation tools Select Select Molecule Selection tools Select Similar Group Select Atom Bond tool Rotate Translate Manipulation tools Scale y The selection tools The tool palette contains the following selection tools e the Select tool which is the default workspace tool Use it to select individual objects e the Select Molecule tool which selects an entire molecule e the Select Similar tool wh
220. e tool by clicking on it in the tool palette The cursor is displayed as the Scale tool shown to the left Using the Scale tool To zoom in on objects 1 Position the Scale tool anywhere in the workspace 2 Click and drag toward the right hand side or top of the workspace All objects in the workspace are scaled to a larger size To zoom out from objects 1 Position the Scale tool anywhere in the workspace 2 Click and drag toward the left hand side or bottom of the BioMedCAChe User Guide 3 39 Chapter 3 CAChe Basics workspace All objects in the workspace are scaled to a smaller size Using the workspace style bar The workspace style bar consists of four drop down lists which display settings for e element type for an atom e charge of an atom e hybridization of an atom bond type Use the style bar boxes in conjunction with e the Atom Bond tool e the selection tools Using the style bar with the Atom Bond tool Choose atom and bond properties from the style bar s drop down lists before you draw atoms and bonds using the Atom Bond tool To use the style bar with the Atom Bond tool 1 Select the arrow button in the Element Type box and choose the element type for the atom that you want to draw from the drop down list Periodic Table 2 Select the arrow button in the Hybridization box and choose the hybridization value for the atom that you want to draw from the 3 40 BioMedC
221. ean up ring geometry Correcting hydrogen bond geometry To correct hydrogen bond geometry 1 Select a workspace selection tool by clicking on it in the tool palette 2 Using the selection tool select the portion of your molecule or the entire molecule for which you want to correct H bond geometry 3 The objects you have selected are highlighted in the workspace Choose Beautify H Bonds CAChe sequentially orients each OH or SH hydrogen atom to 4 14 CAChe for Windows User Guide Perfecting your molecule NOTE maximize hydrogen bonding This menu option moves only hydrogen atoms by rotations and applies to water hydroxyl or thiol groups only The Comprehensive command Deleting hydrogens The Beautify Comprehensive menu option corrects valence hybridization geometry and ring structure in one step This option is equivalent to choosing Valence Hybridization Rings and Geometry in order from the Beautify menu To correct valence hybridization ring structure and geometry in one step 1 Select a workspace selection tool by clicking on it in the tool palette 2 Using the selection tool select the portion of your molecule or the entire molecule for which you want to correct valence hybridization ring structure and geometry The objects you have selected are highlighted in the workspace 3 Choose Beautify Comprehensive CAChe satisfies the valence and hybridization rules of t
222. echanics ZINDO Tabulator Mechanics MOPAC Tabulator Mechanics MOPAC Tabulator MOPAC Tabulator MOPAC Tabulator MOPAC Tabulator MOPAC Tabulator MOPAC Tabulator MOPAC Tabulator CAChe for Windows User Guide Setting up a workspace experiment Procedure Procedure Computational Number Name Applications 18 AMI transition state geometry MOPAC with AM1 wavefunction in Tabulator water 19 PM3 transition state geometry MOPAC with PM3 wavefunction in water Tabulator 20 existing geometry and Tabulator wavefunction 25 rigid or optimized map Mechanics unlimited search labels 26 AMI rigid or optimized map 1 MOPAC search label 27 PM3 rigid or optimized map 1 MOPAC search label 28 AMI rigid or optimized map 2 MOPAC search labels 29 PM3 rigid or optimized map 2 MOPAC search labels 30 AMI rigid or optimized map 1 MOPAC search label in water 31 PM3 rigid or optimized map 1 MOPAC search label in water 32 AMI rigid or optimized map 2 MOPAC search labels in water 33 PM3 rigid or optimized map 2 MOPAC search labels in water 36 single pass sequence of Mechanics conformations unlimited search labels CAChe for Windows User Guide 10 13 Chapter 10 Performing Workspace Experiments 10 14 Procedure Number 37 38 39 40 41 42 45 46 47 48 49 50 51 Procedure Name multiple pass sequence of conformations unlimited search labels
223. ect the Lock Geometry radio button ON a E Se Select OK to close the Set Dihedral Angle dialog box A geometry label identifies the participating atoms and displays the value of the dihedral angle and an L in the workspace to indicate that the angle is locked 7 Choose File Save to save the chemical sample file 8 Run the optimization experiment of your choice CAChe for Windows User Guide 13 9 Chapter 13 Optimization and Energy Calculations Viewing optimized structures 13 10 lt t gt When you optimize a chemical sample CAChe automatically saves the optimized structure in the chemical sample file Sometimes viewing the optimized structure alone can answer questions about factors that affect a molecule s geometry such as steric interactions However you often need to view the differences between the original and the optimized structure If you save the chemical sample file using a different file name before optimizing the original structure and the optimized one are both available to compare One way to view differences is to superimpose one structure on the other You can also compare distances and angles using geometry labels to measure the geometry of both structures precisely Refer to Chapter 8 Investigating Molecular Geometry for details about superimposing molecules CAChe for Windows User Guide Calculating current energy Calculating current energy You can measure the ener
224. ect the bonds that you want to change shape by clicking on the bonds with a selection tool CAChe for Windows User Guide 6 23 Chapter 6 Viewing Chemical Samples 6 24 2 Choose View Bond Attributes to display the Bond Attributes dialog box Bond Attributes BEI Type Color Shape Draw Bonds as Single Lines Multiple Lines C Single Cylinders r Scale cylinders such that Each Cylinder z is displayed as for V Display Bonds Cancel Make Default Select the Shape tab to display the following list of shape options for bonds o single lines o multiple lines o single cylinders o multiple cylinders In the Draw bonds as panel select the radio button next to the shape option you want to apply to each selected bond so that the relevant radio button is enabled Select the arrow button in the Scale cylinders such that box and choose a scaling option from the drop down list Click in the is displayed as text box and enter the factor by which you want to scale the radius of each selected bond Select OK to close the Bond Attributes dialog box The selected bonds are displayed in the shape you specified with a radius representing the scaling options you chose CAChe for Windows User Guide Changing the appearance of bonds Changing bond color Bonds can be colored by e atom color colors the selected bonds with the same color specified for the atom attached at eac
225. ects 5 Save all of the projects that you want to save Select Cancel to skip any projects that you do not want to save 12 44 BioMedCAChe User Guide Quitting ProjectLeader Quitting ProjectLeader NS To quit ProjectLeader 1 Choose File Exit If you have any unsaved changes in open windows you are prompted to save changes 2 Do one of the following a Select Save to save the changes before quitting ProjectLeader a Select Discard to quit ProjectLeader without saving the changes a Select Cancel to keep ProjectLeader running BioMedCAChe User Guide 12 45 Chapter 12 Using ProjectLeader 12 46 BioMedCAChe User Guide 1 Optimization and Energy Calculations Overview This chapter describes e optimizing with CAChe to discover low energy conformations of your molecule calculating the current energy of a chemical sample Contents Optimizing chemical samples 13 2 Maintaining mutual orientations 13 8 Classical or quantum mechanics 13 3 Viewing optimized structures 13 10 Optimizing with classical mechanics 13 3 Calculating current energy 13 11 Optimizing with quantum mechanics 13 4 Calculating current energy with classical Selective optimization 13 6 mechanics 13 11 Optimizing substituted portions of a molecule Calculating current energy with quantum 13 6 mechanics 13 11 Investigating reactive sites at the surface of Including solvation effects 13 12 enzymes 13 8 Chapter 13 Optimization and
226. ecule tool Use the Select Molecule tool to select one or more visible molecules e deselect one or more molecules The Select Molecule tool and cursor are shown to the left Refer to Chapter 5 Modifying Chemical Samples for details about using the Select Molecule tool The Select Similar tool Use the Select Similar tool to 3 31 Chapter 3 CAChe Basics 3 32 e select visible objects of a similar type for example all atoms of the same element type or all bonds of the same bond type e deselect objects of a similar type The Select Similar tool and Select Similar cursor are shown to the left Refer to Chapter 5 Modifying Chemical Samples for details about using the Select Similar tool and how to define criteria for similarity The Select Group tool Use the Select Group tool to select a visible atom and all the atoms with which it shares a group The Select Group tool and Select Group cursor are shown to the left Refer to Chapter 5 Modifying Chemical Samples for details about using the Select Group tool The Atom Bond tool Use the Atom Bond tool to e draw atoms and bonds The Atom Bond tool and Atom Bond cursor are shown to the left Refer to Chapter 4 Creating Chemical Samples for details about using the Atom Bond tool to draw the constituent atoms and bonds of your molecule The Rotate tool Use the Rotate tool to e rotate objects in two or thr
227. ed CAChe for Windows User Guide Viewing a surface Viewing labeled surfaces 6 To view the portion of the wireframe which is parallel to the x y plane select the X Z Planes check box so that it is enabled If you have many surfaces displayed at one time you may find several labels cluttering up the workspace Displaying surface labels is useful for selecting a surface and for viewing the name of a surface Displaying surfaces as labeled is the default view option To view a surface label 1 Do one of the following to select everything in the workspace a Choose Edit Select All a Press Ctrl A a Click anywhere in the workspace background Every object in the workspace is highlighted to show that it is selected 2 Choose Analyze Surface Attributes to display the Surface Attributes dialog box 3 Select the Show Label check box so that it is enabled 4 Select OK to show labels for all surfaces currently being displayed and to close the Surface Attributes dialog box All surfaces in the workspace are now labeled To hide a surface label 1 Select a surface by clicking on its label with the Select tool The surface is highlighted to show that it is selected 2 Choose Analyze Surface Attributes to display the Surface Attributes dialog box es Select the Show Label check box so that it is disabled E Select OK to hide labels for all currently selected surfaces and to close the Surface Attribut
228. ed in the cell The copied object remains on the Windows Clipboard until you copy or cut another object so you can continue to paste copies of the object until you have the required number of copies BioMedCAChe User Guide Viewing sample properties Viewing sample properties ProjectLeader s main workbook is used to display chemical samples and the results of experiments and statistical analyses In addition to ProjectLeader s main workbook you can open the Sample Properties workbook to view information about the following components of the chemical samples atoms bonds orbitals molecule groups electronic spectra vibrational spectra improper torsion angles crystals bond angles dihedral angles atom distances molecular orbitals Slater type orbital basis functions Gaussian type orbital basis functions Each component is displayed on a different sheet in the workbook NOTE Sample properties can only be viewed if the information is available in the Chemical Sample file Experiments can be performed on the sample properties in the Sample Properties workbook in the same way as in the ProjectLeader workbook Information can also be copied into the ProjectLeader workbook where further experiments can be performed To view the sample properties 1 Select the chemical sample that you are interested in 2 To display the Sample Properties workbook do one of the following a choose View Sample Properties
229. ed red the default color of a single bond Because there are no colors for fractional bond orders it is often useful to display bond order by both color and by scaling bond radius Displaying partial charge and bond order To view atomic partial charge and calculated bond order 1 Run an atomic partial charge or calculated bond order experiment on your chemical sample file 2 Choose View Partial Chg and Calc Bond Order CAChe colors atoms by partial charge polarity where positively charged atoms are red and negatively charged atoms are yellow Atoms are also labeled with partial charge and scaled to reflect partial charge Bonds are colored by calculated bond order according to the CAChe color tables The following example shows a furan molecule viewed by CAChe for Windows User Guide 16 7 Chapter 16 Investigating Atom and Bond Properties partial charge and calculated bond order lt t gt Refer to CAChe color tables p 15 13 for further details about bond colors Displaying partial charge with labeled atoms To view atoms labeled with partial charge 1 Run an atomic partial charge or calculated bond order experiment on your chemical sample file 2 Choose View Atom Attributes to display the Atom Attributes dialog box 16 8 CAChe for Windows User Guide Viewing atom and bond properties Atom Attributes Ixl Type Color Shape Lebel DAt o F Hybridization F Charge M Partial
230. ee dimensions BioMedCAChe User Guide Using CAChe The Rotate tool and Rotate cursor are shown to the left A lt p Refer to Chapter 7 Manipulating Molecules for information on how to use the Rotate tool and how to define the center of rotation for the tool The Translate tool Use the Translate tool to e move objects in the workspace in two dimensions The Translate tool and Translate cursor are shown to the left A lt 4 Refer to Chapter 7 Manipulating Molecules for details about using the Translate tool and how to define the center of rotation for the tool The Scale tool Use the Scale tool to 2 e zoom in on objects 3 e zoom out from objects The Scale tool and Scale cursor are shown to the left A lt t gt Refer to Chapter 7 Manipulating Molecules for information on how to use the Scale tool Using the Select tool The Select tool is the default workspace tool Use the Select tool to e select one or more workspace objects by clicking on them e select a group of workspace objects by clicking and dragging around them e select a group of workspace objects by clicking on them while holding down the Shift key e deselect a selected workspace object by clicking on it BioMedCAChe User Guide 3 33 Chapter 3 CAChe Basics e deselect a group of selected workspace objects by clicking and dragging around them while holding down the Shift key dese
231. elationships QSPR between molecular structure and properties such as boiling points octanol water partition coefficients and dipole moments BioMedCAChe User Guide Introduction to ProjectLeader Once you have performed several experiments and analyses you may wish to plot a scatter plot of the results The straight line fitting in ProjectLeader s scatter plots provides a powerful way of identifying trends in your results ProjectLeader experiments The following list includes some of the experiments that are available with ProjectLeader These experiments can be performed on one or more chemical samples simultaneously e optimization to find a low energy structure for steric energy heat of formation or total energy e net positive and negative charge for a molecule e molecular formula weight and refractivity e ring count and size e investigation of molecular orbital energies such as HOMO and LUMO energies e calculation of the dielectric steric total energy and heat of formation of a structure at its current geometry e investigation of visible and UV visible spectra data zero order first order and second order molecular or valence connectivity indices e dipole moment and dipole vectors x y and z e electron affinity e shape index order 1 2 and 3 e octanol water partition coefficient Experiments can also be performed on sample components such as atoms bonds and molecular orbitals ProjectLe
232. elect the files that you want to import You can add multiple Chemical Sample files or multiple SD and MOL files but you cannot import a mixture of Chemical Sample files and SD or MOL files simultaneously Hold down Shift and select the first and last files in a group to select all of the files in that group Hold down Ctrl and select more files to add single files to the selection In order to display multiple chemical samples ProjectLeader will insert new rows directly below the cell that you have selected Select Open a If you are importing Chemical Sample files or MOL files the structures are displayed in the Chemical Sample column and the process of adding the files is complete a If you are importing SD files the Import an MDL SD File BioMedCAChe User Guide Adding chemical samples Choose a name from this list Select this option to import additional data BioMedCAChe User Guide dialog box is displayed Continue with steps 6 through 8 below to complete the process CAChe reads SD or MOL files and translates them to CAChe Chemical Sample files one chemical sample per file Because multiple chemical samples can be contained in one SD file and only one chemical sample can be saved in each CAChe Chemical Sample file you are prompted to define the way in which you want to name the new Chemical Sample files In the Import an MDL SD file dialog box choose a name from the scrolling list of possible names
233. elect the portion of your molecule that you want displayed as a line drawing by clicking on objects with a selection tool The objects are highlighted to show that they are selected 2 Choose View Lines Atoms are displayed as their atomic symbol label and bonds as multiple lines colored by atom color Atom colors are not changed To color selected atoms by element choose View Color by Element The following example shows a molecule displayed as a line drawing To view your chemical sample as a line only drawing 1 Select the portion of your molecule that you want displayed as a line only drawing by clicking on objects with a selection tool The objects are highlighted to show that they are selected 2 Choose View Lines Only Atoms are displayed as small circles and bonds as multiple small z buffered cylinders colored by atom color Atom colors are not changed To color selected atoms by element choose View Color by Element 6 4 CAChe for Windows User Guide Using CAChe model types To view your chemical sample as a ball and cylinder model 1 Select the portion of your molecule that you want displayed as a ball and cylinder model by clicking on objects with a selection tool The objects are highlighted to show that they are selected Choose View Ball amp Cylinder Atoms are displayed as shaded spheres with a van der Waals radius of 1A scaled to 0 2A Bonds are displayed as multiple cylinders
234. en To display hidden objects 1 From the 3D Structure window or the Sample Property View choose to View Show Selection Only uncheck it and restore the display of all objects When you are viewing selections only the visible objects change when you change selection Viewing selection only is often used with either a Sample Property view or the Sequence View Window and selections are made in one of those windows Often a better way to simplify the view is to hide atoms and bonds with the View Hide Unselected and View Hide Selected commands CAChe for Windows User Guide Coloring by molecules Coloring by molecules Giant molecules crystal lattices and complex chemical samples often contain many separate molecules or chains You can visually separate molecules by coloring each with a different color NSS To color molecule 1 From the workspace choose View Color by Molecule All molecules that contain more than three atoms and have at least one atom selected are identified and each is colored in turn with a color from the twelve CAChe atom colors Unless the colors have been changed with View Color Palette the colors used are cyan dark red gold green blue white grey red yellow bright green dark blue purple If there are more than twelve molecules present the colors are reused CAChe for Windows User Guide 6 31 Chapter 6 Viewing Chemical Samples Viewing multiple windows You can op
235. en many 3D structure windows and one sample properties window for each chemical sample When you open a new 3D structure window of the same chemical sample file CAChe displays the molecular structure at a different orientation Opening multiple document windows allows you to look at your chemical sample from a number of different perspectives or in different ways simultaneously If you change the chemical structure in one window all other windows containing the same chemical sample reflect those changes To open a new 3D structure window of a chemical sample 1 Choose Window New 3D Structure Window A new window opens displaying the contents of the active document window at a different perspective To open a new sample properties window of a chemical sample 1 Choose Analyze Chemical Properties Spreadsheet A new window opens displaying the contents of the active document window as a spreadsheet workbook 6 32 CAChe for Windows User Guide Viewing chemical sample data Viewing chemical sample data The CAChe chemical sample is a database of information about your chemical sample You can view and modify the information in a sample property workbook To open a new window showing chemical sample properties 1 Choose Analyze Chemical Properties Spreadsheet A new window opens displaying the contents of the active document chemical sample in a workbook E ChemicalS ample2 2 Jol x A B D E F G
236. ent window If you already have a blank ChemicalSample1 window open you do not need to open a new chemical sample file If you do not have a blank document window currently open you need to open a new chemical sample file To open a new chemical sample file 1 Choose File New A blank chemical sample file document window opens 4 2 CAChe for Windows User Guide Working with chemical sample files Opening an existing chemical sample file Alternatively you may want to open a chemical sample file that you have already worked on and saved To open a saved chemical sample file 1 Choose File Open to display the Open dialog box Open BE Look in Filename Files of type Chemical Sample csf Cancel I Open as read only Help 2 Select the arrow button in the Files of type box to display a drop down list of file types Choose Chemical Sample csf from the drop down list 4 Select the arrow button in the Look in box to display a drop down list of drives that you can access 5 Choose the drive where the file that you want to open is located 6 Click and drag the scroll bar in the scrolling list to display the folder that contains the file that you want to open 7 Double click on the folder to open it A list of files is displayed in the scrolling list 8 Do one of the following a Click in the File name text box and type the file name of the file that you want to open
237. entified by their PDB names To deselect a group lt gt t Coloring residues S 1 Position the Select Group tool over the selected group you want to deselect 2 Press the shift key and the left mouse button to deselect the group The group is grayed out to show that it is deselected You can also use the Sequence View window to quickly select residues See The selection tools p 9 24 for details To color all residues by the same scheme BioMedCAChe User Guide Viewing biomolecules 1 Choose View Color by Residue Residue Colors 21x Scheme OK Residue Type CGF OK C Sequence Protocol Cancel C alpha Specific Color Apply Chemical type Color Codes Color Band Hydrophobic Amido Aromatic Basic Hydroxyl containing The Residue Colors dialog opens 2 Select the Scheme and Method 3 Choose OK The colors of all atoms in an amino acid residue are assigned based on the Scheme and Method selected The change in color applies to selected unselected visible and hidden atoms To learn about the coloring schemes and methods see Coloring sequences by properties p 9 28 for details Highlighting and displaying the backbone To highlight a backbone 1 Choose Edit Select Backbone All atoms that are marked as backbone atoms are selected and highlighted All other atoms connected to the backbone are deselected BioMedCAChe User Guide Chapter
238. eps of the second procedure within the one that you are modifying CAChe for Windows User Guide 11 17 Chapter 11 Using the Procedure Editor To modify a procedure 1 In the tree view of the Navigator window select the procedure that you wish to modify 2 Perform one of the following actions to display a Procedure window a Press the right mouse button and choose Open from the popup menu a Double click on the selected procedure The name of the procedure is displayed in the title bar of the Procedure window 3 If required you can a adda step a call another procedure a move a step a view the settings of a step Refer to the following sections for details about performing each of these actions 4 If required change the description of the procedure by typing into the Description text box 5 When all the modifications have been made choose File Close to close the Procedure window 6 Choose File Save to save the modifications to the procedure NOTE You can import a step from a previous version of CAChe by using the File Import Step option Alternatively you can drag setting files into the Procedure window 11 18 CAChe for Windows User Guide Modifying a procedure Adding a step You can add a step to a procedure Toadda step 1 Select the step in the procedure after which you want to insert a new step 2 Select the New button to display a popup menu Alternatively choose File
239. erent properties the style bar boxes do not display any values To change atom or bond properties 1 Use one of the selection tools to select the objects whose values you want to change For example if you want to change a bond from double to single select the bond with the Select tool If you want to change all the atoms in a molecule to another element type select the molecule with the Select Molecule tool The current value of the object you selected is displayed in the relevant style bar box if you selected one object or objects of a similar type No value is displayed in the style bar boxes if you selected more than one object with different properties Choose the value or property you require from the drop down list of the relevant style bar box to change the value or property of the selected object For example choose single from the Bond Type drop down list if you want to change a double bond to a single bond Choose the new element type from the Element Type drop down list if you want to change the atoms of a selected molecule to another element type The value or property of the selected object changes to the value or property you chose from the list BioMedCAChe User Guide Using CAChe Help Using CAChe Help CAChe offers two forms of on line Help context sensitive Help which displays information on any part of the interface such as a portion of a dialog box a workspace tool or a menu optio
240. eriments consist of calculations using classical and quantum mechanical theories The calculations explore the characteristics of your chemical sample predicting properties such as electron distribution and generating conformations that possess low potential energy or heat of formation values Some experiments produce computer simulated representations of the calculated properties For example you can view an electron density surface that predicts reactivity sites superimposed on your molecule Other experiments display a three dimensional energy graph next to a series of conformations for a molecule so you can view the relationship between energy and molecular geometry Animate the series of conformations along an axis of the graph to compare low energy structures that may be separated from each other by high energy barriers or rotate the graph along any axis to view its energy values more clearly The experiments in computer aided chemistry use mathematical models derived from computational chemistry to calculate molecular properties and geometries The next section describes how CAChe applies these models during the experimental process BioMedCAChe User Guide 2 7 Chapter 2 Introduction to CAChe The advantages of CAChe Geometry optimization Electronic properties 2 8 CAChe provides you with a three dimensional modeling tool that helps you to visualize a structure By simply rotating and examining amodel of a molecul
241. es and to investigate chemical reactions by locating transition states MOPAC can calculate the geometry energetics and reaction profiles of molecules in their excited states It can include solvent effects in these calculations Excited state calculations are important in simulation of photochemical processes MOPAC calculates heats of formation rather than the energy required to separate the molecule into isolated nuclei and electrons as in quantum chemical methods such as Extended Htickel Theory and ZINDO In this section energy and heat of formation are used interchangeably Although MOPAC uses many concepts from quantum theory thermodynamics and advanced mathematics a detailed understanding of these areas is not necessary MOPAC was written and designed with non theoretical chemists in mind In CAChe one version of the MOPAC application is available MOPAC2KComputeEngine MOPAC is also available on CAChe GroupServers How MOPAC differs from Mechanics 20 12 MOPAC is a quantum mechanical method Molecular Mechanics is a classical description using equations from Newtonian physics based on the atom hybridizations and bond types you draw when you build a molecule Quantum mechanical methods use the Schr dinger equation to determine bond strengths atomic hybridizations partial charges and orbitals from the positions of the atoms and the net charge Because quantum mechanical methods describe bonds they can describe chemical
242. es containing experimental details are created and stored in automatically generated folders The folders are prefixed with the same name as your chemical sample file For example if your chemical sample file is named sample csf the automatically generated folders are named as follows e sample io contains input output files sample iso contains isosurface files sample map contains energy map files The following tables list all the files created by CAChe experiments for a chemical sample file named sample csf and the location of the experimental files CAChe for Windows User Guide Viewing experimental results Sample io folder Sample iso folder File name DYNAMICS LOG DYNAMICS OUT HUCKEL LOG HUCKEL OUT MECHANCS OUT MECHANCS LOG MOPAC LOG MOPAC OUT TABULATE OUT ZINDO LOG ZINDO OUT File name EP DENS ISO NF DENS ISO CAChe for Windows User Guide Location Creator SAMPLE IO Dynamics SAMPLE IO Dynamics SAMPLE IO ExtHiickel SAMPLE IO ExtHiickel SAMPLE IO Mechanics SAMPLE IO Mechanics SAMPLE IO MOPAC SAMPLE IO MOPAC SAMPLE IO Tabulator SAMPLE IO ZINDO SAMPLE IO ZINDO Location Creator SAMPLE ISO Tabulator SAMPLE ISO Tabulator Type Description text log file text output file text log file text output file text output file text log file text log file text output file text output file text log file text output file Typ
243. es dialog box All surfaces in the workspace are no longer labeled CAChe for Windows User Guide 15 21 Chapter 15 Investigating Electron Distribution 15 22 CAChe for Windows User Guide 16 Investigating Atom and Bond Properties Overview This chapter describes the following CAChe experiments that calculate atom and bond properties the atomic partial charge experiment which displays a chemical sample with atoms sized to reflect their partial charge and enables you to view possible reactivity sites and the most polar bonds in a sample the bond order experiment which displays a chemical sample with bonds scaled or colored to reflect calculated bond order the bond strain experiment which displays a chemical sample with bond strain represented by colors that indicate the order of magnitude of the strain energy Contents Calculating atomic partial charge 16 2 Displaying partial charge with scaled and Calculating bond properties 16 4 colored atoms 16 10 Calculating bond order 16 4 Displaying bond order and partial charge 16 11 Calculating bond strain 16 5 Displaying bond order with color 16 11 Viewing atom and bond properties 16 7 Displaying bond order by scaling bond radius Displaying partial charge and bond order 16 7 f 16 12 Displaying partial charge with labeled atoms Displaying bond strain 16 13 16 8 Chapter 16 Investigating Atom and Bond Properties Calculating atomic partial charge 16 2
244. es from which you can open the file 3 Choose the folder or drive where the file is located from the drop down list BioMedCAChe User Guide Viewing biomolecules NOTE BioMedCAChe User Guide Do one of the following o To move up a level of folders to locate the folder containing the file select the dialog box button shown to the left o To locate the file in a subfolder click and drag the scroll bar in the scrolling list to display the folder where the file is located and double click on the folder to open it 4 Select the arrow button in the Files of type box and choose PDB pdb ent from the drop down list 5 Do one of the following o Click and drag the scroll bar in the scrolling list to locate the file that you want to open and select the file by clicking on it o Click in the File name text box and type the file name of the file that you want to open 6 Select Open to open the file and to close the Open dialog box If the PDB file contains alternative coordinates for atoms you will see the dialog below and the first coordinates will be used CAChe Workspace The PDB file holds atoms with alternative coordinates only the first location will be read If you need to load the alternative coordinates you must modify the PDB file using a text editor to make the alternative first before loading the file into CAChe CAChe uses a het_ dictionaryCIF txt file that resides in the CAChe directo
245. es other than the standard settings 2 12 BioMedCAChe User Guide Performing experiments with CAChe You can perform experiments on a chemical sample and its conformation or on an atom or bond You can also discover a transition state and reaction path for a chemical reaction between two samples 4 Once you have finished running experiments take a look at the results Some experimental results can be viewed from the chemical sample file For example properties such as atomic partial charge or bond strain can be viewed by coloring or scaling atoms and bonds Isosurfaces representing electronic properties can be superimposed on the molecule in the chemical sample file i ic o gt 3 b 5 Other experiments produce a separate file such as a map file where you can view and analyze experimental data in the form of three dimensional graphics which can be manipulated in the same way as a molecule in a chemical sample file For example you could animate a series of low energy conformations while viewing the corresponding value on an energy graph or rotate the graph around the x y and z axes 5 Use what you have learned to plan new experiments or create new chemical samples lt t gt Refer to Chapter 10 Performing Workspace Experiments Chapter 11 Using the Procedure Editor and Chapter 12 Using ProjectLeader for a detailed description of the experimental process in CAChe Workspac
246. es to display all sequences folded at the window boundary BioMedCAChe User Guide 9 29 Chapter 9 Manipulating Biomolecules 9 30 amp To unwrap sequences 1 Uncheck Format Wrap Lines to display all sequences on a single line that can be scrolled Tohidea sequence 1 In the Sequence View window select the name of the sequence you want to hide Choose View Hide Sequence to hide the sequence Alternatively close all 3D structure and sample property windows for the biomolecule The sequence for the structure is removed from the sequence view To display the sequence again 1 Choose Analyze Sequence in the 3D structure window BioMedCAChe User Guide Changing biomolecules Changing biomolecules You use the CAChe sequence window to edit modify delete mutate build and analyze biomolecules at the secondary structure level As you modify your molecules keep the following tips in mind e Commands from the Edit menu work on the active sequence only The name of the active sequence is highlighted in yellow e Editing operations immediately change the 3D structure e You should tile your windows so that you can see the structure in a 3D workspace while making editing changes Deleting residues deletes the residue group its atoms its bonds and other dependent objects Inserting residues adds the residue group and all atoms and bonds belonging to that residue e Inserting re
247. etry 8 38 To create a search label while defining a geometry label 1 Select the required number of atoms for the distance or angle you want to label by clicking on the first atom with the Select tool then holding down the Shift key and clicking on the remaining atoms For example select two atoms if you want to create a search label for an atom distance three atoms if you want to create a search label for a bond angle or four atoms if you want to create a search label for an improper torsion or dihedral angle Choose one of the following menu options gt Adjust Atom Distance o Adjust Bond Angle o Adjust Improper Torsion Adjust Dihedral Angle The Set Atom Distance Set Bond Angle Set Dihedral Angle or Set Improper Torsion dialog box is displayed Select the Define Geometry Label check box so that it is enabled Select the Search radio button so that it is enabled A range of default values and steps between those values are displayed in the text boxes beneath the Search radio button Set Dihedral Angle 21x Angle 179 528213 4 degree Cancel Apply C Define Geometry Label C Unlock Geometry C Lock Geometry between 5 80 000000 and 180 000000 using 24 steps of 15 000000 degree CAChe for Windows User Guide Working with search labels 5 If you want to change the default values do one or all of the following o Click in the between text box and enter a n
248. etry 0G moaca For Help press F1 The Procedure and Parameter Data windows may be displayed by double clicking an appropriate object in the Navigator window The Navigator window is divided into two panes 11 4 CAChe for Windows User Guide The Procedure Editor interface e the left hand side shows a tree view of the entire experiment environment the right hand side lists the child components contained in the current folder Use the splitter bar between the two panes to adjust the portion of the screen filled by each pane The following symbols are used in the Navigator window to depict different types of object within the experiment environment a folder usually containing other objects or sub folders a CAChe experiment a procedure a parameter data set Bm amp D lt t gt Refer to Managing the experiment environment p 11 8 for details about managing experiments in the Navigator window CAChe for Windows User Guide 11 5 Chapter 11 Using the Procedure Editor The Procedure window The Procedure window dialog box allows you to modify the definition of a procedure The title bar contains the title of the procedure HS Procedure EDens_MM_MOPAC AM1_H20 Geo Eg The number of chemical sample Arguments Single chemical sampe Ss Procedure Steps Buttons to modify the ses Fena SX T New Open Delete Up Down y Call MM_GeoPreOpt using Samplet y Call MO
249. ettings command in order to use this option Alter viewing distance and depth using the following options e viewing distance controls the perspective of images on the screen Perspective can be exaggerated to enhance the 3D effect e near clipping clips the front portions of your molecule as it encounters the front of the three dimensional viewing box This gives you a cross sectional view of the remaining portion of your molecule e far clipping clips the back portions of your molecule as it encounters the back of the three dimensional viewing box This gives you a cross sectional view of the remaining portion of your molecule amp To change workspace perspective and distance 1 Choose Options View Settings The View Settings dialog box is displayed View OpenGL r Settings Viewing Distance Near Clipping Ear Clipping Cancel Make Default 2 To align your workspace view with the x y or z axis select the radio button next to the axis you require so that the radio button is enabled CAChe for Windows User Guide 6 45 Chapter 6 Viewing Chemical Samples 10 To align your workspace view through selected atoms select two or three atoms by clicking on them with a selection tool cursor The Through Selected Atoms radio button is no longer grayed out Select the Through Selected Atoms radio button so that it is enabled To decrease the vie
250. ew value for the start of the value range o Click in the and text box and enter a new value for the completion of the value range o Click in the using text box and enter a new value for the number of steps throughout which you want the range of values to be varied 6 Select OK to close the Set Atom Distance Set Bond Angle Set Dihedral Angle or Set Improper Torsion dialog box and to define the search label with the specified value range and number of steps A search label displays the value of the distance or angle in the workspace and an S to indicate that the label is a search label The following example shows a search label CAChe for Windows User Guide 8 39 Chapter 8 Investigating Molecular Geometry Changing a geometry label to a search label 8 40 You can modify an existing geometry label to change it into a search label To change a geometry label into a search label 1 Select the geometry label by clicking on the numeral portion of the label with the Select tool The geometry label is highlighted to show that it is selected Choose the relevant menu option for the selected geometry label type from one of the following gt Adjust Atom Distance gt Adjust Bond Angle o Adjust Improper Torsion gt Adjust Dihedral Angle The Set Atom Distance Set Bond Angle Set Dihedral Angle or Set Improper Torsion dialog box is displayed Select the Search radio button so that it is enabled
251. example if you have chosen to view your chemical sample in ball and cylinder mode the molecule reverts back from a line drawing into a ball and cylinder model If you further manipulate or change a molecule before CAChe can reapply the current display style the chemical sample remains in its simplified line drawing mode so speeding up the rate of screen display for the molecule NS To use faster motion mode 1 Choose Options Use Faster Motion A check mark is displayed next to the drop down list option to indicate that faster motion mode is enabled Objects in the workspace are temporarily displayed as a line drawing when you next perform a manipulation or editing action on your chemical sample When you complete the manipulation or editing of your chemical sample the display style reverts to the currently chosen mode 7 12 BioMedCAChe User Guide Duplicating molecules Duplicating molecules If your molecule includes fragments that are repeated you can build the fragment once and copy it In CAChe you can either duplicate an object or copy and paste it Duplicating workspace objects When you duplicate an object the new copy of the object is offset from the original object slightly and becomes the only object selected You can then manipulate the newly duplicated structure into a new location by using position mode The contents of the Windows Clipboard is not affected by duplicating an object To duplica
252. f lt procedure gt where lt procedure gt is the name of the original procedure To clone an existing experiment 1 Inthe tree view of the Navigator window select the experiment that you wish to clone 2 Choose Edit Copy 3 Choose Edit Paste lt t gt Refer to steps two to eight of Creating a new experiment p 11 25 for details about changing the settings of an experiment CAChe for Windows User Guide 11 27 Chapter 11 Using the Procedure Editor Importing a CAChe experiment 11 28 You can import an existing CAChe experiment into the experiment environment The Open dialog box is used to allow you to select an experiment to import Open Look in Sue i ststi CS SCSY cl HS cachetmp ExpEnvironment Fiene f Files of type Property Index Files idx x Cancel You can import an experiment into the Workspace or ProjectLeader folder of the Navigator window You can also import procedures into the procedure index folder and parameter data into the parameter data folder To do this you should select the procedure index folder or the parameter data folder respectively before using the File Import command NS To import a CA Che experiment 1 Inthe tree view of the Navigator window select one of the following folders a select the Workspace folder if you want the experiment to be available in the Workspace a select the ProjectLeader folder if you
253. f the experiment Some common experimental states that you see during the course of an experiment are a Pending The experiment has been submitted to your PC or to a remote server if you are using CAChe with GroupServer and the experiment is waiting to start because the server is busy with another experiment a Executing The experimental property is currently being computed a Returning Output Files The experimental results are being transferred into automatically generated files on your PC or are being transferred from a remote server to your PC if you are using CAChe with GroupServer The Experiment Status dialog box also displays information generated by the computational applications such as steric energies and heats of formation The relevant computational applications involved in the CAChe for Windows User Guide 10 21 Chapter 10 Performing Workspace Experiments experiment also appear minimized at the bottom of the CAChe application window in the Windows taskbar When the experiment is finished the scrolling window in the Experiment Status dialog box displays the final results of the experiment and the time taken to complete the experiment Stop Extract and Retry are disabled The relevant computational applications involved in the experiment no longer appear minimized at the bottom of the CAChe application window in the Windows taskbar 12 Click and drag on the scroll bar of the scrolling window to
254. f a geometry label color geometry labels by label type or by the standard text color defined in the CAChe color palette CAChe for Windows User Guide 8 21 Chapter 8 Investigating Molecular Geometry Hiding geometry labels Hide or display selected geometry labels in the workspace NS To hide geometry labels 1 Select the geometry label that you want to hide by clicking on the numeral portion of the label with the Select tool 2 Choose View Geometry Label Attributes to display the Geometry Label Attributes dialog box Geometry Label Attributes 29 x Label Color r Label Geometry Labels with V Lock State M Display Geometry Label Cancel Make Default 3 Select the Display Geometry Labels check box so that it is disabled 4 Select OK to close the Geometry Label Attributes dialog box The geometry label that you selected is no longer displayed in the workspace To redisplay geometry labels 1 Do one of the following to select everything in the workspace o Click on an empty area of the workspace with a selection tool o Choose Edit Select All o Press Ctrl A 2 Choose View Geometry Label Attributes to display the Geometry Label Attributes dialog box 8 22 CAChe for Windows User Guide Working with geometry labels 3 Select the Display Geometry Labels check box so that it is enabled 4 Select OK to close the Geometry Label Attributes dialog box All geometry labels in the
255. ffect of increasing the average temperature slightly but if the rest of the molecule is minimized no problems should arise Use this approach with caution and only with small portions of the molecule Generating a Dynamics trajectory a i i s N i D CAChe Dynamics generates a trajectory according to the settings that you specify A trajectory is a collection of structures arranged sequentially in time Each structure has a potential and a kinetic energy associated with it as well as a temperature You can examine the energies and the related structures simultaneously in two side by side windows by opening the map file dynamics map which is created when you perform an experiment in Dynamics Generating trajectories can give you information about e the various conformations that occur as a result of normal molecular motion the structure energy relationships of the molecule BioMedCAChe User Guide 20 9 Chapter 20 CAChe Computational Applications e regions of the conformational space occupied by the system when applying a high temperature and therefore a large amount of kinetic energy to give the molecule enough energy to escape a local energy minimum 20 10 BioMedCAChe User Guide Understanding MOPAC Understanding MOPAC MOPAC concepts BioMedCAChe User Guide MOPAC the Molecular Orbital Package developed by James J P Stewart provides a choice of methods for computing
256. fferent printer from the one displayed in the Printer panel select the arrow button in the Name box and choose a printer from the drop down list The printer s status type and location are displayed in the Printer panel of the dialog box CAChe for Windows User Guide 4 23 Chapter 4 Creating Chemical Samples 3 To change the properties of the printer select Properties to display a dialog box containing specific options for your printer type HP LasewWet 4 4M Plus PS Properties 12 x Paper Graphics Device Options PostScript Resolution Halftoning Use printer s settings Use settings below Screen frequency 95 0 Screen angle js 0 Special T Print as a negative image T Print as a mirror image Scaling fi oo X Restore Defaults 4 Select the Paper Graphics Device Options or Postscript tab to display and select the options relevant to your printer NOTE The bitmap created depends on the resolution set for your printer Therefore high printer resolution will create a smoother print but will take longer to print Lower printer resolution will be faster to print and can be useful for very large shaded spheres e g large atoms 5 Select OK to close the dialog box of printer properties and to return to the Print Setup dialog box 6 Select OK in the Print Setup dialog box to save the selected printer and its properties and to close the Print Setup dialog box
257. fining secondary structure 21 4 Sequence property parameters 21 9 Understanding Dihedral Angles for Building Understanding Sequence Alignment 21 12 Peptides 21 6 Alignment concepts 21 12 3D structure concepts 21 6 Predefined dihedral angles for regular D i i s N i D Chapter 21 CAChe BioComputations Understanding Residue Names Residue names used in CAChe are those defined in the Protein Data Bank Contents Guide Atomic Coordinate Entry Format Description Version 2 1 draft October 25 1996 Amino acids are defined in the following table Name 3 a i a Formula Mol wt Alanine ALA A C3 H7 N1 02 89 09 Arginine ARG R C6 H14 N4 02 174 2 Asparagine ASN N C4 H8 N2 03 132 12 Aspartic acid ASP D C4 H7 N1 04 133 1 ASP ASN ambiguous ASX B C4 H71 2 N11 2 031 2 132 61 Cysteine CYS C C3 H7 N1 02S1 121 15 Glutamine GLN Q C5 H10 N2 03 146 15 Glutamic acid GLU E C5 H9 N1 04 147 13 GLU GLN ambiguous GLX Z C5H91 2 N11 2 031 2 146 64 Glycine GLY G C2 H5 N1 02 75 07 Histidine HIS H C6 H9 N3 02 155 16 Isoleucine ILE I C6 H13 N1 02 131 17 Leucine LEU L C6 H13 N1 02 131 17 Lysine LYS K C6 H14 N2 02 146 19 Methionine MET M C5 H11 N1 02 S1 149 21 Phenylalanine PHE F C9 H11 N1 02 165 19 Proline PRO P C5 H9 N1 02 115 13 Serine SER S C3 H7 N1 03 105 09 Threonine THR T C4 H9 N1 03 119 12 Tryptophan TRP W C11 H12 N2 02 204 23 Tyrosine TYR Y C9 H11 N1 03 181 19 Valine VAL V C5 H11 N1 02 117 15
258. formation window and the spherical marker in the graph window displays the corresponding graph location To display a conformation in the conformational analysis list double click on the conformation in the list A second conformation window opens displaying the selected CAChe for Windows User Guide Viewing map files conformation 9 To view the first conformation in the map file range of conformations select the rewind button shown to the left in the 44 Animate Along Horizontal Axis Animate All Conformations or Animate Analyzed Conformations dialog box The conformation window displays the first conformation in the range The marker in the graph window moves to the beginning of the graph 10 To view the last conformation in the range select the forward button shown to the left in the Animate Along Horizontal Axis Animate All Conformations or Animate Analyzed gt gt Conformations dialog box The conformation window displays the last conformation in the range The marker in the graph window moves to the end of the graph 11 To modify the range of steps by which you are animating the molecule do one of the following a Select the up or down arrow buttons in the Step by text box to increase or decrease the value displayed a Click in the Step by text box in the Animate Along Horizontal Axis Animate All Conformations or Animate Analyzed Conformations dialog box and enter the number of steps by whic
259. ft key To deselect a group of selected objects near to each other 1 Position the Select tool to one side of the group of objects you want to deselect Hold down the Shift key and click and drag the Select tool to form a selection box around the group of objects you want to deselect The objects are grayed out to show that they are deselected If the objects you want to deselect are not close to each other you can also deselect more than one object by holding down the Shift key while you click on subsequent objects To deselect more than one object by clicking Position the Select tool over the object you want to deselect Hold down the Shift key and deselect the object by clicking on it Position the Select tool over the second object you want to deselect Hold down the Shift key and deselect the second object by clicking on it The second object you deselected is grayed out to show that it is deselected Position the Select tool over the third object you want to deselect Hold down the Shift key and deselect the third object by clicking on it The third object you deselected is grayed out to show that it is deselected Continue to hold down the Shift key and click on objects until you have deselected everything you want BioMedCAChe User Guide Using CAChe Using the Select tool to select every visible object in the workspace Select everything displayed in the workspace using any of the three selecti
260. g Mechanics The electrostatic term is calculated from dipole dipole interactions for the standard non augmented force fields For the augmented force fields the dipoles are decomposed in to atomic charges before evaluation Partial charges can only be added to a structure if they already exist in the structure file The potential energy of the molecule varies as the nuclear positions of the atoms change and can be thought of as a multidimensional potential energy surface The potential energy surface has hills corresponding to strained high energy conformations and valleys corresponding to low energy conformations The goal of molecular mechanics optimization is to adjust the positions of the atoms until finding an optimum molecular geometry This optimum geometry corresponds to a minimum or valley in the potential energy surface Molecular mechanics optimization techniques find an optimum geometry by systematically moving all atoms until the net force acting on each atom approaches zero The CAChe Mechanics application implements Allinger s standard MM2 force field and MM3 force fields CAChe significantly augments these force fields by providing rules that estimate the force field parameters for cases not addressed by the standard force fields Augmentations enable minimization calculations for square planar trigonal bipyramidal and octahedral atoms The Mechanics computational application consists of the MechanicsComputeEngine
261. g box The selected locked atoms no longer display the L label CAChe for Windows User Guide 8 33 Chapter 8 Investigating Molecular Geometry To redisplay locked atom labels 1 Select the locked atoms whose label you want to redisplay by clicking on the atoms with a selection tool 2 Choose View Atom Attributes to display the Atom Attributes dialog box 3 Select the Label tab to display a list of options for labeling atoms Select the Locked State check box so that it is enabled 5 Select OK to close the Atom Attributes dialog box The selected locked atoms display an L label to indicate that they are locked Selecting locked atoms You can select all the locked atoms in the workspace whether or not the atoms are labeled as locked Y To select all locked atoms 1 Choose Edit Select Locked Atoms All locked atoms in the workspace are highlighted to show that they are selected 8 34 CAChe for Windows User Guide Disabling locked geometry Disabling locked geometry You can enable or disable locked geometry at any time Locks are enabled by default until you disable them CAChe allows you to disable e locked geometry labels e locked atoms Disabling the locks on geometry labels and atoms allows you to move the participating atoms around the workspace However if you do not return the participating atoms of a locked geometry label to their locked values you create a broken lock which is d
262. g in motion While Mechanics methods can produce low energy conformations for molecular systems they offer no information about the motions of the atoms A molecular dynamics trajectory approximates the real motions in a molecular system by using the same force field equations that describe the potential energy of a molecule in terms of molecular geometries to evaluate the forces on each atom D E i s N i D By integrating Newton s equation of motion atomic velocities can be obtained from the forces on each atom For any given temperature an initial set of velocities can be selected from the Maxwell Boltzmann distribution and a trajectory through time can be generated for any molecular system The CAChe Dynamics program uses the same force fields as the CAChe Mechanics program and it utilizes the Verlet algorithm to update the velocities The Verlet algorithm is a second order numerical integration of Newton s equation of motion This dynamics simulation conserves the total potential plus kinetic energy and the volume of the entire system This type of simulation is also known as a microcanonical ensemble at temperature T Dynamics is intended to provide a window into the types of internal motion molecules undergo While it attempts to duplicate real BioMedCAChe User Guide 20 7 Chapter 20 CAChe Computational Applications Temperature 20 8 molecular motions there are some practic
263. g on it in the tool palette The cursor is displayed as the Rotate tool shown to the left To rotate objects around the z axis 1 Position the Rotate tool outside of the circle that indicates the center of the workspace 2 Click and drag the Rotate tool All objects in the workspace are rotated around the z axis of the workspace coordinates To rotate objects around the x and y axes 1 Position the Rotate tool inside the circle that indicates the center of the workspace 2 Click and drag the Rotate tool All objects in the workspace are rotated around the y axis if you drag the Rotate tool to the left and right and around the x axis if you drag the Rotate tool up and down Dragging the tool diagonally moves objects around the x and y axis Use the Translate tool to move workspace objects in two dimensions To select the Translate tool 1 Select the Translate tool by clicking on it in the tool palette BioMedCAChe User Guide Using CAChe ih The cursor is displayed as the Translate tool shown to the left Using the Translate tool To move objects in two dimensions 1 Position the Translate tool anywhere in the workspace 2 Click and drag across the workspace All objects in the workspace move in the direction that you dragged the tool The Scale tool Use the Scale tool to e zoom in on workspace objects e zoom out from workspace objects Y To select the Scale tool Q 1 Select the Scal
264. g on the item For example the scrolling list shown below displays a list of files Select a file by clicking on it beauben csf a benzen2 csf benzenel csf benzene2 csf btane csf chem1 csf chem2 csf chem3 csf ad To select an item ina scrolling or non scrolling list 1 Position the cursor over the item you want to select 2 Press the left mouse button to select the item The item is highlighted The scrolling list shown below displays folders in the cache folder on a computer s C drive Open a folder to view the files inside by double clicking on the folder icon or name eyes 3 cache C app C benzen2 io C benzene2 io C bin To open an item in a scrolling or non scrolling list 1 Position the cursor over the item you want to select 2 Press the left mouse button twice in quick succession to select and open the item at the same time If the item is a folder the files within that folder are displayed in the dialog box If the item is a file the file opens BioMedCAChe User Guide Using CAChe Scrolling and non scrolling windows Windows display information Many windows have scroll bars that allow you to view text that has scrolled off the screen The following window is a scrolling window CalcMgr 2 0bl Mar 25 1996 09 30 31 IMOPACManager 2 0bl Mar 25 1996 09 52 49 IMOPACComputeEngineSmall 2 0bl Mar 25 1996 09 39 58 Cycle 1 Time 1 4 Time left 863997 0 Grad 37 657
265. g workspace objects Select workspace objects individually in groups or molecule by molecule Use one of the four selections tools to select what you require in the workspace When you select a workspace object it becomes highlighted in the workspace to show that it is selected while other objects appear grayed out to show that these objects are deselected You can also select workspace objects from the Sample Property Window described in Selecting chemical sample data p 6 34 and you can select objects by searching for specific properties using the Edit Find command Edit Select Neighbors Select Locked atoms TIP Objects such as atoms bonds and labels can be hidden in one or more views and possibly visible in other views Hidden objects in one view can be selected using the selection tools in a different view where they are visible Since commands operate on any selected objects whether hidden or visible it is important to remember which hidden objects are selected If you forget which objects are selected use the command View Hide Unselected to hide all unselected objects and to display any hidden selected objects The selection tools The workspace palette contains four selection tools e the Select tool e the Select Molecule tool the Select Similar tool e the Select Group tool Select a tool by clicking on it in the tool palette As you point at a tool icon with the cursor the name of the tool
266. geometry labels 8 25 partial charge and MO polarity 15 13 surfaces 15 13 tables 15 13 threshold values 15 12 Color dialog box 6 41 Color index 15 14 Color palette changing 6 41 editing 6 38 view 6 40 Comments adding 12 21 Completing molecules 4 9 Comprehensive command Beautify menu 4 15 Computational applications 20 1 Computational chemistry 2 8 Compute engine data editing 11 23 Computer aided chemistry accuracy 2 10 an overview 2 7 CONFLEX 2 21 20 23 Conformation properties 10 8 Conformation text box 8 45 Conformational analysis window 14 22 1 4 Conformations 14 9 low energy 14 1 Connectivity indexes 12 2 Coordinate covalent bonds 5 33 Copy objects to other Windows applications 7 16 Copying objects 7 14 Copying objects from ChemDraw ISIS Draw 7 17 Copying sample properties 12 18 COSMO 20 19 Creating a group package 11 31 chemical samples 4 1 experiments 11 25 Crystal Shape dialog box 6 55 Crystal structures building a molecular crystal 6 60 building an infinite lattice 6 62 building asymmetric atoms 6 60 creating CrystalStructure files 6 63 defining cell parameters 6 57 defining fractional coordinates 6 58 displaying and hiding crystal boundaries 6 63 importing data from a text file 6 65 selecting a space group 6 55 ShelX files 6 65 Current energy 2 14 10 6 calculating 13 11 Cutting objects 7 18 D Define charge dialog box 5 27 Define custom colors 6 42 Defining atom groups 7 24 search labels
267. gle from a staggered conformation adds to the steric energy of butane Other factors such as hydrogen bonding are stabilizing and reduce the total steric energy for your sample CAChe performs as many optimization iterations as necessary and stops when the steric energy change between iterations becomes acceptably small At the end of an optimization your chemical sample s geometry corresponds to a steric energy minimum although it might not be the absolute global minimum The following example shows how CAChe optimizes a butane molecule with a strained dihedral angle so that the atoms of the CAChe for Windows User Guide 13 3 Chapter 13 Optimization and Energy Calculations optimized molecule do not deviate from the classical mechanical ideal and therefore steric energy is minimized A strained dihedral A perfectly staggered angle in butane dihedral angle Optimizing with quantum mechanics Quantum mechanics uses the presence and positions of electrons between atoms to calculate a minimum energy structure based on the Schr dinger equation Quantum mechanical procedures in CAChe calculate an energy related to the heat of formation for different structures of the molecule until the energy is minimized Quantum mechanics also allows you to compare heat of formation values for different chemical samples as well as comparing the energy values of different conformations of the same molecule Heat of formation energy
268. group and unit cell parameters the necessary transformations are performed to create the unit cell You specify the number of times the unit cell is repeated in three dimensions to build the crystal structure Selecting a space group When you select a space group you are choosing the transform used to build the crystal from asymmetric atoms The choice of space group includes e short International Hermann Mauguin space group symbols e common abbreviated names specific names for the alternate symbols of monoclinic space groups To select a space group 1 Select the crystal structure that you want to change by clicking on it with the Select Molecule Tool 2 Choose Edit Crystal Shape to display the Crystal Shape dialog box Crystal Shape BE Main Fractional Coordinates m Space Groups Space Group m Identification Space Group Name P1 Number 1 Descriptor Crystal System Triclinic Specific Name P1 Build Angles C Asymmetric atoms only C Molecule C Molecular Crystals C Infinite Lattice None m Lattice Boundaries fo 000 1 000 in the a direction P 90 000 a 1 000 A to fo 000 to 11 000 in the b direction p eooo d b hoo A to fo coo 1 000 inthe c direction y 90 000 gt c fioo0 A Conce ay CAChe for Windows User Guide 6 55 Chapter 6 Viewing Chemical Samples 6 56 a In the Space Groups panel select the arrow button in t
269. gy of a chemical sample in its existing geometry without changing or optimizing its current geometry CAChe provides procedures that use one of the following classical mechanics which calculates the current steric or potential energy of the molecule e quantum mechanics which calculates the heat of formation of the molecule CAChe current energy procedures also enable you to e include solvation effects of water while calculating the current energy of your molecule Calculating current energy with classical mechanics CAChe examines bond angles and atom distances in your molecule and compares the geometry to the classical mechanical ideal value Deviations from the ideal accumulate a relative energy quantity known as steric or potential energy CAChe calculates these deviations from the ideal and computes a steric or potential energy value for the molecule without altering its structure Calculating current energy with quantum mechanics Quantum mechanics uses the presence and positions of electrons between atoms to calculate the energy of a structure based on the Schr dinger equation Quantum mechanical procedures in CAChe calculate an energy related to the heat of formation for a molecule NOTE Calculating current energy using quantum mechanics is not available in Personal CAChe CAChe for Windows User Guide 13 11 Chapter 13 Optimization and Energy Calculations Including solvation effects CAChe all
270. h end of the bond Atom color is specified using the Atom Attributes dialog box lt i gt Refer to Changing the appearance of atoms p 6 8 for more information on specifying atom color For example if a bond is drawn between an atom colored by a specific color blue and a carbon atom colored by element type the bond will be half blue and half black atom element color colors the selected bonds with the element color from the periodic table settings lt t gt Refer to Changing view settings p 6 37 for information on how to edit element color settings for the periodic table bond type colors the selected bonds by the type of bond Single bonds are colored with color index 3 double bonds are colored with color index 4 triple bonds are colored with color index 8 weak bonds are colored with color index 5 coordinate bonds are colored with color index 7 and ionic bonds are colored with color index 1 lt t gt Refer to Editing the color palette p 6 38 for information on changing the assigned bond type colors by editing the CAChe color palette calculated bond strain colors the selected bonds by the calculated bond strain The calculated bond strain is mapped onto the bond order values and the color indexes used are the same as for bond type This option is only useful after a calculated bond strain experiment has been run on your chemical sample CAChe for Windows User Guide 6 25 Chapte
271. h you want to animate the molecule 12 To finish the animation do one of the following a Select Done in the relevant Animate dialog box to close the dialog box and to display the conformation at which you finished the animation in the conformation window a Select Cancel to close the relevant Animate dialog box and to display the conformation you had prior to animating the map file CAChe for Windows User Guide 14 29 Chapter 14 Investigating Low energy Conformations Saving map files 14 30 CAChe offers two saving options that are specific to map files You can save the following e the current conformation in the conformation window as a new chemical sample file selected conformations in a conformational analysis window as new chemical sample files You can save one or more conformations from the conformational analysis window Each conformation is saved into a separate chemical sample file NS To save a conformation in the conformation window as a chemical sample file 1 Activate the conformation window which displays the conformation that you want to save as a chemical sample file Choose File Save As Chemical Sample to display the Save As dialog box Click in the File name text box and type the name of the new chemical sample file Select the arrow button in the Save as type box and choose Chemical Sample csf from the drop down list Select Save to save the conformation in the chemical sample
272. haded spheres 6 11 surfaces 15 18 Shape index order 12 3 SHEET 21 5 Shortcuts keyboard A 1 A 2 menu options A 3 toolbar 3 21 A 1 A 6 Show surfaces dialog box 15 9 BioMedCAChe User Guide Single covalent bonds 5 32 Size and element limitations 10 31 Solvation effects 13 2 Solvent effects modeling 20 19 Sparkles 20 16 Specifying analysis criteria 14 24 angles and distances within molecules 8 12 Spectra 20 11 infra red 18 2 UV visible 12 3 18 6 visible 12 3 Starting CAChe 3 2 Stationary geometries 20 17 Statistical analysis 12 23 Status bar 3 6 hiding 3 6 Steric energy 12 3 lowering 2 4 Stop an experiment dialog box 10 24 10 27 10 30 Stopping experiments 10 24 Strain bond 16 12 Structures 7 21 Style bar 3 9 3 40 5 19 hiding 3 12 9 23 sequence view 9 21 Superdelocalizability 10 7 15 5 15 16 Superimposing molecules 8 6 Superposition removing 9 44 Surface attributes dialog box 15 11 15 19 Surface legend dialog box 15 12 Surfaces 15 13 15 15 15 18 15 20 3D 20 22 color 15 13 dotted 15 20 hiding 15 10 interpreting color 15 11 labels 15 21 viewing 15 9 Index Susceptibility 2 14 10 7 15 4 15 16 T Table of procedures 10 10 Tabs 3 27 Tabulator 2 21 20 22 Temperature 20 8 Text boxes 3 23 Tips icon 1 6 6 30 8 10 Title bar 3 9 Title of scatter plots 12 30 Tool palette 3 13 14 14 Toolbar 3 5 buttons 3 21 A 3 hiding 3 5 sequence view 9 19 shortcuts 3 21 A 1 A 6 using 3 21
273. hasizes the valence only approximation used in semi empirical methods Elements parameterized in MOPAC 20 14 MOPAC contains AM1 d parameters for the elements indicated not crossed off in the following periodic table a Haay CIMT BioMedCAChe User Guide Understanding MOPAC MOPAC contains PM3 parameters for the elements indicated not crossed off in the following periodic table NAN Ss RES AGG AIA ege H RRR Pa SEFE AAIE MOPAC contains PM5 parameters for the elements indicated not crossed off in the following periodic table ez E 5 f D a i D For the AM1 d PM3 and PM5 Hamiltonians Rn serves as a capped bond Cb element Cs Ba Po and At serve as and sparkles respectively Xe serves as a dummy atom for all the Hamiltonians When MOPAC encounters one of these elements in your molecule it substitutes the appropriate symbol Also when CAChe processes the results of your MOPAC calculation it replaces the MOPAC symbolic atom with the original element in your molecule A capped bond Cb behaves like a monovalent atom with the exception thatit can alter its electronegativity to achieve exactly zero BioMedCAChe User Guide 20 15 Chapter 20 CAChe Computational Applications NOTE NOTE 20 16 charge in whatever chem
274. hat chemical sample Changing bond shape Bonds can be represented as e single lines e multiple lines e single cylinders e multiple cylinders Scale the radius of a cylinder by e specifying a relative size in angstroms for each cylinder e specifying a relative size in angstroms for a formal bond order of 1 specifying a relative size in angstroms for a calculated bond order of 1 This option is only useful after a calculated bond order experiment has been run on your chemical sample CAChe for Windows User Guide 6 21 Chapter 6 Viewing Chemical Samples Single lines All bond types are displayed as a single line with one line connecting the two atoms as shown in the following example Multiple lines Bonds are displayed as lines with the number of lines connecting the two atoms corresponding to the bond type For example a double bond is displayed as two lines as shown in the following example yA ee 6 22 CAChe for Windows User Guide Changing the appearance of bonds Single cylinders All bond types are displayed as a single cylinder with one cylinder connecting the two atoms as shown in the following example Multiple cylinders Bonds are displayed as cylinders with the number of cylinders connecting the two atoms corresponding to the bond type For example a double bond is displayed as two cylinders as shown in the following example To change bond shape 1 Sel
275. hat the cell contains the procedure used to calculate the property and when the information was last updated The Footnote section displays any footnotes attached to the cell 3 Double click in the Cell text text box to edit the cell contents 4 Click in the Footnote section to add or edit a footnote for the cell 5 Select OK to make the changes and to close the Cell Information dialog box BioMedCAChe User Guide 12 39 Chapter 12 Using ProjectLeader Printing files ProjectLeader enables you to print a copy of a worksheet view or a scatter plot The following sections describe how to e preview a printout change print settings e print a ProjectLeader worksheet or scatter plot Previewing a printout ProjectLeader enables you to view the appearance of a printout before you print S To preview a printout 1 Activate the document window whose contents you want to preview by clicking on the window 2 Choose File Print Preview to enter print preview mode The contents of the window are displayed framed in a page as they would appear in a printout 3 To exit print preview mode choose Close ProjectLeader returns you to the document window Choosing print options You can change the following print options in ProjectLeader which printer to use and its properties e page orientation of a printout e paper size and source 4 To specify a printer and its properties 1 Choose File Page
276. hboring residues waters and HET groups 1 From the workspace choose Edit Select Neighbors The Select Neighbors dialog appears 2 Choose Residues waters HETs from the Select Nearest pull down menu Select Neighbors 21x Number of Atoms 1 Number of Bonds 1 3 Choose the method to Select Nearest by e Selection Radius Number of Atoms Number of Bonds 4 Type the radius number of atoms or number of bonds in the box adjacent to the chosen method 5 Click OK to select the all neighboring residues waters and HETs and add them to the current selection When selecting neighboring residues waters and HETs by number of atoms CAChe creates a list of the atoms closest to the currently selected atoms and orders that list by distance from the selection CAChe then adds the nearest specified number of atoms to the current selection When selecting by number of neighboring bonds CAChe selects CAChe for Windows User Guide 5 17 Chapter 5 Modifying Chemical Samples Selecting water all residues waters and HETs that are closer than the specified number of bonds from the currently selected atoms Using the Select tool in the workspace to select all water molecules in a protein crystal or solvated chemical sample is tedious and error prone CAChe provides a single command that selects all water molecules To select all water molecules 1 Choose Edit Select Water All hidden or visible
277. he introduces computer aided chemistry and CAChe including information about using CAChe to build view and analyze chemical samples running experiments from CAChe using both the workspace and ProjectLeader and an overview of the computational chemistry applications including CONFLEX and MOPAC 1 Introduction to the User Guide S io 6 5 Overview g This chapter describes the structure of this user guide the text styles icons and navigation aids used throughout the manual Understanding the structure and layout of the user guide and the conventions used throughout will aid you in the location of specific information Contents The BioMedCAChe documentation set 1 2 Conventions in this user guide 1 6 New users 1 3 Navigation aids 1 8 About this user guide 1 4 Chapter I Introduction to the User Guide The BioMedCAChe documentation set The BioMedCAChe documentation set consists of e the BioMedCAChe User Guide both on line and printed e the BioMedCAChe Getting Started booklet both on line and printed e the CAChe on line Help release notes for new software versions e installation notes This User Guide covers the functionality of BioMedCAChe explaining how to use BioMedCAChe and some of the underlying concepts 1 2 BioMedCAChe User Guide New users New users If you are using BioMedCAChe for the first time we recommend that you work through the tutorials These can be found in
278. he selected objects and corrects the ring structure and geometry The Beautify Delete Hydrogens menu option deletes all hydrogen atoms from your structure so you can view or experiment on just the backbone of your chemical sample Use the Beautify Valence menu option to replace the hydrogen atoms You can also hide or display hydrogen atoms using the View Suppress Hydrogens menu option Refer to Chapter 6 Viewing Chemical Samples for more information about hiding and displaying hydrogen atoms CAChe for Windows User Guide 4 15 Chapter 4 Creating Chemical Samples To delete hydrogen atoms 1 Select a workspace selection tool by clicking on it in the tool palette 2 Using the selection tool select the portion of your molecule or the entire molecule for which you want to correct valence hybridization ring structure and geometry The objects you have selected are highlighted in the workspace 3 Choose Beautify Delete Hydrogens CAChe deletes all hydrogen atoms in the selected workspace objects 4 16 CAChe for Windows User Guide Saving files Saving files NOTE Saving a new file When you save your chemical sample file in CAChe you save the current orientation of the chemical sample in the workspace and its display style for atoms and bonds chosen from the Atom Attributes and Bond Attributes dialog box options The chemical sample is displayed in the same orientation and disp
279. he Space Group box and choose a group from the drop down list The complete identification for that space group is displayed in the Identification panel of the dialog box The space group name and number the crystal system to which it belongs and the specific name are shown The associated Descriptor is displayed If the space group has more than one descriptor select the arrow button in the Descriptor box and choose the one that you require The Descriptor drop down list is grayed out if there are no choices available for the space group you selected Select Apply to view the crystal structure in the workspace Select OK to accept the changes and to close the Crystal Shape dialog box Space group symbols found elsewhere have equivalent space group nomenclature in CAChe The following table identifies the short International space groups used by CAChe that are equivalent to other published symbols Find the alternative space group nomenclature used in the literature in the column on the right to identify the CAChe equivalent nomenclature on the left CAChe Alternative CAChe Alternative Pmm2 Pmm Imm2 Imm Pmc2 Pmc Iba2 Iba Pcc2 Pce Ima2 Ima Pma2 Pma P4 cm P4cm Pca2 Pca P4 nm P4nm Pnc2 Pne P4 mc P4mc Pmn2 Pmn P4 be P4bc Pba2 Pba 14 md I4md Pna2 Pna 14 cd I4cd Pnn2 Pnn P4mmc P4 mmc Cmm2 Cmm P4mcm P4 mcm Cmc2 Cmc P4nbc P4 nbc Ccc2 Ccc P4 nnm P4 nnm Amm2 Amm P4 mbc P4 mbc Abm2 Abm P4 mnm P4 mnm Ama2 Ama P4 nmc P4 nmc Ab
280. he folder in which you want to save the file select the dialog box button shown to the left a To save the file in a subfolder click and drag the scroll bar in the scrolling list to display the folder where the file is located and double click on the folder to open it 5 Select the arrow button in the Files of type box and choose the file type of the file that you want to open from the drop down list CAChe for Windows User Guide Saving files 6 Do one of the following a Click and drag the scroll bar in the scrolling list to locate the file that you want to open and select the file by clicking on it a Click in the File name text box and type the file name of the file that you want to open 7 Select Open to close the Open dialog box and to open the file CAChe for Windows User Guide 4 21 Chapter 4 Creating Chemical Samples Printing files Previewing a printout CAChe allows you to print a copy of the contents of a workspace When printing window contents are scaled so that all currently visible workspace objects are printed Prints are made as a bitmap at the resolution of your printer You can preview and print the contents of all windows in CAChe regardless of file type The following sections describe how to e preview a printout change print settings e print a CAChe window CAChe allows you to view the appearance of a printout before you print NS To preview a printout 4 22 1
281. he previous one is that the chemical sample file you optimize contains two different structures the substrate which is completely free to optimize and the enzyme whose reactive site is also free to optimize but whose remaining structural mass can be locked Performing the optimization this way saves a great deal of time since the bulk of the chemical sample is not being adjusted Maintaining mutual orientations 13 8 If your chemical sample has a biphenyl structure you may want to investigate the molecule while the two rings are kept at a 60 dihedral angle The following example shows a molecular structure where you may want to lock the angle between two rings before performing an optimization Follow the steps below to perform a selective optimization where the rings are kept at a constant orientation CAChe for Windows User Guide Selective optimization NS To optimize a molecule while retaining a fixed dihedral angle 1 Select all the participating atoms of the dihedral angle by clicking on the first one with the Select tool holding down the Shift key and clicking on the second third and fourth atoms of the dihedral angle Ensure that the first atom you select is the atom that you want to move if you are adjusting the dihedral angle 2 Choose Adjust Dihedral angle to display the Set Dihedral Angle dialog box Click in the Angle text box and type 60 00 Select the Define Geometry Label check box Sel
282. heck box to hide the graph axis title The check mark is no longer displayed in the check box Select the Show Axis Range check box to hide the graph axis range of values The check mark is no longer displayed in the check box Select OK to save the axis display options and to close the Axis Attributes dialog box Select OK to close the Graph Attributes dialog box 14 19 Chapter 14 Investigating Low energy Conformations Changing graph attributes 14 20 You can also choose to hide or display the following graph attributes e all graph axes e all axis labels e the graph function e the spherical graph marker To hide the graph axes of a graph window 1 Activate the graph window of the map file by clicking on it 2 When the graph axes are visible choose View Show Axes The check mark next to the drop down list option disappears to show that the option is disabled The axes of the graph are no longer displayed in the graph window To display the graph axes 1 Activate the graph window of the map file by clicking on it 2 When the graph axes are hidden choose View Show Axes A check mark is displayed next to the drop down list option to show that it is enabled The axes of the graph are displayed in the graph window To hide axis labels 1 Activate the graph window of the map file by clicking on it 2 When axis labels are visible choose View Show Axes Text A check mark is no longer displayed ne
283. heet tab Click on the sheet tab to make the worksheet active Sheet tabs can be renamed Refer to Worksheets p 12 9 for further details Footnotes can be defined for each worksheet cell They are displayed in the footnote display area underneath the ProjectLeader worksheet BioMedCAChe User Guide Using the ProjectLeader workbook Using the ProjectLeader workbook When you start ProjectLeader an empty workbook is displayed The following illustration shows a ProjectLeader workbook to which the following have been added e Chemical Sample files displayed as line drawings here e experiments investigating molecular properties e experimental results contained in the relevant worksheet cells worksheets K ProjectLeader PLPROJ1 olx D Eile Edit Evaluate View Format Window Help e x Chemical Sample Atom Count Conformation Minimum all atoms Energy kcal mole 49 402 1 783 32 495 51 39 300 74 49 182 i g 33 5 610 lt 8 35 25 176 gt Sheet 34 Sheet 2 A Sheet 1 a NOTE The modification state of a project is indicated by a attached to the title of each project window BioMedCAChe User Guide 12 7 Chapter 12 Using ProjectLeader The Chemical Sample column The column title row Worksheet cells The first column in the worksheet is the Chemical Sample column When you add chemical samples to ProjectLeader they are displayed
284. his is a two tabbed dialog box which allows you to define a name description and procedure for the experiment Properties 2 x Properties 2 x General General Experiment BA ge MOPACAMIH20_PLGeo pee eS SS New Experiment Type Procedure Location Common MOPAC Steps Contains Procedure Definition Procedure ti O Browse Package System ProjectLeader ID CAChe SP MOPAC AM1 H20_PLGeo Description i Cancel Original Settings j Cancel Original Settings You can choose the category of experiment property in which you want the new experiment to belong Examples of categories of experiment property include partial charge and electrophilic susceptibility CAChe for Windows User Guide 11 25 Chapter 11 Using the Procedure Editor 11 26 To create a new experiment 1 In the tree view of the Navigator window select the class of experiment property in which you wish to include the new experiment The new experiment will be placed in the folder that you select Perform one of the following actions to display the Properties dialog box a Press the right mouse button and choose New Experiment from the drop down menu a Choose File New Experiment In the Experiment tab enter a name for the new experiment in the Name text box By default the new experiment is called New Experiment Enter the name of the procedure that you wish the experiment to use
285. hold down either the Shift or Ctrl key and press the left mouse button to select the second molecule The second molecule is grayed out to show that it is deselected 5 Continue to hold down either the Shift or Ctrl key while clicking on selected molecules until you deselect all the molecules you require To deselect more than one molecule by clicking and dragging 1 Position the Select Molecule tool to one side of a selected molecule you want to deselect 2 Hold down either the Shift or Ctrl key and click and drag the Select Molecule tool to form a selection box around the selected molecules you want to deselect The molecules you encompassed in the selection box are grayed out to show that they are deselected The Select Similar tool Use the Select Similar tool to k e select all atoms or bonds of a similar type e deselect all atoms or bonds of a similar type CAChe for Windows User Guide 5 9 Chapter 5 Modifying Chemical Samples You can define the criteria for similarity when selecting similar objects with the Select Similar tool by choosing Options Select Similar Settings lt t gt Refer to Defining Similarity p 5 11 for details about how to define similarity criteria W To select the Select Similar tool 1 Select the Select Similar tool by clicking on it in the tool palette The mouse cursor changes to the Select Similar tool shown to z the left Using the Select Similar tool to
286. ial energy of a series of conformations Each conformation is either not optimized rigid map or optimized optimized map The following example shows a three dimensional rigid energy graph Energy 0 34 to 9 63 kcal mole S 2 Oo e gej o _ Dihedral nglel BondAnglet 180 02 to 100 15 to 130 12 degree 180 02 degree CAChe can generate colored electron density surfaces for a chemical sample helping you to predict certain reactive properties The following example shows a line drawing of a furan molecule on the left The electron density surface for the same molecule is shown on the right colored to show susceptibility to attack by an electrophile N BioMedCAChe User Guide Chapter 2 Introduction to CAChe CAChe ProjectLeader can help you automate calculations track chemical samples and maintain a history of work accomplished The following is part of a ProjectLeader table from a quantitative structure activity relationship QSAR analysis of the antibiotic activity of a number of nitrofurans This table can be used to predict the activity of additional nitrofurans One outcome of this analysis is identification of the atoms that are responsible for activity E ProjectLeader NITROFURANS I B Fie Edit Evaluate View Format Window Help Valence Chemical Sample Seles tal log P y Index order 2 4 750 0 979 CHNO 2 546 m Nitrofuran 2 5 050 2 9
287. ially belonged subsequent geometry optimization will return it to the same structure The territories of similar conformers may be located in close vicinity in the conformational space constituting a local network of local territories and less similar conformers may be considered to belong to different localities Therefore the method of perturbing an initial structure to produce a candidate new conformer is also responsible for the efficiency of search To ensure exhaustive generation of all possible starting structures local perturbation is applied to every flexible part in the initial structure The following three modes of perturbation are designed to mimic the elementary process in the thermal movements of a molecule undergoing conformational change corner flap and edge flip for endocyclic parts and stepwise rotation for acyclic parts Corner flap exploits the puckered feature of a ring structure and involves the movement of a corner ring atom to the other side of the local average plane Two to four contiguous dihedral angles are simultaneously changed along the ring The advantages of corner 20 27 D i i s N i D Chapter 20 CAChe Computational Applications Edge flip 20 28 flap are e itis highly efficient in producing a new energy minimum e it can be considered to mimic a barrier crossing step in the elementary process of thermal conformational interconversion e it genera
288. ialog box displays the position of the current conformation in the range of conformations To animate your molecule from the last to the first conformation select the reverse button shown to the left The molecule in the conformation window moves through each variable value to display the range of conformations in reverse order At the same time the spherical marker in the graph window moves in reverse order to each corresponding graph location To display a conformation in a particular location in the range do one of the following In the relevant Animate dialog box select the up or down arrow buttons in the Conformation text box to increase or decrease the value displayed In the relevant Animate dialog box click in the Conformation text box and type the step number of the conformation you want to view The conformation at the specified position in the range is displayed in the conformation window and the spherical marker in the graph window displays the corresponding graph location To display a conformation with a particular variable value do the following In the graph window conformation window or conformational analysis window select the arrow button in the left hand parameter bar box and choose a variable from the drop down list Select the up or down arrow button in the right hand parameter bar box to choose a value for the variable The conformation with the specified variable value is displayed in the con
289. ic Table Settings dialog box Factory Settings is displayed when you select the Color tab Select Factory Settings for All to restore default settings to all elements for all options selected in the Periodic Table Settings dialog box You can also use the Periodic Table Settings dialog box to specify how an atom of a particular element type is corrected using the Beautify menu and how the atom s radius is displayed for a particular atomic charge lt 4 Refer to Defining valence rules p 4 10 for more information on the Periodic Table Settings dialog box Editing the color palette Change the color assigned to workspace objects and atom and bond properties by editing the CAChe color palette The color palette matches one of 14 colors to a property or an object 6 38 CAChe for Windows User Guide Changing view settings You can change any one of the fourteen colors by choosing another pre defined color e creating a new custom color by specifying red green and blue color values and hue saturation and luminosity values Out of the 14 colors in the palette the first 12 colors are assigned an index number These twelve colors appear in dialog boxes that allow you to choose a color for selected bonds and atoms or for elements The remaining two colors in the color palette are not numbered and allow you to change the workspace text color and background color You can change the color for the following a
290. ic is grouped together ensuring that you can easily locate the information that you need There is a comprehensive index at the end of the user guide BioMedCAChe User Guide 2 Introduction to CAChe i ic o 3 b 5 Overview This chapter introduces computer aided chemistry and CAChe including e using CAChe to build view and analyze chemical samples e the accuracy of CAChe calculations compared with measured experimental data e running experiments from CAChe using both the workspace and ProjectLeader e an overview of the computational chemistry applications including CONFLEX and MOPAC Contents Overview of CAChe 2 10 ProjectLeader experiments 2 25 Introduction to computer aided chemistry Using the Procedure Editor 2 27 2 15 The advantages of CAChe 2 16 Calculated versus measured properties 2 17 Performing experiments with CAChe 2 20 Workspace experiments 2 21 Computational chemistry and CAChe 2 28 Introducing the computational applications 2 28 Chapter 2 Introduction to CAChe Overview of CAChe BioMedCAChe is a computer aided molecular design CAMD modeling tool for the Microsoft Windows 98 Windows Me Windows XP or Windows 2000 operating systems CAChe can be used to discover molecular properties and energy values You can also draw and model molecules and perform calculations on a molecule BioMedCAChe and BioCAChe provide insight into biomolecule structure properties
291. ical environment it finds itself It can thus mimic an exactly covalent bond with any atom For example on bonding to a hydrogen it is similar to a hydrogen but if it is bonded to a fluorine atom it behaves like a very electronegative atom If several capped bond atoms are used they behave independently Capped bonds can be used to mimic additional atoms that have been truncated from a crystal structure It is essential that capped bond atoms be placed at a distance of 1 7 A from the atom they are bonded to and that this bond distance be locked so that spuriously large gradients are not calculated Electronic property surfaces cannot be tabulated for molecules that contain capped bond atoms Sparkles behave like 100 ionizable elements For example a sparkle appears much like a barium atom Sparkles represent the neutral atom For example if you wanted to represent the alkaline metal salt of formic acid the formula would be HCOO HCOOCs in the workspace The positive sparkle will donate its electron to the formate ion and the molecule will be neutral Na and K also act as sparkles but they appear as Na and K in the input file Sparkles have no orbitals no heat of atomization and no ionization potentials They have ionic radii of 0 7 A so that two sparkles of opposite sign will form an ion pair with a separation of 1 4 A The and sparkles are assigned very large masses 108 a u so that they behave as fixed
292. ich selects all objects of a similar type e the Select Group tool which selects an atom and all the atoms with which it shares a group BioMedCAChe User Guide 3 13 Chapter 3 CAChe Basics The Atom Bond tool The manipulation tools The scroll bars lt t gt Use the Atom Bond tool to draw atoms and bonds in the workspace Specify element type bond type charge and hybridization first by using the style bar drop down lists The tool palette contains the following manipulation tools the Translate tool which moves objects in the workspace the Rotate tool which rotates workspace objects in three dimensions e the Scale tool which zooms in and out on objects in the workspace Refer to Using the workspace selection tools p 3 29 for further details about the selection tools Refer to Chapter 4 Creating Chemical Samples for details about the Atom Bond tool Refer to Chapter 7 Manipulating Molecules for details about the manipulation tools Use the scroll bars to the right and at the bottom of a CAChe document window to view objects located at the outer edges of the document window or workspace Move the scroll bars to the right of a document window by e clicking and dragging up and down to view objects above and below the currently displayed objects Move the scroll bars at the bottom of a document window by e clicking and dragging to the left and right to view objects
293. ide Using scatter plots 3 To select an entire data set select a data set from the legend All of the data points in the data set are highlighted and the name of the data set is displayed on the vertical axis 4 Use the right mouse button to display the popup menu for any highlighted data point The menu options for any highlighted data point now relate to all of the highlighted data points To toggle the selection of data points a Hold down Ctrl and select the left mouse button to toggle the selection of the selected points All data points that were selected become unselected and data points that were unselected become selected Changing the labeling of the points To label data points 1 To select the data points that you want to label do one of the following a select an individual point to label one point only a select a data set to label an entire data set 2 Click the right mouse button to display the popup menu and choose one of the following menu options Number The number of the point Points are numbered in the order that they appear in the worksheet Name The name of the sample and the number of the point X Value The x value of the point Y Value The y value of the point Value Pairs The x and y values of the points None No label The chosen label is displayed next to the selected points BioMedCAChe User Guide 12 29 Chapter 12 Using ProjectLeader Changing the title of
294. ide hydrogens using the View menu both locked hydrogen atoms and atoms with unsatisfied valence will remain displayed You can also choose to display a warning message if you attempt to save a chemical sample file that contains non standard hybridization or unsatisfied valence Changing view settings for hydrogens and electrons 6 48 To display locked hydrogen atoms and hydrogens attached to atoms with unsatisfied valence 1 Choose Options Valence Settings to display the Valence Settings dialog box Valence Settings 2 x IV Show locked hydrogen atoms and those attached to atoms with unsatisfied valence IV Suppress hydrogens bonded to carbon atoms Cancel I Show electrons attached to Make Default atoms with unsatisfied valence IV When saving files display a warning when any atom has non standard hybridization or unsatisfied valence or the total charge is less than 1 or greater than 1 I Autobeautify electrons Select the Show locked hydrogen atoms and those attached to atoms with unsatisfied valence check box so that it is enabled Select OK to close the Valence Settings dialog box and to save the view setting for hydrogens CAChe for Windows User Guide Changing view settings 4 To display hydrogens not bonded to carbon atoms 1 Choose Options Valence Settings to display the Valence Settings dialog box 2 Select the Suppress hydrogens not bonded to carbon atoms check box so that
295. ied sugars and retinal are in different chains and are not copied Open a new workspace Paste the copied sequence into the new workspace Note that there are two long bonds because some residues are not resolved in the crystal structure They will be removed when the final homology model is constructed Close the 1F88 file Choose File Save and save the structure as bovine rhodopsin csf You will be warned about the large charge on the protein Press OK and continue to save CAChe for Windows User Guide Creating a homology model of the MC4R Building a model of MC4R The melanocortin 4 receptor MC4R a GPCR which is expressed only in the brain is involved in the control of human feeding behavior The agouti related protein AGRP functions as an antagonist of the MC4R Over expression of AGRP in mice gives rise to increased food intake making them obese A 3D structure for the AGRP MCA4R complex could lead to structure based design of drugs that treat eating disorders Here you build a model structure of MC4R from the structure of bovine rhodopsin and a sequence alignment of MC4R and bovine rhodopsin OPSD_BOVIN CLUSTAL W 1 81 multiple sequence alignment Begin here OPSD BOVIN MNGTEG PNFYVPFSNK 016 MOAR MOUSE jf MNSTHHHGMYTSLHLWNRSSHGL 023 OPSD_BOVIN TGVVRSPFEAPQYYLAEPWQFSMLAAYMFLLIMLGFPINFLTLYVTVQHKKLRTPLNYIL 076 MC4R_ MOUSE HGNA
296. ies you require of the printout Select the down arrow button to decrease the number of copies you require a Click in the Number of Copies text box and enter the number of printouts you require 8 Select OK to print the contents of the active document window to a printer and to close the Print dialog box TIP If printing is slow try changing the resolution of your printer as described in step 5 To print a CAChe document window to a file 1 Activate the document window whose contents you want to print to a file by clicking on the window 2 Do one of the following to display the Print dialog box a Choose File Print a Press Ctrl P a Select the toolbar button shown to the left Select the Print to file check box so that it is enabled 4 Select OK The Print to File dialog box is displayed CAChe for Windows User Guide 4 27 Chapter 4 Creating Chemical Samples Print to File Save in Cache al c App Q Btane map C Chem3 iso C Isoprene ic Benzen2 io J Cachetmp J Chemical io L lsoprene rr Benzene2 io Chem io E so io C lsopm2a ic Abin C Chem1 map A soprent io C lsopm2a r Btane io C Chem2 io E lsopren2 io lsoprn2b ic Btane iso E Chem3 io C lsopren2 map C lsopm2b r E File name Dutpu Save as type Printer Files prn x Cancel 5 Select the arrow button in the Save in box and choose a folder or drive in which to save the file from the drop down list 6 Do one
297. iew a dihedral angle value by selecting four atoms and then measuring the rotational angle between the bond connecting the first and second atoms and the bond connecting the third and fourth atoms The following three examples show a dihedral angle with the atoms labeled in the order of selection in each example CAChe for Windows User Guide 8 15 Chapter 8 Investigating Molecular Geometry 8 16 To measure and adjust dihedral angles 1 Select the four atoms that encompass the two bonds between which you want to measure the dihedral angle by clicking on the first atom with the Select tool then holding down the Shift key and clicking on the second third and fourth atom If you are adjusting the dihedral angle ensure that the first atom you select is the atom that you want to move Choose Adjust Dihedral Angle to display the Set Dihedral Angle dialog box Set Dihedral Angle 2x Angle f 0 053938 a degree Cancel V Define Geometry Label Apply Unlock Geometry Lock Geometry m Search between j 80 000000 and 180 000000 using fea steps of 15 000000 degree The current dihedral angle value in degrees is displayed in the Angle text box CAChe for Windows User Guide Specifying angles and distances 3 Do one of the following o Click in the Angle text box and type the new dihedral angle value that you require o Select the Angle text box arrow buttons to increase or dec
298. if you have ZINDO CAChe enables you to view electronic spectra for a molecule created by electron transition between molecular orbitals as electromagnetic radiation in the visible and ultraviolet UV visible region is absorbed by the molecule Absorption bands observed in the UV visible region are associated with changes of orbital occupations so viewing electronic transitions helps identify excited states available for both kinetic and photochemical reactions The relationship between structure and absorption aids the engineering of molecules with specific electronic absorption properties CAChe uses quantum mechanics to compute the energies of excited electronic states When you select a particular spectral transition point on the electronic spectra the molecule is displayed in the workspace with molecular orbital surfaces superimposed on it as shown in the following example You can edit the spectra to adjust the peak width wavelength and area of a selected transition 18 6 CAChe for Windows User Guide Investigating UV visible spectra Viewing UV visible spectra 4 To view UV visible spectra 1 Open one or more chemical sample files for which you have UV visible electronic spectra data 2 Choose Analyze UV visible Transitions to display the UV visible Transitions window If you have more than one chemical sample file open with UV visible spectra data each individual spectrum is displayed in the UV vi
299. ifying bond angle 8 14 Working with search labels 8 37 Specifying dihedral angle 8 15 Specifying a new geometry label as a search Specifying improper torsion angles 8 17 label 8 37 Working with geometry labels 8 19 Changing a geometry label to a search label Defining geometry labels while viewing atom 8 40 distance and bond length 8 19 Defining search labels automatically 8 41 Defining geometry labels from the Adjust menu Manipulating search labels 8 43 8 21 Animating search labels 8 44 Chapter 8 Investigating Molecular Geometry Working with chiral centers CAChe includes helpful functions to make working with the chiral centers in your chemical sample easier CAChe allows you to e identify chiral centers by labeling selected asymmetric carbons e invert the bonded neighbors of a chiral carbon Viewing chiral centers 8 2 Label asymmetric tetrahedral carbons in the workspace with an R or an S to indicate the chirality You can hide or display the labels you add to chiral carbons NS To label chiral centers 1 Select the carbon atoms or molecule for which you want to label chirality by clicking on the atoms or molecule with a selection tool The atoms are highlighted in the workspace to show that they are selected 2 Choose View Atom Attributes to display the Atom Attributes dialog box Atom Attributes 2 xi Type Color Shape Label I Atomic Symbol Tl Hybridization I Locked State I A
300. iment environment Using the tree view Selecting an object NOTE This section outlines the ways in which you can manage the display of the experiment environment This section details how to use the tree view and the list view of the Navigator window To display a new navigator window a Choose Window New Navigator Window A new navigator window is displayed in Procedure Editor The following actions can be performed in the tree view e selecting an object in the tree view e expanding and collapsing folders e renaming objects displaying Procedure and Parameter Data windows You can select a folder or an object within a folder To select an object in the tree view a Position the cursor over the object and press the left mouse button When you have selected an object press the right mouse button to display a pop up menu containing a subset of the menu bar options for that object CAChe for Windows User Guide Managing the experiment environment Expanding a folder NOTE Collapsing a folder NOTE Expand a folder in the tree view to show all the subfolders nested beneath it The presence of subfolders is shown by a plus symbol next to the main folder icon To expand a folder 1 Inthe tree view move the cursor over the plus sign of the folder that you wish to expand 2 Press the left mouse button to expand the selected folder Choosing View Expand All Folders expands every
301. imit is increased to Limit 2 and conformers 18 through 25 are subjected to initial structures When the global minimum or the instant global minimum in a local area is reached the search moves towards a higher energy area and sometime local dips are overlooked in the process The gradual expansion can be utilized to guarantee the thoroughness of the low energy search The search limit is first decided for example 5 kcal mol from the global energy minimum and all the conformers within this first BioMedCAChe User Guide Understanding CONFLEX Local perturbation Corner flap BioMedCAChe User Guide window Limit 1 are used as the initial structures During this search all the conformers are saved even those with energies higher than Limit 1 The limit is increased to Limit 2 and all the conformers in the new window between Limit 1 and 2 are subjected to initial structures in order of increasing energy If local networks of conformers LAN a and LAN b are not connected within the first window LAN b is searched after LAN c in the second window A window width of 7 to 10 kcal mol from the global minimum is generally sufficient to achieve an exhaustive search of the first chemically meaningful window Therefore the variable limitation technique is a useful strategy for keeping the search region under control in the universal search If the perturbation cannot move the starting structure from the territory to which it init
302. imizing a chemical sample The energy minimization procedure is an iterative process Therefore unless there is only one minimum in the potential energy surface the final structure will depend on the starting geometry For example the following graph shows how a starting structure from point A optimized to an energy minimum produces a different low energy conformation than a starting structure from point B on an energy graph Potential energy A q Keal mol y Sequence of conformations 20 4 BioMedCAChe User Guide Understanding Mechanics Generating energy maps with Mechanics Mechanics uses search labels that you add to your molecule before beginning an experiment to generate an energy map t gt Refer to Chapter 8 Investigating Molecular Geometry for more information on search labels When you run the rigid map or optimized map experiment a new assemblage file called energy map is created and saved in an automatically generated folder named with the suffix map Mechanics computes the energies of each conformation resulting from stepping the search labels through the defined range of values The rigid map experiment keeps the structure rigid at the points where search label steps are defined The optimized map experiment optimizes the conformation at each step This computation restricts the relaxation of the molecular structure where search labels are defined that is the more search labels defined the le
303. in the Procedure text box You may enter a name which does not currently exist Alternatively select the Browse button to select an existing procedure The Browse Procedure dialog box is displayed Select a procedure from the list and select OK to add the procedure to the Procedure text box Select the General tab of the Properties dialog box Enter a description of the new experiment in the Description text box Select OK to confirm the details of the new experiment and to close the dialog box The new experiment is added to the folder that you selected in step one If you entered the name of a procedure which does not exist a Procedure window will be displayed to allow you to define it Refer to Modifying a procedure p 11 17 for details about defining a procedure Choose File Save to save the changes to the experiment environment CAChe for Windows User Guide Creating experiments Cloning an existing experiment You can create a new experiment by cloning an existing experiment and modifying its settings A copy of the selected experiment is placed at the same level as the original in the tree hierarchy The procedure referenced within the experiment is also copied The new experiment is assigned the same name as the original with the suffix 2 Similarly the new procedure is assigned the same name as the original with the suffix 2 The description text given to the new copy of the procedure is Copy o
304. in this column You can also open the CAChe Workspace from the Chemical Sample column in order to e view an existing chemical sample contained in the worksheet e create anew chemical sample to add to the worksheet The first row in the worksheet is the column title row The column titles are displayed underneath alphabetically labeled column buttons The property or analysis that you want to calculate is added to the column title cells Experiments and analyses are performed by evaluating worksheet cells The experiment or analysis is defined by the chemical sample in the Chemical Sample column and the experiment or analysis in the column title row Worksheet cells display the status of calculations as they are performed then display the results when experiments are complete Refer to Running a ProjectLeader experiment p 12 20 for more information Mouse actions in ProjectLeader Most tasks in ProjectLeader can be accomplished by using mouse actions Double click on a cell in the Chemical Sample column or the column title row to open a dialog box that lets you define information for that cell Double click on a cell in e the Chemical Sample column to open a sample in that cell BioMedCAChe User Guide Using the ProjectLeader workbook Worksheets the column title row to define the type of information to be displayed in that column a property an analysis or a comment Right mouse click on a cell in
305. inders are z buffered improving depth perception for large molecules CAChe for Windows User Guide CAChe display options e Cylinders displays atoms as small shaded spheres with a van der Waals radius of 1A scaled to 0 05A and bonds as multiple cylinders scaled to 0 1A Colors are not changed Ball and Cylinder displays atoms as shaded spheres with a van der Waals radius of 1A scaled to 0 2A and colored by element and bonds as multiple cylinders scaled to 0 1A colored by atom color e Space Filling Corey Pauling Kolton model displays atoms as shaded spheres with a van der Waals radius of 1A scaled to 1 0A and colored by element e Partial Charge and Calculated Bond Order displays atoms as shaded spheres with a partial charge of 1 a u scaled to 1 0A and colored by partial charge polarity and bonds as single cylinders scaled to 0 1A for a calculated bond order of 1 colored by calculated bond order The Partial Charge and Calculated Bond Order model style is enabled only if you have first run a partial charge or calculated bond order experiment on your chemical sample A t gt Refer to Chapter 16 Investigating Atom and Bond Properties for information on running both a partial charge experiment and a calculated bond order experiment CAChe for Windows User Guide 6 3 Chapter 6 Viewing Chemical Samples Using CAChe model types To view your chemical sample as a line drawing 1 S
306. index Color RGB values Relative value of surface property 1 White 255 255 255 Highest 2 Gray 150 150 150 3 Red 255 0 51 4 Yellow 255 255 51 5 Green 0 255 0 6 Blue 51 51 255 7 Purple 255 0 255 8 Cyan 0 255 255 Lowest CAChe for Windows User Guide 15 13 Chapter 15 Investigating Electron Distribution Electrostatic potential polarity Color index Color RGB values 3 Red 255 0 51 6 Blue 51 51 255 Occupied molecular orbital polarity Color index Color RGB values 6 Blue 51 51 255 5 Green 0 255 0 Partial charge and unoccupied molecular orbital polarity Color index Color RGB values 3 Red 255 0 51 4 Yellow 255 255 51 Bond strain Color index Color RGB values 6 Blue 51 51 255 5 Green 0 255 0 15 14 Electrostatic potential and occupied MO polarity Positive Negative Electrostatic potential and occupied MO polarity Positive Negative Partial charge and unoccupied MO polarity Positive Negative Bond strain kJ mole 0 0 99 1 9 99 CAChe for Windows User Guide Viewing a surface Color index Bond order and bond type Color index 5 Interpreting surfaces Color RGB values Yellow 255 255 51 Red 255 0 51 Color RGB values Green 0 255 0 Red 255 0 51 Yellow 255 255 51 Cyan 0 255 255 White 255 255 255 Purple 255 0 255 Bond strain kJ mole 10 99 99 100 999 99 Bond
307. ing MM geometry MM3 3 Choose Start The geometry is optimized using MM3 Generating peptide conformations After you have built the peptide you locate the lowest energy conformations To generate peptide conformations 1 Using the Select tool in the workspace click on a rotatable C C single bond joining the C atoms outside any rings in the peptide 2 Press Shift and click repeatedly on each remaining rotatable C C bond outside any rings to select several rotations The selected bonds are highlighted 19 6 CAChe for Windows User Guide Investigating peptide conformations 3 Choose Adjust Geometry Label Wizard and change the settings in the Geometry Label Wizard dialog so that rotations around single bonds are explored in two steps from 179 to 61 degrees Geometry Label Wizard 2 x M Generate dihedral search labels for IV Single lonic and Coordinate bonds searching between Cancel 179 and 61 in steps jiza adf a T Double bonds searching between 180 and 90 in 3 steps I Weak bonds searching between 180 and 1150 degree in 15 steps T Include terminal groups Make Default After making the changes so that the dialog appears as above choose OK The peptide structure appears with dihedral labels displayed for each of the previously selected C C bonds 4 Choose Experiment New The Experiment dialog appears 5 Choose a Property of chemical sample c
308. ing an electrostatic potential surface NOTE CAChe investigates the electrostatic potential of a sample by generating an electronic wavefunction using a quantum mechanics computational application and using the data to create a three dimensional surface An electrostatic potential isosurface is created that shows both the polarity of the potential and where in space the potential equals 0 03 a u 418 Kceals mol 75 kJ mol An electrostatic potential surface is particularly useful if you are interested in the reactivity of your sample to a charged or polar reactant CAChe procedures for generating an electrostatic potential surface also enable you to optimize the geometry of the molecule first using classical mechanics quantum mechanics or a combination of both You can combine all optimization procedures with generating electron density for your sample You cannot use procedures that involve MOPAC or ZINDO in Personal CAChe CAChe for Windows User Guide Investigating molecular orbital energies Investigating molecular orbital energies NOTE The following three experiments calculate the energies and shapes of your sample s molecular orbitals by generating an electronic wavefunction in a quantum mechanical computational application e HOMO and LUMO e HOMO 5 to LUMO 4 e all molecular orbitals CAChe procedures for calculating molecular orbital energies also enable you to optimize the geometry of
309. ing or descending alphabetical order NS To sort the entries in the list view 1 Choose one of the following a View List Icons by Name a View List Icons by Description Entries are sorted into ascending alphabetical order CAChe for Windows User Guide Showing properties of a component Showing properties of a component You can select an environment component in the tree view or list view of the Navigator window and display its properties in a Properties dialog box The appearance of the Properties dialog box varies for each type of environment component However the General tab of the Properties dialog box has the following common features Properties BE General Copy of the icon m used in the tree view MOPAC AM1 H20_PLGeo per Type Procedure Type of component Location Common MOPAC Steps and its content Contains Procedure Definition Package System ProjectLeader Package in which the _ ID CAChe SP MOPAC 4M1 H20_PLGeo component resides Description Cancel Original Settings Some properties can be edited to allow you to modify the properties of a particular environment component To display the properties of a component 1 Inthe tree view of the Navigator window select an environment component 2 Choose File Properties The Properties dialog box is displayed CAChe for Windows User Guide 11 13 Chapter 11 Using the Procedure Editor Available prope
310. ing to a blank part of the workspace The type of bond you draw is determined by the current selection in the Bond Type drop down list in the style bar To draw a bond between two existing atoms 1 Select the arrow button in the Bond Type box at the left of the style bar as shown below H Hydrogen x sp3 tetrahedron Charge Single x onic Sin Coordinate A drop down list of bond types is displayed Choose a bond type from the drop down list The bond you draw will be of the chosen bond type Position the Atom Bond tool over an atom you have already drawn Click and drag the Atom Bond tool across the workspace to a blank part of the workspace A bond of the chosen bond type is displayed between the existing atom and a new atom of the currently selected element type The example to the left shows a single bond between two atoms of different element type CAChe for Windows User Guide Completing your molecule Completing your molecule Complete your molecule in one of the following ways continue to draw individual atoms then join them by drawing bonds between each atom continue to draw bonds with an attached atom Finish ring structures by completing the last bond you draw over the first atom that was drawn When your molecule is complete you can e clean up its structure geometry and chemistry change selected atoms to another element type hybridization and atomic charg
311. inst the target in the window where the first superposition takes place Calculating the RMS error 8 10 The RMS indicates the error in molecular geometry between two structures To calculate the RMS error 1 Select the atom s in the structure for which you want the RMS to be calculated 2 Select the same number of corresponding atom s in the second structure in exactly the same order that you selected the atoms in the first structure 3 Choose Analyze Calculate RMS Error The RMS error is displayed in the workspace 4 To move the position of the RMS value click in the centre of the value with the left mouse button and drag to another part of the workspace To select the atoms involved in the RMS calculation 1 Position the Select Group tool over the RMS label and select it using the left mouse button The atoms involved in the calculation are selected 2 Choose Analyze Superimpose The two molecules are superimposed To select the two molecules involved in the RMS calculation 1 Position the Select Group tool over the RMS label and select it using the left mouse button The two molecules that are involved in the calculation are CAChe for Windows User Guide Superimposing molecules selected This enables you to distinguish the molecules involved in the RMS calculation from other molecules in the workspace CAChe for Windows User Guide 8 11 Chapter 8 Investigating Molecular Geometr
312. ions of your molecule by name or property change the atom and bond properties of those selected objects using the workspace style bar change the atom and bond properties of those selected objects using the menu options Contents Modifying atoms and bonds 5 2 Finding workspace objects 5 14 Selecting workspace objects 5 3 Selecting neighbors 5 16 The selection tools 5 3 Selecting water 5 18 The Select Molecule tool 5 6 Changing atom and bond properties 5 19 The Select Similar tool 5 9 CAChe bond types 5 32 The Select Group tool 5 12 Chapter 5 Modifying Chemical Samples Modifying atoms and bonds TIP You can change the components of your molecule and their properties by selecting the objects you want to modify and choosing the new values or properties from either the style bar boxes at the top of the workspace e dialog boxes accessed from the menu that provide further options for modifying your molecule s atoms and bonds Before you can modify the properties of any workspace object you have to select it with one of the selection tools provided in the tool palette to the left of the workspace A quick way to create your molecule is to sketch a chain of atoms and bonds with just one element and bond type You then select individual atoms and bonds and change their properties using the drop down lists in the workspace style bar CAChe for Windows User Guide Selecting workspace objects Selectin
313. ions of your molecule 7 18 Using the Rotate tool 7 3 Cutting workspace objects 7 18 Using the Translate tool 7 5 Deleting workspace objects 7 19 Using the Scale tool 7 8 The undo command 7 19 Manipulating portions of your molecule 7 9 Fusing ring structures 7 21 Using faster motion mode 7 12 Grouping atoms 7 24 Duplicating molecules 7 13 Defining a group 7 24 Duplicating workspace objects 7 13 Selecting groups and portions of groups 7 25 Copying workspace objects 7 14 Changing atom order in groups 7 28 Copying objects from ChemDraw or ISIS Draw Showing residues in Group Atoms dialog box 7 17 7 29 Chapter 7 Manipulating Molecules Using the manipulation tools 7 2 NOTE The CAChe workspace tools allow you to move your chemical sample around the workspace in a variety of ways enabling you to view its properties and spatial geometry more clearly The workspace tool palette provides you with the following three manipulation tools the Rotate tool which rotates objects in two or three dimensions around the workspace x y and z axes e the Translate tool which moves objects around the workspace in two dimensions e the Scale tool which zooms into and out from a workspace object Select a tool by clicking on it in the tool palette When you select a tool the mouse cursor in the workspace changes shape to indicate which tool is currently selected The table below shows the three manipulation tools and their correspondi
314. isplay the protein backbone BioMedCAChe User Guide Viewing biomolecules view the protein as a ribbon Viewing PDB atom names You can view atom names in the workspace To view the PDB atom names 1 Select the atoms or molecule for which you want to view the PDB names by clicking on the atoms groups or molecule with the appropriate selection tool The atoms are highlighted in the workspace to show that they are selected 2 Choose View Atom Attributes to display the Atom Attributes dialog box Atom Attributes 2 x Type Color Shape Label I Hybridization Charge I Partial Charge I Atom Number T Chirality for Asymmetric Carbons T Locked State J Alphanumeric Label T Name Display Atoms Cancel Make Default Select the Label tab to display a list of atom labeling options 4 Select the Name check box so that it is enabled Select OK to display the PDB labels and close the Atom Attributes dialog box Selected atoms are displayed with atom names In large structures atom names may be so small that they are not visible Magnify the protein to see the atom names BioMedCAChe User Guide 9 7 Chapter 9 Manipulating Biomolecules Highlighting residues To highlight a residue 1 Choose the Select Group tool Residues are special types of atom groups 2 Select an atom in a residue All the atoms that share a group with this atom are selected Residues are id
315. isplayed indicating that the toolbar is currently hidden BioMedCAChe User Guide 3 5 Chapter 3 CAChe Basics To redisplay the CAChe toolbar 1 When the toolbar is hidden choose Options Show Toolbar The toolbar is displayed in the CAChe application window A check mark is displayed next to the Show Toolbar drop down list option indicating that the toolbar is currently visible The status bar The status bar is displayed at the bottom of the CAChe application window and describes the action performed by a selected command in a menu drop down list or a selected button in the toolbar In addition the status bar displays the net charge on the molecule the number of atoms and the empirical formula Netchrg 4598 atoms C1410 H2303 N393 0475 P1516 When there is no drop down list option or toolbar button selected the status bar displays the following message For Help press F1 Hiding the status bar You can choose to hide the CAChe status bar To hide the CAChe status bar 1 When the status bar is visible choose Options Show Status Line The status bar is no longer displayed The check mark next to the Show Status Line drop down list option is no longer displayed indicating that the status bar is currently hidden To redisplay the CAChe status bar 1 When the status bar is hidden choose Options Show Status Line The status bar is displayed at the bottom of the CAChe window 3
316. isplayed when you enable locked geometry again Refer to Broken geometry locks p 8 31 for information on repairing broken geometry label locks Moving a locked atom while locks are disabled just moves the locked atom to a new location When locks are enabled again the atom is displayed as locked in the new location When you begin a CAChe experiment disabled geometry label locks and atom locks are automatically enabled and used by the computational applications to freeze the locked coordinates of the participating atoms To disable locked geometry 1 Choose Adjust Enable Locks The check mark next to the Enable Locks drop down list option is no longer displayed indicating that this option is disabled Locked geometry labels and atoms display an LD label to indicate that there are disabled locks present CAChe for Windows User Guide 8 35 Chapter 8 Investigating Molecular Geometry To enable locked geometry 1 Choose Adjust Enable Locks A check mark is displayed next to the Enable Locks drop down list option indicating that this option is enabled Locked geometry labels which have not been broken and locked atoms display an L to indicate that they are locked Broken locked geometry labels display an LB to indicate that a broken lock is present 8 36 CAChe for Windows User Guide Working with search labels Working with search labels Search labels are a form of geometry label that vary the va
317. it in three dimensions and scaling it CAChe uses chemical sample csf files to display and save molecules and associated data After you have created a new chemical sample file in the workspace the menu and workspace will display options to modify and manipulate the molecular structure You can view your molecular structure from any angle 2 Review what you know about your chemical sample and what you want to learn A good problem solving technique is to write down everything you know about a problem before trying to solve it Then make a list of the properties you want to discover uncover You could ask yourself many questions about your particular project It isn t the answers you possess at the moment that are important but the fact that you have looked at your problem closely enough to know what answers will help you 3 Based on your chemical sample and the properties you are interested in run a CAChe experiment to generate the desired data In choosing experimental settings remember that in most cases the standard settings are a good place to start A lt p Refer to Introducing the computational applications p 2 20 for an overview of the computational applications Refer to Chapter 11 Using the Procedure Editor for details about creating experiments and modifying procedures Refer to Chapter 20 CAChe Computational Applications for more detailed information about using procedur
318. it is enabled You can now add orbitals to represent non bonded electrons by using Beautify Valence and Beautify Comprehensive Select OK to close the Periodic Table Settings dialog box and to save the new valence rules applied by using Beautify Valence and Beautify Comprehensive Select Factory Settings to restore default settings for the application of valence rules for the element currently chosen in the Periodic Table Settings dialog box Factory Settings is displayed when you select the Beautify tab Select Factory Settings for All to restore default settings to all elements for all options selected in the Periodic Table Settings dialog box CAChe for Windows User Guide Perfecting your molecule Correcting hybridization To correct hybridization 1 Select a workspace selection tool by clicking on it in the tool palette 2 Using the selection tool select the portion of your molecule or the entire molecule for which you want to correct hybridization The objects you have selected are highlighted in the workspace 3 Choose Beautify Hybridization CAChe examines the hybridization electronic configuration of each selected atom and bond and forces the atomic configurations to match the bond types and atom charges so that electronic configuration is consistent with the number of bonded and non bonded valence electrons You can label atoms with their hybridization using the Atom Attributes dialog b
319. ith Probe Superimpose Target and Probe in New Window OK Cancel Choose the Superposition option to specify where the result appears If you choose to Superimpose Target and Probe in a New Window the new window is titled Superposition Results The probe chemical sample overlaps the target chemical sample in a workspace The selected atoms are highlighted to show that they are selected An RMS error is displayed in the workspace that indicates the error in molecular geometry between the Cy BioMedCAChe User Guide 9 43 Chapter 9 Manipulating Biomolecules Removing superposition 9 44 atoms in the selected residues In the workspace do one of the following to remove the superposition o Choose Edit Undo Superimpose o Press Ctrl Z o Select one molecule by clicking on it with the Select Molecule tool and dragging to move the selected molecule to one side No undo is available if the superposition is done in a new window Simply close the window without saving it to remove the superposition BioMedCAChe User Guide Extending the amino acid repository Extending the amino acid repository By default the amino acid AA repository consists of the templates for the 20 standard amino acids Each of the standard amino acids has the 1 letter code of the amino acid assigned as a keyboard shortcut The shortcut allows you to build a sequence by typing 1 letter codes on the keyboard You may ex
320. itor The dialog box features a Sample n text box where n is the sample number for each of the chemical samples used For example a procedure with two input arguments has a text box for Sample 1 and a text box for Sample 2 The Start button is disabled until the location of all the samples has been specified All output from the procedure is sent to the Output window The dialog box remains open until the procedure has completed or been aborted NS To run a procedure 1 Inthe tree view of the Navigator window select the procedure that you wish to run 2 Choose Run Procedure to display the Run Procedure dialog box 3 Specify the location of Sample 1 in the Sample 1 text box If you are unsure of the location select the Browse button to display the Browse Procedures dialog box 4 Repeat step three for any other required samples Select the Start button to run the procedure using the sample file s specified as input 11 22 CAChe for Windows User Guide Editing the settings of a compute engine Editing the settings of a compute engine NOTE You can edit the input arguments and settings for each of the compute engines available in CAChe Each compute engine has a unique dialog box in which you can edit the settings The dialog box for Mechanics is shown below as an example Mechanics Settings i Lx General Details Output Procedure Argument Run Mechanics on Mechanics Calculatio
321. ity The atoms are highlighted in the workspace 2 Do one of the following gt Choose Edit Invert Chirality o Press Ctrl I The two connecting bonds in the selected chiral center are swapped and the labels R and S are exchanged in the workspace CAChe for Windows User Guide 8 3 Chapter 8 Investigating Molecular Geometry NOTE When you invert a chiral center with four neighboring atoms that are equally free to move you can control which atoms are swapped by first locking the geometry of the two atoms you want to remain unchanged Refer to Locking atoms p 8 32 for details 8 4 CAChe for Windows User Guide Mirroring a molecule Mirroring a molecule NOTE CAChe allows you to mirror the x y and z coordinates of selected atoms about the y and z plane through the center of the workspace Mirroring a molecule is most useful for generating the enantiomer mirror image of a chemical sample To mirror a molecule 1 Select the atoms or molecule that you want to mirror by clicking on the atoms or molecule with a selection tool The atoms are highlighted in the workspace to show that they are selected 2 Choose Edit Mirror The selected atoms or molecule are mirrored about the y z plane of the workspace CAChe cannot mirror a structure with locked atoms or atoms that participate in locked geometry if the mirroring involves breaking the locks If you want to mirror such a molecule disable
322. ize BEI Experiments Procedures Parameter Data In System System To User User Fl Workspace J chemical sample EJ optimized geometry Dele n standard procedure OG_ I Workspace I ProjectLeader n fastest procedure OG_M Sy MM geometry MM2 OG Sy MM geometry MM3 OG Sy MM AM1 geometry OG_ dy MM PM3 geometry 0G zj gt Experiments Available In Experiments Available In Create Package User User x System System Description No selection a Close L This is a three tabbed dialog box that allows you to copy files between user and group packages CAChe for Windows User Guide 11 31 Chapter 11 Using the Procedure Editor 11 32 To create a group procedure package 1 Create experiments procedure definitions and parameter data as required in your own user package Refer to Creating anew experiment p 11 25 for details about creating an experiment Refer to Modifying a procedure p 11 17 for details about modifying a procedure Refer to Expert modification p 11 30 for details about modifying a parameter data set Choose File Organizer The Organizer dialog box is displayed This dialog box is displayed with an active tab which reflects the currently selected component in the tree view In the Experiment tab select the Create Package button The Create Package dialog box is displayed Select Package Set User C Prog
323. k on an empty cell in the Chemical Sample column The CAChe Workspace is opened displaying a new empty Chemical Sample file The selected worksheet cell is colored pink to indicate that it is linked to the Chemical Sample file that is currently displayed in the Workspace 2 Draw a molecule and save the Chemical Sample file The chemical sample is displayed in the relevant ProjectLeader worksheet cell lt t gt Refer to Chapter 4 Creating Chemical Samples for details about drawing and saving the molecule Copying objects from ChemDraw ISIS Draw or ChemFrontier You can copy any selected object to the Windows Clipboard from ChemDraw ISIS Draw or ChemFrontier and paste it into a ProjectLeader worksheet Likewise you can copy an object to the Windows Clipboard from a ProjectLeader worksheet in MDL format and paste it into one of these programs To copy and paste an object from ChemDraw ISIS Draw or ChemFrontier 1 Select the object that you want to copy by clicking on it with a selection tool 2 Do one of the following a choose Edit Copy a press Ctrl C 3 Select an empty cell in the Chemical Sample column in which to paste the object BioMedCAChe User Guide 12 15 Chapter 12 Using ProjectLeader 12 16 Do one of the following a choose Edit Paste a press Ctrl V The Save As dialog box is displayed Enter a name for the file and select Save A copy of the selected object is past
324. l Samples CAChe bond types Single covalent bonds Double covalent bonds 5 32 CAChe recognizes the following seven types of bonds e single covalent bonds e double covalent bonds e triple covalent bonds e weak bonds e ionic bonds e coordinate covalent bonds dative bonds e nm coordination bonds Single covalent bonds share two electrons between two atoms in a single bond created by the overlap of one orbital from each bonded atom Each atom contributes one of its valence electrons to the bond The following example shows a single covalent bond displayed as a cylinder Double covalent bonds share four electrons between two atoms in two bonds created by the overlap of two orbitals on each atom Each atom contributes two of its valence electrons to the bond The following example shows a double covalent bond displayed as multiple cylinders CAChe for Windows User Guide Changing atom and bond properties Triple covalent bonds Weak bonds lonic bonds Coordinate covalent bonds Triple covalent bonds share six electrons between two atoms in three bonds created by the overlap of three orbitals on each atom Each atom contributes three of its valence electrons to the bond The following example shows a triple covalent bond displayed as multiple cylinders Weak bonds allow you to explicitly represent the weak interactions between two atoms A common example is the hydrogen bond shown below in the
325. l mode is necessary You choose the initial displacement by specifying a vibrational mode and a positive or negative direction for the initial motion A DRC with no damping simulates the motion of the atoms of the single molecule in the gas phase where none of the kinetic energy gained from losing potential energy would be lost and would thus be converted into kinetic energy D i i s N i D For DRC calculations you may specify that only geometry information is output and included in the map file when atom coordinates the heat of formation or time has changed by a certain amount This is useful when you want to run the trajectory for a long time but do not want to generate very large output files Modeling solvent effects with COSMO MOPAC contains a method for modeling the effect of highly polar solvents COSMO Conductor like Screening Model developed by Klamt and Sch rmann approximates the dielectric screening BioMedCAChe User Guide 20 19 Chapter 20 CAChe Computational Applications Large molecules 20 20 energy of a solvent by the method of image charges It assumes that the medium is a conductor For water this is a very good approximation The method is generalized by constructing a conducting polygonal surface based on the van der Waal s atom radii and an effective solvent radius A good example of the method is modeling the solvent effect of water on the geometry of al
326. l to select a molecule by e clicking on a molecule in the workspace NS To select a molecule 1 Position the Select Molecule tool over the molecule you want to select 2 Press the left mouse button to select the molecule The molecule is highlighted to show that it is selected Hidden atoms in the molecule are selected To display selected hidden atoms choose View Hide Unselected Using the Select Molecule tool to select more than one molecule Use the Select Molecule tool to select more than one molecule by e clicking on the molecules in the workspace while holding down either the Shift or Ctrl key e clicking and dragging around the molecules in the workspace To select more than one molecule by clicking 1 Position the Select Molecule tool over the molecule you want to select 2 Press the left mouse button to select the molecule CAChe for Windows User Guide 5 7 Chapter 5 Modifying Chemical Samples The molecule is highlighted to show that it is selected 3 Position the Select Molecule tool over the second molecule you want to select 4 Hold down the either Shift or Ctrl key and press the left mouse button to select the second molecule The second molecule is highlighted in the workspace to show that it is selected 5 Continue to hold down either the Shift or Ctrl key while clicking on molecules until you select all the molecules you require To select more than one molecule by clicking
327. lating Molecules To undo an editing action 1 Choose Edit Undo Workspace objects resume their position or state prior to the last editing action that you performed on the workspace To redo an editing action after choosing undo 1 Choose Edit Redo Workspace objects resume their position or state after the last undo action you performed NOTE The Undo option from the Edit menu does not apply to the option Edit Save which you cannot undo 7 20 BioMedCAChe User Guide Fusing ring structures Fusing ring structures CAChe allows you to bond two ring structures together by fusing selected atoms from one ring onto selected atoms from the other ring When fusing cyclic structures you can either e fuse two atoms where the first atom you select is replaced by the second atom you select The second atom inherits all the connections of the first atom in addition to its own and its valence is automatically adjusted e fuse two bonds by fusing two sets of atoms The first atom you select in the first set is replaced by the second atom in that set and the first atom in the second set is replaced by the second atom in that set Once you fuse ring structures use the Beautify menu to correct the bond lengths geometry and hybridization of the resulting structure NS To fuse two atoms 1 Select an atom in the first ring structure by clicking on it with the Select tool The atom is highlighted to sh
328. lay ratio of a bond order of one to your choice of measurement in Angstroms Many models use alternating single and double bonds resonance structures to represent delocalized m electrons in rings For example in benzene all of the C C bonds are the same length This could not be the case if half the bonds are double and half are single Calculating bond order using a CAChe experiment and displaying the results by scaling bond cylinders by calculated bond order shows CAChe for Windows User Guide Calculating bond properties that all the C C bond orders are equal and greater than the C H bond orders The cylinders between carbons are roughly one and a half times thicker than those between carbons and hydrogens illustrating the bond order of 1 5 The following example shows a benzene molecule with bonds sized to reflect calculated bond orders Calculating bond strain Bond strain is a purely classical mechanical quantity calculated every time a classical mechanical calculation is performed As a result this property is often a subset of the results when you experiment with other properties CAChe examines bond angles and atom distances in your molecule and compares the geometry to the classical mechanical ideal value Deviations from the ideal accumulate a relative energy quantity known as steric or potential energy CAChe calculates these deviations from the ideal to discover bond strain After you run a bond strain e
329. lay style in which you saved the file when you next open it Refer to Chapter 6 Viewing Chemical Samples for information on the Atom Attributes and Bond Attributes dialog boxes You can save all files of all file types in CAChe using the menu options described in the next sections Saving a new file and Saving an existing file When you change a new or existing file in CAChe an asterisk is displayed next to the file name in the workspace title bar to indicate that the file is changed and you need to save it Once you save the file the asterisk disappears To save a previously unsaved file 1 Choose File Save If this is the first time you are saving the file the Save As dialog box is displayed CAChe for Windows User Guide 4 17 Chapter 4 Creating Chemical Samples Save As Save in Ja Cache x ce Ea App C Btane iso C Chem3 io C lsopren2 rr L Benzen2 io C Btane map 3 Chem3 iso C Isoprene ic Benzene2 io C Cachetmp C Chemical io C lsoprene r bin E Chemt io E Iso io E lsopm2a ic BOND io E Chem1 map A Isoprent io C lsopm2a r Btane io C Chem2 io C lsopren2 io C lsopm2b ic File name Save as type JExperiments exp O Cancel Help 2 Select the arrow button in the Save in box to display a drop down list of p a folders in the directory structure above the currently open folder a available drives on which you can save the file 3 Choose the folder or d
330. layed in the parameter bar at the bottom of the window and a small spherical 14 12 CAChe for Windows User Guide Viewing map files marker indicates the corresponding energy location in the graph in the left window the graph window The graph displayed in the graph window can be rotated in two or three dimensions The colors of the graph in the graph window represent the relative energies of graph locations and their equivalent conformations The two windows are interactive If you click on a graph location in the graph window the conformation window displays the conformation that corresponds to the selected point on the graph You can also move the marker step by step along the graph using the up down left and right arrow keys The conformation window displays the corresponding structure as the marker moves throughout the graph Both windows contain atool palette similar to the workspace tool palette a parameter bar that displays the x y and z parameters of the graph If you close a graph window and save the map file the next time the file is opened only the conformation window is displayed 4 To display a graph window 1 Choose Window New Graph Window The graph window corresponding to the conformation window is displayed CAChe for Windows User Guide 14 13 Chapter 14 Investigating Low energy Conformations Using the tool palettes The tool palette in both map file windows contain too
331. lculation of quantitative structure activity relationships QSAR between molecular structure and pharmacological activity and quantitative structure property relationships QSPR between molecular structure and properties such as boiling points octanol water partition coefficients and dipole moments You can use ProjectLeader to perform a variety of experiments such as e atom and bond count e net positive and negative charge for a molecule e molecular properties such as molecular formula weight and refractivity e elemental analysis calculating the percent weight of each element e zero order first order and second order molecular connectivity indices e dipole moment and dipole vectors x y and z e dielectric steric and total energy of a structure e electron affinity 2 18 BioMedCAChe User Guide Performing experiments with CAChe e shape index order 1 2 and 3 e octanol water partition coefficient Experiments can be performed on entire chemical samples or on chemical sample components such as atoms bonds and molecular orbitals i 2 5 o 3 b 5 S Using the Procedure Editor The Procedure Editor allows you to create your own experiments and change parameter settings from the default settings supplied with CAChe The Procedure Editor allows you to display the experiment environment in a tree view From this view you can perform a wide range of functions These functions inc
332. le search labels automatically and to close the Geometry Label Wizard dialog box Search labels display the value of the selected dihedral angles in the workspace and an S to indicate that the labels are search labels Manipulating search labels You can manipulate search labels in exactly the same way as geometry labels using the following actions selecting search labels by clicking on the numeral portion of the search label in the workspace changing the appearance of search labels by choosing View Geometry Label Attributes to display labeling and coloring options e modifying search labels and their values by choosing Atom Distance Bond Angle Improper Torsion or Dihedral Angle from the Adjust menu and editing search label values in the Set Atom Distance Set Bond Angle Set Dihedral Angle or Set Improper Torsion dialog box e deleting search labels using the Delete key lt t gt Refer to Working with geometry labels p 8 19 for more information on performing the above actions on geometry labels CAChe for Windows User Guide 8 43 Chapter 8 Investigating Molecular Geometry Animating search labels You can animate your molecule so that it steps through every conformation created by the search labels you added to it You can e animate the molecule from the first to the last conformation in the range animate the molecule from the last to the first conformation in the range stop at an
333. lect Group tool by clicking on it in the tool palette The mouse cursor changes to the Select Group tool shown to the left Using the Select Group tool to select a group To select a group 1 In the workspace select the Select tool and do one of the following o position the cursor to one side of the group you want to select hold down the left mouse button and drag the cursor to form a selection box around the group o select an atom and hold down either the Shift or Ctrl key while you select each of the remaining atoms in the group by clicking on it The atoms are highlighted to show they are selected Choose Edit Group Atoms to display the Group Atoms dialog box Enter a name for the group of selected atoms in the Group Name text box Select gt gt Group gt gt to display the new group in the Defined Groups list Select OK to close the Group Atoms dialog box Select the Select Group tool and select an atom in the defined group All the atoms that share a group with this atom are selected even hidden atoms To deselect a group 1 CAChe for Windows User Guide In the workspace position the Select Group tool over the selected group you want to deselect Press the left mouse button to deselect the group The group is grayed out to show that it is deselected Chapter 5 Modifying Chemical Samples Using the Select Group tool to select an RMS error label NS To select an RMS error la
334. lect a component and revert it to its original definition This action discards any overwritten version created by editing the component The original definitions for each component are stored in the System or Group directories This action removes the modified definitions that reside in the User directory exposing the originals in the System or Group directory To return to the original settings 1 In the tree view of the Navigator window select the component that you wish to use 2 Choose Edit Original Settings The component is reverted to its original settings NOTE Only definitions in the User directory can be overwritten 11 36 CAChe for Windows User Guide Exporting environment components Exporting environment components The following components can be exported experiments procedures e parameter data The type of component which can be exported depends on the current selection in the tree view of the Navigator window The Export command uses the Save As dialog box Save in ja User x c gi F cachetmp ExpEnvironment 5 cache ini Tepconf txt Save as type Procedures 4 x Cancel NS To export an environment component 1 In the tree view of the Navigator window select the component that you wish to export 2 Choose File Export to display the Save As dialog box Enter a name for the exported component in the File Name text box 4 Select a dire
335. lect a group of selected workspace objects by clicking on them while holding down the Shift key e select every visible object in the workspace e invert the selection by clicking on empty space while holding down the Shift key This has the same effect as Edit Invert Selection gt To select the Select tool 1 Select the Select tool by clicking on it in the tool palette The cursor is displayed as the default arrow cursor or Select tool ts shown to the left Using the Select tool to select objects Use the Select tool to select objects by e clicking on objects in the workspace e clicking and dragging around objects in the workspace Selecting more than one object Clicking and dragging is a useful way of selecting more than one object when the objects are close to each other You can also select more than one object by using the Shift key To select a group of objects near to each other 1 Position the Select tool to one side of the group of objects you want to select 2 Press and hold down the left mouse button and drag the Select tool to form a selection box around the objects you want to select The objects are highlighted to show that they are selected 3 34 BioMedCAChe User Guide Using CAChe If the objects you want to select are not close to each other you can select more than one object by holding down the Shift key while you click on subsequent objects To select more than one object using the
336. lected are hidden You will find this command very useful when working with complex molecules because it allows you to see clearly selected objects by quickly hiding all those that are not selected To display hidden selected atoms Do one of the following 1 Choose View Show All or 1 Do one of the following to select all atoms o Choose Edit Select All o Press Ctrl A 2 Choose View Atom Attributes to display the Atom Attributes dialog box 3 Select the Display Atoms check box so that it is enabled A check mark appears in the Display Atoms check box 4 Select OK to close the Atom Attributes dialog box All of the atoms in the workspace are now visible Hiding and displaying hydrogen atoms You can show or hide all the hydrogen atoms in your chemical sample without deleting the atoms As with hiding atoms hiding hydrogen atoms does not affect any calculations you run on the chemical sample while hydrogens are hidden To hide hydrogen atoms 1 When hydrogens are visible choose View Suppress Hydrogens CAChe for Windows User Guide 6 19 Chapter 6 Viewing Chemical Samples A check mark is displayed next to the drop down list option to indicate that hydrogens are hidden Depending upon the setting in Options Valence Settings either all the hydrogen atoms in the workspace are hidden or only the hydrogen atoms connected to carbon are hidden To display hydrogen atoms 1 When hydrogens ar
337. lected residues within or between sequences Pasted residues are inserted as new chains Building peptides and proteins 9 34 To build a peptide 1 Inthe Sequence View window click the name of the chemical sample to activate it for modification The sequence name is highlighted in yellow 2 Choose the Residue tool A flashing I beam cursor appears at the beginning of the sequence BioMedCAChe User Guide Changing biomolecules NOTE Building by homology NOTE BioMedCAChe User Guide 3 Type the 1 letter code for each residue in the peptide or protein The new residue is inserted at the cursor creating a new chain The box moves to the right and contains an asterisk that indicates the end of the chain The 3D structure displayed in the workspace is updated to contain the new residue The new chain is added to the workspace away from any other structures When you add a residue the Psi and Phi angles used are the same as specified in the ribbon Since genes have changed through evolution proteins are usually members of families of related proteins that have similar sequences and 3D structures As a result it is possible to predict an unknown structure from its sequence by using the X ray structure of a homologous protein If you have the sequence for a protein with an unknown 3D structure and you have a homologous protein with a 3D structure you can build the unknown 3D structure from the known one
338. lecule including any hidden atoms Selecting more than one object e clicking and dragging a selection box around objects with the tool selects those objects For example click and drag around a group of atoms with the Select tool to select all the atoms in the group e clicking on one object then holding down the Shift key or holding down the Ctrl key while clicking on other objects selects all those objects For example to select adjacent atoms click on one atom then hold down the Shift key and click on the adjacent atom Continue to hold down the Shift key until you have selected everything you want e select every visible object in the workspace by clicking anywhere in the workspace with any selection tool Hidden objects are not selected Moving one or more objects in the workspace e hold the Alt key click and drag on one or more selected objects to move the selected object or objects across the workspace Deselecting one object e clicking on a selected object while holding down either the Shift or Ctrl key deselects the object NOTE You cannot deselect an object if it is the only selected item in the workspace because CAChe requires that at least one object in the workspace must be selected CAChe for Windows User Guide 5 5 Chapter 5 Modifying Chemical Samples Deselecting more than one object e clicking on a selected object while holding down either the Shift or Ctrl key then clicking on addi
339. lights 3 Select OK The dialog closes and residues in the New Selection sequence that are conserved in all the sequences from the Master list and the New Selection list highlight All other residues dim Superimposing biomolecules You can compare the molecular geometry of two biomolecules by superimposing one or more residues from one onto the corresponding residues in the other CAChe superimposes the Cy atoms of the selected residues from both biomolecules to coincide with each other as much as possible 9 42 BioMedCAChe User Guide Comparing biomolecules You can then compare any differences in structural geometry indicated by the RMS label displayed in the workspace To superimpose two molecules by residue 1 Select the residues that you want to be superimposed on another k structure s residues by clicking on the residues in the sequence window with the Select tool NOTE Only sequences from two different chemical samples can be superimposed The order in which residues are selected is not important 2 Choose Edit Superimpose Sequences The Superimpose dialog box appears which allows you to choose which chemical sample is the target which is the probe and where the superposition takes place Select Probe and Target Probe Atom Group Target Atom Group ChemicalS ample2 ChemicalS ample2 ChemicalS ample3 r Superimposition options Superimpose Probe onto Target C Replace Target w
340. lines and the perspective from which you view your chemical sample save customized workspace settings build crystal structures Contents CAChe display options 6 2 Editing chemical sample data 6 35 Using CAChe model types 6 4 Changing view settings 6 37 Changing the appearance of atoms 6 8 Changing element color 6 37 Changing atom labeling 6 8 Editing the color palette 6 38 Changing atom shape 6 11 Changing drawing settings 6 43 Changing atom color 6 14 Changing workspace perspective and distance Hiding and displaying electrons 6 16 6 44 Hiding atoms 6 18 Changing workspace stereo display 6 46 Hiding and displaying selected atoms 6 18 Changing view settings for valence 6 48 Hiding and displaying hydrogen atoms 6 19 Saving settings 6 51 Changing the appearance of bonds 6 21 Building crystal structures 6 54 Changing bond shape 6 21 Selecting a space group 6 55 Changing bond color 6 25 Defining cell parameters 6 57 Hiding bonds 6 28 Defining fractional coordinates 6 58 Hiding and displaying selected bonds 6 28 Building asymmetric atoms 6 60 Viewing selection only 6 30 Building a molecular crystal 6 60 Coloring by molecules 6 31 ae an see latice PERT ae Viewing multiple windows 6 32 SPEE eee oe Viewi hemical le dat 6 33 Creating CrystalStructure files 6 63 iewing chemical sample data ShelX files 6 65 Selecting chemical sample data 6 34 Chapter 6 Viewing Chemical Samples CAChe display options CAChe offers many different options f
341. lly does not propagate itself and can therefore be applied to every ring atom In many cases as many starting structures as the number of ring atoms can be obtained and and and so on Whilst corner flap is efficient for small to medium ring structures it is sometimes an unsuccessful technique for larger rings For example a ring atom that is lying on the average local ring plane and flanked by a pair of gauche bonds of the same sign cannot be flapped Corner flap alone cannot produce all the nearby energy minima for larger rings where mechanisms of conformational interconversion involving more than four contiguous bonds exist Edge flip is where two adjacent ring atoms are simultaneously given the corner flap in opposite directions where a ring bond is flipped Edge flip is best illustrated by the chair to twist boat conversion of cyclohexane An edge flip perturbation mode which proved to be effective for large rings consists of simultaneous small flapping of two adjacent ring atoms towards the inside of the ring In contrast to the other two perturbation methods both directed towards the outside of the ring this mode is a local inflection occuring for ring structures with a large cavity space The edge flip involves rotation of two to five contiguous ring bonds and are called when certain combinations of three contiguous dihedral angles patterns A G G appear along the ring Careful structural adjustments are given in BioMedCAChe
342. log box A pop up window is displayed containing information about the dialog box component that you clicked on For example if you click on a text box in the dialog box the pop up window describes the function of the text box and the type of information that you type into the text box Viewing the CAChe Help system You can view the CAChe Help system in two ways e from the workspace Help menu e from the toolbar Help button Accessing the Help system from the Help menu To access the Help system from the Help menu 1 Choose Help CAChe Help Topics to display the Contents tab Accessing the Help system from the toolbar To access the Help system from the toolbar 1 Select the toolbar button shown to the left to display the Contents tab 3 44 BioMedCAChe User Guide Quitting CAChe Quitting CAChe To quit CAChe BioMedCAChe User Guide 1 Choose File Exit If you have any unsaved changes in open windows an alert box asks you if you would like to save changes Do one of the following a Select Yes to save the changes and quit CAChe a Select No to quit CAChe without saving the changes a Select Cancel to keep CAChe running 3 45 Chapter 3 CAChe Basics 3 46 BioMedCAChe User Guide 3 Q lt 3 ui Ri OH d ABLSIWAHIDOL Using CAChe The following chapters describe how to use CAChe Chapter 4 Creating Chemical Samples Chapter 5 Modifying Chemi
343. log box Select the arrow button in the Size box located in the Paper panel and choose a paper size from the drop down list Select the arrow button in the Source box located in the Paper panel and choose a paper source from the drop down list Select OK to save the paper size and source settings and to close the Page Setup dialog box 12 41 Chapter 12 Using ProjectLeader Printing a ProjectLeader window You can print a ProjectLeader worksheet or scatter plot To print a ProjectLeader window to a printer 1 Activate the document window whose contents you want to print by clicking on the window 2 Do one of the following a Choose File Print a Press Ctrl P The Print dialog box is displayed 3 In the Copies panel of the Print dialog box do one of the following a In the Number of Copies text box select the up arrow to increase the number of copies of the printout you require or select the down arrow button to decrease the number of copies you require a Click in the Number of Copies text box and enter the number of printouts you require 4 Select OK to print the contents of the active document window to a printer and to close the Print dialog box 12 42 BioMedCAChe User Guide Exporting a ProjectLeader worksheet Exporting a ProjectLeader worksheet You can export a ProjectLeader worksheet in sdf file format for use in other applications such as chemical database programs NS To exp
344. log boxes e inthe workspace using the selection tools e in the workspace using the Atom Bond tool inthe workspace using the manipulation tools Selection tools Click and drag in the workspace using the selection tools to draw a selection box around the objects you want to select To click and drag using the selection tools 1 Select the selection tool you want to use 2 Position the cursor to one side of the object or group of objects you want to select 3 Hold down the left mouse button and drag the cursor to form a selection box around the objects you want to select The selected objects encompassed by the selection box are highlighted while other workspace objects are grayed out Atom Bond tool Click and drag in the workspace using the Atom Bond tool to draw a bond and connecting atom To click and drag using the Atom Bond tool BioMedCAChe User Guide 1 2 3 Select the selection tool you want to use Position the cursor over an atom or bond Hold down the left mouse button and drag the cursor a short distance across the workspace A bond and connecting atom are displayed in the workspace attached to the atom or bond where you started drawing 3 19 Chapter 3 CAChe Basics Double click Manipulation tools Click and drag in the workspace using the manipulation tools to move rotate and scale objects To click and drag using the manipulation tools Using the menu bar Menu opti
345. lors labels on the selected atoms with the same color selected in the Color atoms by panel of the Color tab options standard text color colors labels on the selected atoms with the standard text color lt t gt Refer to Editing the color palette p 6 38 for information on changing the standard text color by editing the CAChe color palette To change atom color and atom label color 1 Select the atoms that you want to change color by clicking on the atoms with a selection tool 2 Choose View Atom Attributes to display the Atom Attributes dialog box Atom Attributes 12 x Type Color Shape Label r Color Atoms By C Partial Charge Polarity Last Residue Molecule or Backbone Color Specific Color Color Label With Atom Color Standard Text Color IV Display Atoms Cancel Make Defaut 3 Select the Color tab to display the following list of color options for atoms o color atoms by element o color atoms by partial charge polarity o by last residue molecule or backbone color o color atoms by specific color 4 Inthe Color Atoms By panel select the radio button next to the color option you want to apply to each selected atom ensuring CAChe for Windows User Guide 6 15 Chapter 6 Viewing Chemical Samples that the relevant radio button is enabled 5 Ifyou select the Specific Color radio button also select the arrow button in the box and choose
346. lphanumeric Label I Name IV Display Atoms Cancel Make Default CAChe for Windows User Guide Working with chiral centers 3 Select the Label tab to display a list of atom labeling options 4 Select the Chirality for Asymmetric Carbons check box so that it is enabled 5 Select OK to close the Atom Attributes dialog box All selected asymmetric tetrahedral carbon atoms are labeled with an R or an S to indicate the chiral center and the chirality When drawing and modifying a structure it is not uncommon that the four substituents and the central atom will be situated in or close to the plane In this instance CAChe may display an incorrect chiral assignment The correct chiral assignment is displayed after the structure has been beautified or optimized Inverting chiral centers To invert the bonded neighbors of a chiral carbon select a chiral center and swap two connecting bonds The R and S labels that indicate chirality are also exchanged after you invert chirality There are two exceptions to the way CAChe swaps bonds while inverting chirality e if two bonds of the central atom are in a ring structure and two are not the two that are not part of a ring become inverted e if the chiral center has three or more bonds in fused ring structures you cannot invert chirality To invert chirality 1 Usea selection tool to select the carbon atom at the chiral center for which you want to invert chiral
347. ls The Experiment Status dialog box is displayed which shows details of the calculations as they are performed and the status of the experiment 3 To stop an experiment select the experiment in the Experiments Submitted dialog box and select Stop The Stop an Experiment dialog box is displayed 4 Select the required radio button as described in the previous section Stopping an experiment 5 Select OK to close the Stop an Experiment dialog box and to stop the experiment 6 To reattempt to generate output files if the experiment halts because of lack of storage space on your computer select Retry CAChe for Windows User Guide 10 27 Chapter 10 Performing Workspace Experiments Output file generation continues and output files are saved as normal 7 Select Close to close the Experiments Submitted dialog box 10 28 CAChe for Windows User Guide Viewing server information Viewing server information You can view a list of experiments being performed on a particular server This is useful if you are using CAChe GroupServer with CAChe so that you can see on which server active experiments are currently being processed NS To view server information 1 Choose Experiment Show Server Information to display the Select a Server dialog box Select a Server x cache localhost peake luncheon shaw matron i Cancel Help The Select a Server dialog box lists available servers If
348. ls that function in exactly the same way as the workspace tools Select tool Select Molecule tool Conformation window Select Similar tool only Group Select tool Atom Bond tool Rotate tool Translate tool Scale tool You can rotate translate and zoom in to the map and conformation window using the tools and also select items with the three selection tools in the conformation window Using the Select tool in the graph window changes the position of the spherical marker in the graph lt t gt Refer to Chapter 5 Modifying Chemical Samples for information on using the selection tools Refer to Chapter 7 Manipulating Molecules for information on using the Rotate Translate and Scale tools Using the parameter bar The parameter at the bottom of both windows contains a drop down list from which you can choose to view in ascending or descending order e the values plotted along the x and y axes for a two dimensional graph e the values plotted along the x y and z axes for a three dimensional graph 14 14 CAChe for Windows User Guide Viewing map files To use the parameter bar 1 Map file display options Select the arrow button in the left hand parameter bar box to display a drop down list of the parameters plotted along the graph axes An example of left hand and right hand parameter bar boxes is shown below Sequence he 23 000 step Choose the parameter whose values you
349. lude e creating new experiments e modifying procedures by adding deleting or moving steps e editing compute engine data e editing parameter data e creating new packages for use by groups of users lt t gt Refer to Chapter 11 Using the Procedure Editor for full details about using the Procedure Editor BioMedCAChe User Guide 2 19 Chapter 2 Introduction to CAChe Computational chemistry and CAChe CAChe uses computational chemistry as an essential part of computer aided chemistry By applying computational molecular models derived from mathematical equations to a chemical sample you create you can calculate molecular properties such as the position and behavior of electrons and nuclei in certain conditions The computational chemistry tools that CAChe uses are derived from classical mechanics and quantum mechanics and are applied to your chemical sample by a number of computational applications that perform calculations based on specified parameters Using classical mechanics CAChe can optimize molecular geometry determine a series of low energy conformations between high energy barriers simulate the normal motion of atoms according to time temperature and the calculated forces of the atoms Using quantum mechanics CAChe can e predict electron density and distribution in a molecule e investigate molecular orbital energies e optimize molecular geometry e determine transition state geometr
350. lue of the atom distance or bond angle represented by the geometry label Search labels are used in CAChe experiments to define a range of conformations for a molecule while computing the energy of each conformation When creating a search label you specify a range of values for an atom distance bond angle improper torsion or dihedral angle During the CAChe experiment the labeled distance or angle is moved through the range of search label values to create a number of conformations for the molecule so that the energy of each conformation can be measured For example you can vary a dihedral angle through 360 degrees stopping every 15 degrees to compute the energy of the molecule at those conformations Refer to Chapter 13 Optimization and Energy Calculations and Chapter 14 Investigating Low energy Conformations for information on how CAChe experiments use search labels You can define search labels in three ways specify anew geometry label as a search label while creating the geometry label e modify an existing geometry label to become a search label e use the Geometry Label Wizard to create one or more search labels automatically Specifying a new geometry label as a search label You can define a search label for an atom distance bond angle dihedral angle or improper torsion angle while creating a new geometry label CAChe for Windows User Guide 8 37 Chapter 8 Investigating Molecular Geom
351. lues and steps between those values are displayed in the text boxes beneath the Single lonic and Coordinate bonds searching between check box If you want to change the default values click in the relevant text box and type a new value for the start or end of the value range or for the number of steps throughout the range To include double bonds in the search label generation select the Double bonds searching between check box so that the radio button is enabled A range of default values and steps between those values are displayed in the text boxes beneath the Double bonds searching between check box If you want to change the default values click in the relevant text box and type a new value for the start or end of the value range or for the number of steps throughout the range To include weak bonds in the search label generation select the Weak bonds searching between check box so that it is enabled CAChe for Windows User Guide Working with search labels A range of default values and steps between those values are displayed in the text boxes beneath the Weak bonds searching between check box 8 Ifyou want to change the default values click in the relevant text box and type a new value for the start or end of the value range or for the number of steps throughout the range 9 To include terminal groups select the Include terminal groups check box so that it is enabled 10 Select OK to generate dihedral ang
352. ly a radius value to a specific atomic charge for the currently selected element select the list item containing the charge and corresponding radius values that you require Select OK to close the Periodic Table Settings dialog box All atoms of the element you chose with the atomic charge you specified are displayed in the workspace with the radius you specified The radius value applies to all new atoms of that element that you draw which possess the atomic charge you specified and all atoms in saved chemical sample files with the atomic charge you specified Changing a bond using the style bar Change the bond type of a selected bond using the Bond Type box in the style bar at the top of the workspace E Carbon x sp3 tetrahedron Charge E Single Bond Type box To change bond type using the Bond Type style bar box 1 5 28 Select the bond or group of bonds whose bond type you want to change by clicking on the bonds with a selection tool CAChe for Windows User Guide Changing atom and bond properties The bond or group of bonds are highlighted to show that they are selected 2 Select the arrow button in the Bond Type box to the right of the style bar A drop down list of bond types is displayed 3 Choose the bond type you require from the drop down list The bond type you have chosen is displayed in the Bond Type box and the selected bond changes to the bond type you have chosen Cha
353. m Distance Set Bond Angle Set Dihedral Angle or Set Improper Torsion dialog box is displayed 3 Select the Define Geometry Label check box so that it is enabled 4 Select the Lock Geometry radio button so that it is enabled CAChe for Windows User Guide 8 29 Chapter 8 Investigating Molecular Geometry 5 Select OK to close the Set Atom Distance Set Bond Angle Set Dihedral Angle or Set Improper Torsion dialog box A geometry label displays the value of the distance or angle in the workspace and an L to indicate that the label is locked The following example shows a locked geometry label To lock an existing geometry label 1 Select the geometry label you want to lock by clicking on the numeral portion of the label with the Select tool 2 Choose Adjust Lock The geometry label displays the value of the distance or angle in the workspace and an L to indicate that the label is locked To unlock a geometry label 1 Select the locked geometry label by clicking on the numeral portion of the label with the Select tool 2 Choose Adjust Unlock The geometry label no longer displays an L 8 30 CAChe for Windows User Guide Locking geometry labels Broken geometry locks Locks change to broken locks if the geometry of the locked structure changes Changes can occur while you are editing your chemical sample with locks disabled Running some experiments using the computational applications Mechanics ZI
354. m M1 to A32 This deletes the first extra cellular segment of rhodopsin This segment is not needed for the model of MC4R Choose the Select tool Using the CLUSTAL W 1 81 k multiple sequence alignment shown in the table above select each residue in bovine rhodopsin and use the Residue Type drop down on the Style ribbon to change the rhodopsin ALA J a Pafe Psif 41 8 Residue Type drop down Secondary structure drop down Phi angle box Psi angle box residue one at a time into the residues that are in MC4R The residue changes but the backbone Phi and Psi angles remain unchanged from rhodopsin To change the loops Insert loop residues present in MC4R but not in rhodopsin and delete loop residues present in rhodopsin but not in MC4R After all of the loops are constructed Delete everything past the last long bond R 214 NCMV Note that the first long bond has been fixed by adding residues in MC4R NS To refine the initial MC4R model 1 Inthe Sequence view choose View Secondary Structure The line SS appears below the sequence Letters in this line denote the secondary structure H denotes a residue in a helix 2 Select the residues in the first helix 19 18 CAChe for Windows User Guide Creating a homology model of the MC4R 10 11 12 CAChe for Windows User Guide From the workspace Choose Edit Group Atoms Type the Group Name T 1 and choose gt gt Group gt gt The group named TM1 is added to
355. map directory for your chemical sample Look in ja oxytocin map cl File name seqsrch map Files of type Map map 7 Cancel T Open as read only Help A Choose seqsrch map and Open Two windows appear side by side E E CAChe5 oxytocin 2 oxytocin 3 map seqsrch map 2 Pija E3 m E CACheS oxytocin 2 oxytocin 3 map Sequence xj 1 000 a step CAChe for Windows User Guide Click on the graph to move the ball to a new conformation The 3D structure in the workspace changes to that of the newly chosen conformation Choose File Save As Chemical Sample to save low energy conformations As you save each conformation you may find it useful later if you include the sequence number or the conformation number in the new file name 19 9 Chapter 19 Investigating Biomolecules Including water 19 10 The conformations you found in the previous section are those for the isolated peptide Without solvents the ionic ends of the peptide will attract and the conformations with the NH3 and CO groups near one another will be more stable A polar solvent like water will stabilize extended structures You can model the effect of solvation by adding water molecules to the peptide chemical sample To add water it is useful to have a chemical sample containing water molecules To create a water droplet 1 From the workspace menu choose File New A new workspace opens Choose Edi
356. me will take up a significant part of the total time when the number of stored structures increases Therefore with this option CONFLEX will perform the comparison at 0 10 20 and every 10 iterations until 200 iteration and every 50 iterations thereafter This strategy reduces the total computing time by 30 to 60 20 29 Chapter 20 CAChe Computational Applications Comparison Comparison using conformational distance The similarity between two conformers can be quickly identified by comparing the root mean square of differences in the corresponding pair of dihedral angles f4 and f This method is fast and accurate To save time the dihedral angles of a stored conformer are retrieved for comparison rather than re calculating those dihedral angles each time N dihedral A B 2 don S G AYN r 20 30 BioMedCAChe User Guide 2 1 CAChe BioComputations Overview This chapter explains the theories and methods behind the following CAChe biocomputations e Residue names Protein secondary structure e Dihedral angles used for building peptides e Sequence property predictions for e antigenicity e hydrophobicity hydrophilicity e flexibility e Sequence alignment algorithm Contents Understanding Residue Names 21 2 polypeptide conformations 21 6 Understanding Protein Secondary Structure Understanding Sequence Property Definition 21 4 Predictions 21 8 Secondary structure concepts 21 4 Sequence property concepts 21 8 De
357. mentLibrary e Chemical sample files c CACHE InstallationNotes e CAChe installation documents c CACheUser cachetmp e Calculation queue and files while c CACheUser ExpEnvironment calculations are running e User procedure packs 2 5 D 2 2 lt c CACHE XLATORS cachemap d11 e Translation libraries used during cachetrn dll file input and output crystalstructure dll fio dll gaussian dll pdbio dll ShelX dl1l BioMedCAChe User Guide B 3 Appendix B CAChe File Management B 4 BioMedCAChe User Guide Index Overview This is a full index for the BioMedCAChe User Guide Index Symbols csf files 4 3 ins files 6 65 seq files generating 20 5 xsf files 6 64 Numerics 310 helix 21 7 3D cursor 3 15 A Adding chemical samples in ProjectLeader 12 12 Adjusting atom distance 8 13 Agouti related protein 19 22 All conformations dialog box 14 27 Allinger N L 20 3 Alpha helix 21 7 Amino acid creating nonstandard 9 47 nonstandard 9 45 Amino acid repository 9 45 Analysis criteria 14 24 Analyzing map files 14 22 Angle bond 8 14 dihedral 8 15 improper torsion 8 17 Animate geometry labels dialog box 8 44 Animating map files 14 26 search labels 8 44 Application window 3 4 Arrow buttons 3 24 Assemblage file 20 6 Atom attributes dialog box 5 21 6 13 8 2 8 33 9 7 16 8 I 2 Atom properties 10 7 changing 5 19 Atom bond tool 3 14 3 19 3 32 4 4 Atomic partial charge 2 15 10 7
358. mical sample can result in e abnormally strained bond distances e an unreasonable molecular geometry that produces meaningless energy values in CAChe experiments CAChe displays a warning message if you attempt to scale selected portions of your chemical sample while in position mode To manipulate selected workspace objects 1 Select the atoms and bonds that you want to rotate translate or scale by clicking on them with a selection tool The selected atoms and bonds are highlighted to show that they are selected 2 Do one of the following to enter position mode gt o Choose Edit Move Selected o Select the toolbar button shown to the left A check mark is displayed next to the Move Selected drop down list option to indicate that you are in position mode The Rotate tool is automatically enabled and the cursor changes to the Rotate tool A black circle is displayed in the center of the BioMedCAChe User Guide 7 9 Chapter 7 Manipulating Molecules 7 10 workspace The selected atoms and bonds are displayed as a separate group from the rest of the molecule with all connecting bonds temporarily hidden An example is shown below To rotate the selected object click and drag the Rotate tool inside the black circle to rotate the object along the x and y axes or outside of the black circle to rotate the object along the z axis To translate the selected object use the Translate tool to click and drag the
359. mology model of the MC4R 19 15 Chapter 19 Investigating Biomolecules e dock a ligand into a protein e locate the receptor dock the ligand into the receptor using distance adjustments e refine the ligand protein complex using mechanics and dynamics e model additional small molecule ligands using CONFLEX and property calculations with MOPAC e dock favorable candidates into ligand binding site by superposition on the original ligand NOTE The Sequence View is available only in CAChe WorkSystem Pro BioCAChe and BioMedCAChe Since this chapter uses the Sequence View it is applicable only to WorkSystem Pro BioCAChe or BioMedCAChe 19 2 CAChe for Windows User Guide Investigating peptide conformations Investigating peptide conformations CAChe enables you to build peptides from their sequence and search for their lowest energy conformations CAChe can use either molecular mechanics or quantum mechanics to compute the energies of the peptide structures Most often you will use molecular mechanics to determine the stable conformations of peptides because it is the fastest and most accurate method for organic structures Conformational analysis in the workspace allows you to locate the lowest energy conformations Selected conformations can be refined further using quantum mechanics in MOPAC Building a peptide To build a peptide efficiently from the Sequence View window first set the secondary structu
360. mponent properties The Workspace experiment component Properties dialog box contains an Experiment tab that allows you to select the procedure associated with the experiment 11 16 CAChe for Windows User Guide Modifying a procedure Modifying a procedure A procedure is a named sequence of steps which are applied to one or more chemical samples The procedure specifies the compute engine or engines used in the experiment You can modify a procedure by e adding or deleting steps rearranging the order in which the steps are performed e changing the settings of the compute engine used A Procedure window allows you to modify the selected procedure The Procedure window has five buttons that you can use The New button allows you to select new compute engine steps from a popup list Yy The Open button allows you to view and change the Open settings for a selected compute engine step aN The Delete button allows you to remove the selected Delete step from the procedure The Up button allows you to move a selected step T nearer the beginning of the procedure Each time the button is selected the step is moved one step upwards The Down button allows you to move a selected step nearer the end of the procedure Each time the button Bom is selected the step is moved one step downwards The New button can also be used to insert a new step that calls another procedure This saves you having to duplicate all the st
361. mula is used aw ee P is the average property for residue i p is the property published and shown in the reference tables and w is the window size The window size is the number of residues included in the average 21 8 BioMedCAChe User Guide Understanding Sequence Property Predictions Sequence property parameters Sequence property parameters are defined according to this table Antigenicity Antisenicity Hydropathy Hopp and Kyte and Hydro Parker TOER i a 1 letter Woods Antigenicity Doolittle phobicity Hydro code Hydro philicity Welling Hydro Sweet philicity b phobicity Eisenberg Index Index Index 4 A 0 500 2 100 0 115 1 800 0 400 B 1 600 8 500 0 000 3 500 1 115 C 1 000 1 400 0 120 2 500 0 170 D 3 000 10 000 0 065 3 500 1 310 E 3 000 7 800 0 071 3 500 1 220 F 2 500 9 200 0 141 2 800 1 920 G 0 000 5 700 0 184 0 400 0 670 H 0 500 2 100 0 312 3 200 0 640 I 1 800 8 000 0 292 4 500 1 250 K 3 000 5 700 0 206 3 900 0 670 L 1 800 9 200 0 075 3 800 1 220 M 1 300 4 200 0 385 1 900 1 020 N 0 200 7 000 0 077 3 500 0 920 P 0 000 2 100 0 053 1 600 0 490 Q 0 200 6 000 0 011 3 500 0 910 R 3 000 4 200 0 058 4 500 0 590 S 0 300 6 500 0 026 0 800 0 550 T 0 400 5 200 0 045 0 700 0 280 V 1 500 3 700 0 013 4 200 0 910 W 3 400 10 000 0 114 0 900 0 500 X 0 200 0 000 0 000 0 490 0 000 Y 2 300 1 900 0 013 1 300 1 670 Z 1 600 6 900 0 000 3
362. multaneously You can perform more than one CAChe experiment at a time To start a new experiment while another experiment is running 1 Do one of the following to display another Experiment dialog box from which you can start the next experiment a Select Extract in the Experiment Status dialog box of the current experiment a Choose Experiment New a Select the toolbar button shown to the left a Choose File Open to open an Experiment dialog box or experiment file exp which you have previously saved 2 Select a chemical sample file property class property and procedure from the Experiment dialog box and select Start as described in the previous section Running an Experiment The second experiment begins 10 26 CAChe for Windows User Guide Viewing active experiments Viewing active experiments You can view a list of experiments that have been submitted and are either currently being performed or if you are using CAChe in conjunction with GroupServer experiments that are waiting for a free server To view submitted experiments 1 Choose Experiments Show Submitted Experiments to display the Experiments Submitted dialog box 4 Experiments Submitted by Alison Peake Px Experiment Mol Server Status The Experiments Submitted dialog box displays experiments submitted by a user 2 To view more detailed information on an experiment select the experiment in the list and choose Detai
363. multiple cylinders display style Ionic bonds represent strong attractions between centers of opposite charge The electrons that participate in ionic bonds are localized at the negatively charged atom The following example shows an ionic bond in the multiple cylinders display style Coordinate covalent bonds or dative bonds are formed when a lone pair from one atom combines with an empty orbital of another atom The following example shows a coordinate bond in the multiple cylinders display style CAChe for Windows User Guide 5 33 Chapter 5 Modifying Chemical Samples mt coordination bonds 5 34 These bonds involve donation of electrons from a m bond to an empty orbital of a metal The only way to create 1 coordination bonds is to click and drag with the Atom Bond tool away from the center of a bond to an empty location in the workspace or from one existing atom to another The following example shows a m coordination bond in the multiple cylinders display style CAChe for Windows User Guide Viewing Chemical Samples Overview This chapter describes how to use the CAChe workspace to change the appearance of chemical samples by viewing atoms and bonds in a number of different display options without changing molecular structure e customize display attributes for workspace objects such as the color assigned to elements the appearance of atom and bond properties the appearance of workspace text and
364. n e the CAChe Help system accessible from the Contents and Index tabs Use the tabs to navigate through the Help system to view overview or procedural information on CAChe Viewing context sensitive Help You can view context sensitive Help in two ways e from the toolbar context sensitive Help button e from a dialog box context sensitive Help button Accessing context sensitive Help from the toolbar To access context sensitive Help from the toolbar k 1 Select the toolbar button shown to the left The cursor changes to display a question mark indicating that you are in context sensitive Help mode 2 Click on an item in the workspace or select a menu option or toolbar button A pop up window is displayed containing information about the object that you clicked on or the menu option or toolbar button that you selected For example if you clicked on a tool in the tool palette the pop up window contains the tool name and describes the tool s function BioMedCAChe User Guide 3 43 Chapter 3 CAChe Basics Accessing context sensitive Help from a dialog box To access context sensitive Help from a dialog box 1 Select the Windows query button shown to the left located in z the top left corner of the dialog box The cursor changes to display a question mark indicating that you are in context sensitive Help mode 2 Click on a radio button check box text box scrolling list or button in the dia
365. n Type Optimization Method Optimize Structure w Conjugate Gradient x Force Field Parameter Set CAChe MM3 Augmented E STANDARD bee Iteration Control Maximum Updates 300 Convergence Value 0 001 Convergence Units kcal mol x Cancel Original Settings You can display the Settings dialog box for a compute engine from the Procedure window if e anew step is added to a procedure e an existing step is viewed Editing a compute engine step only changes the settings for the compute engine in the procedure featured in the Procedure window The inputs for each compute engine fall into three categories Arguments This information is taken from the argument specified for the procedure in which the compute engine is used Settings The control data for the compute engine Parameter data The names of particular classes of parameter data e g MM2 Standard CAChe for Windows User Guide 11 23 Chapter 11 Using the Procedure Editor To edit the settings of a new compute engine step 1 From the Procedure window select the New button to display the Settings dialog box For details about displaying the Procedure window refer to Modifying a procedure p 11 17 2 Modify the settings for the compute engine as required Refer to the on line Help system for CAChe for details of the settings available for each compute engine 3 Select OK to save the changes to the compute engine Alte
366. n overcome small barriers to lower energy structures A lt t gt Refer to Chapter 14 Investigating Low energy Conformations for further details Reaction and transition state experiments 2 16 CAChe performs the following experiments from the workspace on reaction and transition state structures produced by a chemical reaction e Map reaction generates a potential energy map of conformations determined by geometry search labels in the sample for each structural element you want to vary with structures for each map point optimized BioMedCAChe User Guide Performing experiments with CAChe e Search for saddle calculates a saddle point transition state structure from a reactant and a product molecule of a chemical reaction e Refine transition state refines the structure and energy of a transition state structure using a minimize gradient calculation e Verify transition state calculates a transition state structure s vibrational transitions where a single negative vibration confirms a true transition state i 2 o 3 b 5 e Find reaction paths produces a map file containing the structures a chemical sample in a transition state geometry will pass through on the way to the reactant or product structures A lt 4 Refer to Chapter 17 Investigating Reactions for further details ProjectLeader experiments ProjectLeader is often the best place for a
367. n the chemical sample in the Workspace select the terminal carbon and hydrogen atoms of the polymer and save the Chemical Sample file BioMedCAChe User Guide Running a ProjectLeader experiment Adding a chemical sample column property sample component analysis or comment to a worksheet ProjectLeader experiments are defined by assigning a property sample component or analysis to a worksheet column then evaluating the cells in that column The chemical sample information for the row provides ProjectLeader with enough information to evaluate the cells If no column is appropriate to provide information for the property of a sample component a new column containing an appropriate sample component is automatically inserted You can add Chemical Sample columns to a ProjectLeader worksheet in addition to the Chemical Sample column that represents the first column in a worksheet This enables you to compare the results of calculations between different columns of chemical samples To add a chemical sample column 1 Double click on an empty column title cell to display the Enter Property dialog box 2 Select the Chemical Sample radio button 3 Select OK The column title cell is labeled Chemical Sample and chemical samples can be added to the column Toadda property to a worksheet BioMedCAChe User Guide 1 Double click on an empty column title cell to display the Enter Property dialog box 2 Select the P
368. nd colors Displaying bond order by scaling bond radius 16 12 To view bond order by scaled bond radius 1 Run an atomic partial charge or calculated bond order experiment on your chemical sample file 2 Choose View Bond Attributes to display the Bond Attributes dialog box 3 Select the Shape tab to display a list of shape options for bonds CAChe for Windows User Guide Viewing atom and bond properties 4 Select the arrow button in the Scale cylinders such that box and choose Formal Bond Order of 1 from the drop down list 5 Click in the is displayed as text box and type a value for the radius to which bonds with a formal bond order of will be scaled The value must be between 0 001 and 0 999 6 Select OK to close the Bond Attributes dialog box Bonds are scaled to the specified radius Displaying bond strain NS To view bond strain 1 Run a bond strain experiment on your chemical sample file 2 Choose View Bond Attributes to display the Bond Attributes dialog box 3 Select the Color tab to display a list of color options for bonds 4 Select the Calculated Bond Strain radio button so that it is enabled 5 Select OK to close the Bond Attributes dialog box Bonds are colored to reflect bond strain according to the CAChe color tables A gt Refer to CAChe color tables p 15 13 for further details about bond colors CAChe for Windows User Guide 16 13 Chapter 16 Investigating At
369. nd optimized After the last experiment completes choose File Save As and name the file MC4R final csf You have refined the homology model of the structure of MC4R CAChe for Windows User Guide Creating a homology model of the MC4R Once the structure is created you examine it to verify that the inter helix interactions that participate in GPCR activation mechanisms are present 1 Gether U and Kobilka B K G protein coupled receptors II Mechanism of agonist activation J Biol Chem 1998 273 17979 17982 Ballesteros J Kitanovic S Guarnieri F Davies P Fromme B J Konvicka K Chi L Millar R P Davidson J S Weinstein H and Sealfon S C Functional microdomains in G protein coupled receptors J Biol Chem 1998 273 10445 10453 CAChe for Windows User Guide 19 21 Chapter 19 Investigating Biomolecules Docking Agouti Related Protein into the MC4R 19 22 Agouti related protein AGRP functions as an antagonist of the MCAR and binds to the MCAR Site directed mutagenesis experiments suggest that a conserved Arg Phe Phe motif mediates key interactions of this protein ligand with the MCAR residues Gly Cys Val NOTE Docking requires some experimental information on which residues on the receptor bind to which residues on the ligand To view AGRP 1 Get AGRP 1HYK from the Protein Data Bank 1HYK pdb Open 1HYK pdb in the workspace Examine the structure and check
370. nd so are the surfaces they generate However susceptibility experiments and surfaces yield more accurate results for a wider range of chemical samples Superdelocalizability experiments produce more accurate results in the following conditions e your sample s HOMO energy is less than the default energy of 8eV for electrophilic superdelocalizability 2eV for nucleophilic superdelocalizability and 5eV for radical superdelocalizability e your sample s LUMO energy is greater than the default energy of 8eV for electrophilic superdelocalizability 2eV for nucleophilic superdelocalizability and 5eV for radical superdelocalizability the energies of the attacking molecule s frontier orbitals are between the HOMO and LUMO energies of your sample There are three different experiments that produce molecular orbital surface files e HOMO and LUMO e HOMO 5 to LUMO 4 e all molecular orbitals The HOMO and LUMO experiment creates only two surface files one for your sample s highest occupied molecular orbital HOMO and one for its lowest unoccupied molecular orbital LUMO Since these two orbitals often determine your sample s reactivity this experiment can be quite useful Note that if there are degenerate HOMOs or LUMOs all will be generated The HOMO 5 to LUMO 4 experiment generates a total of eleven orbital surfaces if your sample has that many including the HOMO and LUMO The all molecular orbitals experimen
371. ng HOMO and LUMO energies 15 7 Generating electron density colored by Calculating HOMO 5 to LUMO 4 energies electrostatic potential 15 3 15 8 Generating an electron density surface colored Calculating all molecular orbital energies 15 8 by susceptibility 15 4 Viewing a surface 15 9 Generating an electron density surface colored Hiding a surface 15 10 by superdelocalizability 15 5 Interpreting surface color 15 11 Generating an electrostatic potential surface CAChe color tables 15 13 15 6 Interpreting surfaces 15 15 Investigating molecular orbital energies Changing display options for surfaces 15 18 15 7 Chapter 15 Investigating Electron Distribution Investigating electron density surfaces CAChe generates surfaces from the following experiments electron density nucleophilic susceptibility electrophilic susceptibility radical susceptibility nucleophilic superdelocalizability electrophilic superdelocalizability radical superdelocalizability electrostatic potential HOMO and LUMO HOMO 5 to LUMO 4 all molecular orbitals You can also use CAChe procedures for generating electron density surfaces to optimize the geometry of the molecule first using classical mechanics quantum mechanics or a combination of both You can combine all optimization procedures with generating electron density for your sample NOTE You cannot use procedures that involve MOPAC or ZINDO in Personal CAChe 15 2 CAChe for Windows U
372. ng example shows a geometry label 5 Select OK to accept the geometry label and close the Set Atom Distance Set Bond Angle Set Dihedral Angle or Set Improper Torsion dialog box CAChe for Windows User Guide Working with geometry labels Defining geometry labels from the Adjust menu If you do not need to adjust atom distance or bond angle values you can also add geometry labels to your chemical sample directly from the Adjust menu without displaying the Set Atom Distance Set Bond Angle or Set Dihedral Angle dialog box You cannot define an improper torsion geometry label in this way To define a geometry label directly from the Adjust menu 1 Select the required number of atoms for the distance or angle you want to label by clicking on the first atom with the Select tool then holding down the Shift key and clicking on the remaining atoms For example select two atoms if you want to label atom distance three atoms if you want to label a bond angle or four atoms if you want to label a dihedral angle 2 Do one of the following o Choose Adjust Define Geometry Label o Press Ctrl L A geometry label identifies the participating atoms and displays the value of the distance or angle in the workspace Changing geometry label appearance Once you have added geometry labels to your chemical sample you can also choose to e hide or display geometry labels e hide or display the value and locked state o
373. ng mouse cursors Manipulation tool Tool palette icon Mouse cursor e the Rotate tool e the Translate tool am e the Scale tool E Q When you use the manipulation tools all objects in the workspace are rotated translated or scaled To rotate translate and scale selected objects only choose Edit Move Selected to enter position mode Refer to Manipulating portions of your molecule p 7 9 for more information BioMedCAChe User Guide Using the manipulation tools Using the Rotate tool Rotating a chemical sample with the Rotate tool mimics the movement of the chemical sample in the x y and z directions When you first draw a molecule and rotate it the rotation is centered around the center of the workspace i e around the origin of the workspace s three dimensional coordinate system You can alter the center of rotation to the center of a currently selected object This is described in the section Defining the center of rotation p 7 4 Use the Rotate tool to e rotate workspace objects around the x and y axes e rotate workspace objects around the z axis S To select the Rotate tool BioMedCAChe User Guide 1 Select the Rotate tool by clicking on it in the tool palette 2 The mouse cursor changes to the Rotate tool shown to the left A black circle is displayed in the center of the workspace as shown in the following example 7 3 Chapter 7 Manipulating Molecules
374. nging a bond using the Bond Attributes dialog box You can also change a bond s type using the Bond Attributes dialog box The dialog box also provides access to display options that you can apply to one or more selected bonds lt t gt Refer to Chapter 6 Viewing Chemical Samples for details about changing the appearance of a bond To change bond type using the Bond Attributes dialog box 1 Select the bond or group of bonds whose type you want to change by clicking on the bonds with a selection tool The bond or group of bonds are highlighted to show that they are selected 2 Choose View Bond Attributes to display the Bond Attributes dialog box CAChe for Windows User Guide 5 29 Chapter 5 Modifying Chemical Samples Bond Attributes 29 x Type Color Shape lV Display Bonds Cancel Make Default 3 Select the Type tab to display the Type box Select the arrow button in the Type box to display a drop down list which is identical to the Bond Type drop down list in the style bar Select the bond type you require from the drop down list 6 Select OK to close the Bond Attributes dialog box The selected bond or group of bonds changes to the bond type that you have chosen in the Bond Attributes dialog box Changing bond type while connecting atoms Another way to change bond type is to select the two atoms participating in the bond and connect the atoms using the Edit
375. ns in the zeolite e fix the location of an atom that might move out of the workspace area when you scale and rotate several structures at once You can also unlock atoms at any time To lock an atom 1 Select the atoms you want to lock using a selection tool 2 Choose Adjust Lock The atoms are locked at their current x y z workspace coordinates and are labeled with an L The following example shows labeled locked atoms 8 32 CAChe for Windows User Guide Locking atoms NSS To unlock atoms 1 Select the atoms you want to lock by clicking on the atoms with a selection tool 2 Choose Adjust Unlock The selected atoms are unlocked and the L label is no longer displayed Hiding locked atom labels You can show or hide the L label which indicates a locked atom NS To hide locked atom labels 1 Select the locked atoms whose label you want to hide by clicking on the atoms with a selection tool 2 Choose View Atom Attributes to display the Atom Attributes dialog box Atom Attributes 2 x Type Color Shape Label T Atomic Symbol I Hybridization VV Charge I Patt T Chirality for Asymmetric Carbons T Locked State I Alphanumeric Label J Name Iv Display Atoms Cancel Make Defaut 3 Select the Label tab to display a list of options for labeling atoms 4 Select the Locked State check box so that it is disabled Select OK to close the Atom Attributes dialo
376. nt radio button then select Next 3 Select an option from the Kind of sample component drop down list then select Next 5 Select a procedure from the Kind of procedure scrolling list 5 Select OK If you have more than one Chemical Sample column in a worksheet you will be prompted to select a column 6 From the Column Select dialog box do one of the following a select a column from the list and choose OK to perform the calculation on that column a select Automatic to perform the calculation on the Chemical Sample column to the nearest left of the new column BioMedCAChe User Guide Running a ProjectLeader experiment The sample component is displayed in the column title cell at the top of the relevant column When you evaluate any cell in this column the chosen sample component is calculated To add a statistical analysis to a worksheet 1 Double click on an empty column title cell to display the Enter Property dialog box Select the Analysis radio button then select Next Select one of the types of regression from the Kind of analysis scrolling list then select Next Select the column that contains the data you want to predict from the Predict scrolling list Select one or more columns to include in the regression from the Using scrolling list Select OK The regression equation regression coefficient and cross validation are given in the column title When you evaluate any cell in this col
377. o Click in the Red Green and Blue text box and enter the values you require for the new color The values in the Hue Sat and Lum text boxes change accordingly Click in the Hue Sat and Lum text boxes to change these values The values in the Red Green and Blue text boxes change accordingly A sample of the color you are creating is displayed in the Color Solid box 5 Click on Add to Custom Colors when the color displayed in the ColorlSolid box is the color you require The new color appears in the Custom colors panel of the Color dialog box 6 Select OK to close the Color dialog box The new custom color replaces the color you selected in the Define Colors dialog box scrolling list 7 Select OK to close the Define Colors dialog box All workspace objects represented by that color index number are displayed in the new custom color Changing drawing settings CAChe allows you to change the width of lines or text in the workspace Workspace objects affected by changing drawing settings include geometry and search labels atom labels graph labels and axes The thinnest line width will give the fastest screen rendering but prints as hair lines on high resolution hard copy Choose one of the other three line widths for lines that scale proportionately on the printer To change drawing settings 1 Choose Options Drawing Settings The Drawing Settings dialog box is displayed CAChe for Windows User Guide 6 43
378. o the left Zooming in and out on workspace objects To zoom in and out on workspace objects 1 Position the Scale tool anywhere in the workspace 2 Click and drag with the Scale tool to the right or upwards in the workspace to zoom in on workspace objects Workspace objects increase in size as you drag the Scale tool 3 Click and drag with the Scale tool to the left or downwards in the workspace to zoom out from workspace objects Workspace objects decrease in size as you drag the Scale tool 7 8 BioMedCAChe User Guide Manipulating portions of your molecule Manipulating portions of your molecule When you use the manipulation tools in the way described in the previous section Using the manipulation tools all objects present in the workspace are rotated translated or scaled CAChe also allows you to manipulate selected portions of your molecule while the remainder of the workspace objects remain stationary Using position mode you can rotate translate or scale selected portions of your chemical sample This enables you to carry out tasks such as positioning selected fragments for bonding or rotating selected functional groups to visualize individual properties more clearly The changes you make to atom positions while in position mode actually change the x y and z coordinates of molecular components Because of this use caution when scaling objects in position mode Scaling selected portions of a che
379. o the right to increase the width of the column All molecular line drawings in the Chemical Sample column increase in size in proportion to the column button A Sorting rows You can sort the rows in a ProjectLeader worksheet according to the following properties in ascending A to Z or numeric or descending Z to A or reverse numeric order e cell type where data are sorted in the following order numerics molecular formula then textual data text only where formulae for the molecula ordering convention is observed carbon atoms hydrogen atoms then remaining atoms in alphabetical order e text handling where the case of textual data is observed NS To sort rows 1 Select the column by which you want to sort the rows 2 Choose View Sort to display the Sort dialog box The column that you selected is displayed from the drop down list in the Primary Key panel 12 34 BioMedCAChe User Guide Changing workbook display options 3 Select either Ascending A to Z or numeric or Descending Z to A or reverse numeric order from the Primary Key panel 4 If required select a column to be used as a secondary key in the Secondary Key panel from the drop down list 5 Select either Ascending or Descending from the Secondary Key panel 6 Select the Options tab This enables you to determine the sort mode and text handling 7 Inthe Sort Mode panel do one of the following a select Cell type to sort numeri
380. object in the tree view You can collapse a folder in the tree view to hide all the subfolders nested beneath it A folder that has been expanded is shown by a minus symbol next to the main folder icon To collapse a folder 1 Inthe tree view move the cursor over the minus sign of the folder that you wish to collapse 2 Press the left mouse button to collapse the selected folder Choosing View Collapse All Folders collapses all expanded objects in the tree view CAChe for Windows User Guide 11 9 Chapter 11 Using the Procedure Editor Renaming an object You can rename an object in the tree view To rename an object 1 Select the object that you wish to rename 2 Do one of the following a Click on the selected object with the left mouse button a Choose File Rename The object name is highlighted 3 Enter a new name Displaying a Procedure window You can display a Procedure window from the tree view To display a Procedure window 1 Do one of the following a Double click on a procedure name in the tree view a Double click on an experiment object that uses the procedure A Procedure window is displayed Displaying a Parameter Data window You can display a Parameter Data window from the tree view To display a Parameter Data window a Double click on a parameter data set in the tree view A Parameter Data window is displayed 11 10 CAChe for Windows User Guide Managing the e
381. object is highlighted to show that it is selected Do one of the following o Choose Edit Copy o Press Ctrl C o Select the toolbar button shown to the left Do one of the following o Choose Edit Paste o Press Ctrl V o Select the toolbar button shown to the left A copy of the selected object is pasted in the center of the active workspace The copy is highlighted in the workspace to show that it is selected while all other workspace objects are grayed out Do one of the following o Click and drag in the workspace with a selection tool to move the selected copy to the location you want o Use the Translate tool to click and drag across the workspace to the location where you want to place the copied object The pasted copy moves to the location where you dragged it BioMedCAChe User Guide Duplicating molecules The copied object remains on the Windows Clipboard until you copy or cut another object or quit CAChe so you can continue to paste copies of the object until you have the required number of copies To copy and paste an object to another workspace BioMedCAChe User Guide 1 Select the object that you want to copy by clicking on it with a selection tool The object is highlighted to show that it is selected Do one of the following o Choose Edit Copy o Press Ctrl C o Select the toolbar button shown to the left Do one of the following o Choose File Open to open the chemic
382. ocalizability and amplitudes of UV visible absorption surfaces The Tabulator uses the molecule file as input and produces new output isosurface files To convert the results of some CAChe computations into three dimensional graphics data the Tabulator computes the value of wavefunctions at all points in a three dimensional grid To derive an isosurface the Tabulator connects points of the same value throughout the grid The Tabulator uses as input the wavefunction data generated by the computational applications Recall that ExtHtickel MOPAC ZINDO and DGauss compute wavefunction data for all molecular orbitals but you can save a subset of the data in your molecule file You can tabulate data and visualize properties for any subset of the data that you saved in your chemical sample file The Tabulator carefully orders the molecular orbitals according to increasing energy This may not be consistent with the numbering order in ExtHtickel MOPAC ZINDO and DGauss Therefore molecular orbital numbers reported by the Tabulator may not exactly correspond with the molecular orbital numbers reported by the other applications especially MOPAC and ZINDO Tabulator computes coordinates for an electronic property of your molecule once the computational applications have finished calculating the property Tabulator creates separate isosurface files for each property you tabulate You do not open the isosurface file to view the electronic propert
383. of the components of a dialog box Arrow Directory Help Close button buttons button button o e a Open P etails Lookin E Cache zl E EE buttons App C Btane io J Chem2 io FURAN m Benzen2 io C Btare iso C Chem3 io C FURANT i Scrolling list Benzene2 io Q Btane map a Chem3 iso Q FURAN i bin J Cachetmp J Chemical io C FURAN is BOND io C Cher1 io C FURAN io C FURANZ i Bond map LI Chem1 map CI FURAN iso C FURANX i Scroll bars gt Text box BE OoOO Files of type fan Files Cancel Help Buttons Chemical Sample csf Brookhaven pdb ent MDL MolFile mol mdl Map map Drop down list Text boxes Text boxes allow you to enter information using the keyboard For example in the example dialog shown earlier you can use the File name text box to select the existing text delete it and type in a new file name NS To enter text into a text box 1 Position the cursor in the required text box and press the left mouse button This activates the text box and fixes the position of the cursor 2 Type the text you want to add to the text box The text is added at the position of the cursor BioMedCAChe User Guide 3 23 Chapter 3 CAChe Basics Arrow buttons Check boxes 3 24 4 Arrow buttons indicate the presence of a drop down list Select an arrow button to display a drop down list NS To select
384. of the following es a To create a new folder in which to save the file select the dialog box button shown to the left a To move up a level of folders to locate the folder in which you want to save the file select the dialog box button shown to the left a To save the file in a subfolder click and drag the scroll bar in the scrolling list to locate the folder in which you want to save the file and double click on the folder to open it 7 Click in the File name text box and enter a name for the file that you are saving 8 Select the arrow button in the Save as type box and choose a file type from the drop down list for the file that you are saving 9 Select Save to print the contents of the selected document window to a file and to close the Print to File dialog box The image is saved using the file name and file type that you specified and in the folder you selected TIP If printing is slow try changing the resolution of your printer Refer to Choosing print options p 4 23 for details 4 28 CAChe for Windows User Guide 5 Modifying Chemical Samples Overview Once you have drawn your molecule you can change its atom and bond characteristics by selecting atoms and bonds and applying new attributes This chapter describes how to e use the CAChe workspace selection tools to select portions of your molecule the entire molecule or similar workspace objects e use the CAChe Find command to select port
385. og box 4 Select OK to close the Bond Attributes dialog box The selected bonds are not visible in the workspace To display hidden bonds Do one of the following 6 28 CAChe for Windows User Guide Hiding bonds 1 Choose View Show All All of the bonds in the workspace are now visible Alternatively 1 Doone of the following to select all the objects in the workspace o Click on an empty area of the workspace with a selection tool o Choose Edit Select All o Press Ctrl A 2 Choose View Bond Attributes to display the Bond Attributes dialog box 3 Select the Display Bonds check box so that it is enabled A check mark appears in the Display Bonds check box 4 Select OK to close the Bond Attributes dialog box All of the bonds in the workspace are now visible CAChe for Windows User Guide 6 29 Chapter 6 Viewing Chemical Samples Viewing selection only TIP 6 30 Simplifying the view of giant molecules crystal lattices and complex chemical samples often aids understanding and analysis You can simplify a view by displaying only selected objects like backbone atoms To show only the selection 1 From the 3D Structure window or Sample Property View choose View Show Selection Only All displayable objects such as atoms bonds and labels which are selected are displayed and all other objects are hidden The menu item View Show Selection Only is checked indicating that objects are hidd
386. om and Bond Properties 16 14 CAChe for Windows User Guide Investigating Reactions Overview This chapter describes the CAChe experiments that investigate the conformations of your molecule during a chemical reaction including the following transition state experiments e search for saddle which generates a transition state structure e refine transition which refines a transition state structure using a minimize gradient calculation e verify transition which calculates the molecule s vibrational transitions to verify the transition state geometry The following reaction path experiment is also described e map reaction which produces an optimized energy map by varying one or two search labels and measuring the energy of each resulting conformation using quantum mechanics e find reaction paths which generates structures in a reaction that your chemical sample will pass through as it proceeds from a transition state geometry to either the product or reactant side of the reaction pathway Contents Investigating transition state structures 17 2 Viewing transition state structures 17 3 Investigating reaction path structures 17 4 Viewing reaction path structures 17 5 Chapter 17 Investigating Reactions Investigating transition state structures 17 2 A lt t gt Vv NOTE CAChe uses quantum mechanics to investigate transition state structures in a reaction path from a reactant molecule to a produc
387. om configuration can be corrected if necessary You can also add structures such as water molecules before building the molecular crystal 8 Select OK to accept the changes and to close the Crystal Shape dialog box NS To build a molecular crystal 1 Select the crystal structure using the Select Molecule Tool 2 Choose Edit Crystal Shape to display the Crystal Shape dialog box In the Build panel select Molecular Crystals 4 Select Apply to view the structure in the workspace Select OK to accept the changes and to close the Crystal Shape dialog box The molecular crystal is built using the bonds present in the workspace and the asymmetric atoms If no bonds are present the crystal is built using a formula that estimates bond lengths according to covalent radii and electronegativity According to this formula when the distance between two atoms is less than the estimated bond length they are considered bonded Bond types are then assigned depending on the types of atoms and the distance between them If atoms are closer than one half the normal bond length they are considered too close and no bond is formed After the molecule is built from asymmetric atoms using this bond formation formula the molecular crystal is built CAChe for Windows User Guide 6 61 Chapter 6 Viewing Chemical Samples Building an infinite lattice 6 62 You can build an infinite lattice crystal by entering the fractional coordina
388. omponent C1 in the main workbook The selected properties associated with this Atom List will automatically be copied Bach Next OK Cancel BioMedCAChe User Guide 12 19 Chapter 12 Using ProjectLeader Running a ProjectLeader experiment 12 20 A lt t gt Y A lt t gt Y lt gt v NOTE A ProjectLeader experiment can be the calculation of a property or the calculation of an analysis ProjectLeader experiments can be run on entire chemical samples or on components of chemical samples Experiments can be run from the ProjectLeader workbook or from the Sample Properties workbook Refer to Viewing sample properties p 12 17 for details of viewing sample properties and copying the information into the ProjectLeader workbook To run a ProjectLeader experiment on one or more chemical samples or sample components you use the following steps 1 Addachemical sample column property sample component analysis or comment to a worksheet Refer to Adding a chemical sample column property sample component analysis or comment to a worksheet p 12 21 2 Select a server on which to run the experiment Refer to Selecting a server p 12 24 3 Select the cells on which you want to experiment Refer to Selecting cells p 12 24 4 Evaluate the cells Refer to Evaluating the cells p 12 25 Before performing an experiment to calculate polymer properties you must ope
389. on a molecule representing electronic properties such as electron density or susceptibility to attack The calculations are performed by a range of computational applications which apply mathematical models from classical mechanics quantum mechanics and dynamics to the chemical sample in the workspace Workspace experiments generate the following types of information e low energy conformations of your molecule the geometry of a series of low energy conformations mapped against energy in a two or three dimensional graph e distribution of electronic properties of your chemical sample calculated as a shaded surface superimposed on the molecule e atom and bond properties including partial charge bond order and bond strain e transition state and reaction path conformations of your molecule e infrared vibrational and UV visible electronic spectra with motion vectors or molecular orbitals superimposed on a molecule in the workspace for any transition in the spectra CAChe for Windows User Guide Introduction to workspace experiments Some CAChe experiments produce complicated three dimensional output or a large amount of textual information which is saved in a new output file based on the name of the original chemical sample file CAChe performs experiments locally on your computer unless you have access to a Unix based CAChe GroupServer lt i gt Refer to Chapter 11 Using the Procedure Editor fo
390. on formed by the varying search labels is optimized before the energy is calculated CAChe steps the search labels through their defined range of values and optimizes each resulting conformation An optimized map takes much longer to generate than a rigid map because of the optimization step CAChe provides procedures that use one of the following e classical mechanics which generates a potential energy optimized map e quantum mechanics which generates a heat of formation optimized map CAChe for Windows User Guide 14 7 Chapter 14 Investigating Low energy Conformations NOTE You cannot generate an optimized energy map using quantum mechanics with Personal CAChe or BioCAChe The optimized conformational energy is plotted as a function of the lowest energy position of any two of the structural elements to create the optimized map Generating an optimized energy map with classical mechanics Classical mechanical procedures measure the potential energy of each conformation of a molecule formed by varying the search labels Each conformation is then optimized by lowering deviations from classical mechanical ideal geometry The potential energy of each optimized conformation is then plotted in an energy graph You can add up to eight search labels to generate an optimized energy map using classical mechanical procedures However because of the time required to complete the calculations it is more practical to add a m
391. on it o Ifthe element you require is not shown in the list double click on Periodic Table to display the Periodic Table dialog box 3 Select the Charge tab to display the Charge VDW Radius list 4 To add anew list item select Add to display the Define Charge dialog box Define Charge x Charge 0 Van der Waals Radius fo 0000000 5 Click in the Charge text box and type a value for atomic charge 6 Click in the Van der Waals Radius text box and type a value for atomic radius 7 Select OK to close the Define Charge dialog box The charge and van der Waals radius values are displayed in the Charge VDW Radius list in the Periodic Table Settings dialog CAChe for Windows User Guide 5 27 Chapter 5 Modifying Chemical Samples 10 11 12 13 box To change an existing list item select the list item containing the atomic charge and radius values you want to change and select Change to display the Define Charge dialog box Click in the Charge or Van der Waals Radius text box and type anew value for atomic charge or radius Select OK to close the Define Charge dialog box The new charge and van der Waals radius values are displayed in the Charge VDW Radius list in the Periodic Table Settings dialog box To remove an existing list item select the list item containing the atomic charge and radius values you want to remove and select Remove The list item disappears from the list To app
392. on of computer aided chemistry by letting you specify first the chemical property that you want evaluated then the procedure for evaluating that property By contrast CAChe Workspace requires you to choose the procedure then select the property to be evaluated ProjectLeader is not part of BioCAChe Personal CAChe Quantum or Ab Initio CAChe ProjectLeader offers the ability to perform calculations on several chemical samples at the same time A wide range of experiments is available including experiments similar to those you can perform in the Workspace plus experiments not available in the Workspace such as calculating connectivity indexes dipole vectors and the octanol water partition coefficient Experiments may be performed on entire chemical samples or on chemical sample components such as atoms bonds and molecular orbitals Refer to ProjectLeader experiments p 12 3 for a full list of the experiments available in ProjectLeader Viewing and analyzing columns of experimental data for several chemical samples at once enables you to establish mathematical relationships between one set of data and another thus aiding e the process of calibration by comparing the results of measurements on specific instruments with the known standard results the calculation of quantitative structure activity relationships QSAR between molecular structure and pharmacological activity and quantitative structure property r
393. on tools To select every visible object in the workspace 1 2 Select a selection tool by clicking on it Click in a blank area of the workspace Every visible object in the workspace is highlighted to show that it is selected Hidden objects are not selected Although you can select every object in the workspace you cannot deselect every object in the workspace CAChe requires that there is at least one selected object in a workspace or active window NOTE The menu command Edit Select All selects all visible and hidden objects Using the Select tool to invert the selection in the workspace Invert the current selection in the workspace using any of the three selection tools To invert the visible selection in the workspace 1 2 Select a selection tool by clicking on it Do one of the following a Click in a blank area of the workspace a Choose Edit Invert Selection Newly selected objects in the workspace are highlighted to show that they are selected NOTE The menu command Edit Invert Selection inverts the selection of both visible and hidden objects BioMedCAChe User Guide 3 37 Chapter 3 CAChe Basics The Rotate tool Using the Rotate tool The Translate tool 3 38 Use the Rotate tool to rotate workspace objects in two and three dimensions around the x y and z axes To select the Rotate tool 1 Select the Rotate tool by clickin
394. onformations a Property sequence of conformations and a Using Global Min Search with MM3 CAChe for Windows User Guide 19 7 Chapter 19 Investigating Biomolecules The Experiment dialog should look similar to this ui Experiment iOi x Input List oe oxytocin csf Start Server Edit cache localhost hd Make Default Property of chemical sample conformations z Property sequence of conformations he The collection of low energy conformations generated by sequentially searching an unlimited number of geometry labels xl Using Global Min Search with MM2 DE limited conformation search using CONFLE is performed This experiment is useful for large molecules or as an initial test A sequence of x 6 Choose Start CONFLEX runs and automatically searches for low energy structures in rings and around the rotatable bonds that have search labels For peptides this is a lengthy process requiring many hours When CONFLEX completes it creates a sequence file in the map directory and opens it automatically in the CAChe workspace if CAChe is running You use the workspace to analyze the results from CONFLEX Analyzing peptide conformations amp To analyze the peptide conformations 1 Choose File Open set the Files of Type to Map map and 19 8 CAChe for Windows User Guide Investigating peptide conformations Potential_E 45 04 to 18 63 Kcal mol navigate to the
395. ons Sequence Yiew of x x Phi 180 psif180 Sequences after alignment Alignment is the process of inserting gaps so that the score of adjacent residues is maximized The scoring used in CAChe is the BLOSUM5O substitution matrix augmented with a single column of Da 5 5 oC s D a i D BioMedCAChe User Guide 21 13 Chapter 21 CAChe BioComputations weights for any group that is not a standard amino acid The BLOSUMS0 Substitution Matrix Used in CAChe ARNDCQEGH 0 2 1 5 2 1 2 1 1 1 0 2 1 2 1 1 3 1 0 3 2 0 1 N lt lt SHAVMTUTMNEAT TOAMOINOZI gt D 2 7 1 3 0 4 3 3 2 3 3 1 1 3 1 3 1 implementation of the Needleman Wunsch algorithm follows that of Gotoh as described by Durbin et al The Needleman Wunsch global alignment gives the highest scoring 1 1 3 1 2 2 2 8 1 4 13 3 3 3 3 2 2 3 2 2 4 1 1 5 3 1 1 1 i 0 0 1 0 1 1 1 3 1 1 0 0 2 3 2 6 3 0 4 3 2 3 1 1 1 3 2 3 1 3 0 1 3 2 3 8 0 1 1 3 0 2 2 10 2 3 3 4 1 4 3 0 1 1 2 1 2 3 2 4 1 4 3 4 3 3 1 3 1 4 1 LKMFPSTWYV 2 3 4 4 2 2 3 4 3 2 5 3 3 4 3 1 2 1 1 1 3 0 1 3 2 1 2 0 3 3
396. ons To animate your molecule from the last to the first conformation select the reverse button shown to the left To display a particular conformation in the range do one of the following o Select the up or down arrow buttons in the Conformation text box to increase or decrease the value displayed o Click in the Conformation text box and enter the step number of the conformation you want to view To view the first conformation in the range select the rewind button shown to the left The molecule moves to the first conformation in the range To view the last conformation in the range select the forward button shown to the left The molecule moves to the last conformation in the range To modify the range of steps by which you are animating the molecule do one of the following o Select the up or down arrow buttons in the Step by text box to increase or decrease the value displayed o Click in the Step by text box and type the number of steps by which you want to animate the molecule 10 To finish the animation do one of the following CAChe for Windows User Guide o Select Done to close the Animate Geometry Labels dialog box and to display the conformation at which you finished the animation in the workspace o Select Cancel to close the Animate Geometry Labels dialog box and to display the conformation before the animation 8 45 Chapter 8 Investigating Molecular Geometry 8 46 CAChe for Windo
397. ons 3 20 1 Select the selection tool you want to use 2 Position the cursor in the workspace Hold down the left mouse button and drag the cursor across the workspace The selected object is moved scaled or rotated Double click on the following items to open them in the Open and Save As dialog box scrolling lists e folders e files This user guide uses the following convention for choosing options from a menu s drop down list Menu Drop down list option For example File Save You can also perform some menu drop down list options using either keyboard shortcuts or toolbar buttons Refer to Toolbar shortcuts p 3 21 for details about toolbar buttons and their equivalent menu options Refer to Appendix A Keyboard and Toolbar Shortcuts for a list of keyboard shortcuts that are equivalent to menu options BioMedCAChe User Guide Using CAChe Using the toolbar The following section describes how to use the toolbar buttons To select a toolbar button 1 Position the cursor over the required button 2 Press the left mouse button The name of the button appears in the a yellow tool tip box near the cursor and a short description of the function of the button status bar at the bottom of the screen 3 Release the left mouse button The command to which the toolbar button provides a shortcut is performed Toolbar shortcuts The following diagram shows the menu options that are eq
398. operty of box and choose the class of property on which you want to experiment from the drop down list For example if you want to investigate the property of a chemical sample choose chemical sample from the drop down list Select the arrow button in the Property box and choose the property on which you want to experiment from the drop down list 10 19 Chapter 10 Performing Workspace Experiments 10 20 10 1 For example if you want to investigate the electron density of a chemical sample choose electron density from the drop down list The display box underneath the Property box describes the selected property Select the arrow button in the Using box and choose a procedure from the drop down list For example if you want to use a procedure that applies MM geometry with a PM3 wavefunction choose MM geometry with PM3 wavefunction from the drop down list The display box underneath the Using box describes the selected procedure and the computational application that will perform the experiment Refer to Choosing a property class p 10 5 for a more detailed description of the selected property and Choosing a procedure p 10 9 for a more detailed description of the selected procedure Select the arrow button in the Server box and do one of the following Choose cache localhost from the drop down list if you are using CAChe as a standalone CAChe product Choose the remote serve
399. option takes more time performs more computations and captures more low energy structures In contrast to the optimized energy map the sequential search focuses computational power and time on the low energy regions of the potential energy surface When you perform a multiple pass sequential search you are likely to obtain the same low energy conformers that are found by an optimized map However these conformations will be closer to the true minima because this computation allows the relaxation of the entire structure apart from the searched label The sequential search is also a more economical computation so you can compute more search labels in less time than the exhaustive map BioMedCAChe User Guide Understanding Dynamics Understanding Dynamics This section provides reference information about the kinds of computations possible using dynamics methods and specific information about the CAChe computational application Dynamics Dynamics concepts Dynamics methods approximate the movements of atoms The potential energy of a molecular system is governed by the empirical force field The CAChe computational application Dynamics uses the same force fields as the Mechanics application The kinetic energy of a molecular system is derived from the atomic velocities which in turn are chosen to reflect the temperature of the simulation By executing Dynamics simulations you can observe the molecular systems that you are studyin
400. or each atom in the workspace Chapter 18 Investigating Spectra The following example shows a display of motion vectors from several selected transitions To edit transition properties 1 Fora single transition double click the transition For more than one transition select the transitions for which you want to edit properties then choose View Transition Attributes The View Transition Attributes dialog box is displayed View Transition Attributes 24x Wavenumber 2357 53 cm1 Cancel Width 100 cm 1 Area fo 005776 debye 2 Click in the Wavenumber Width or Area text box to edit the peak width wavelength or area of the selected transitions 3 Select OK to close the View Transition Attributes dialog box 18 4 CAChe for Windows User Guide Investigating infrared spectra NS To change axis attributes 1 Double click either spectral axis to display the View Axis Attributes dialog box View Axis Attributes 21x Wavelength Range 4000 00000 to 0 00000 cm l Cancel Intensity Range fo coooa to fi 05 00000 Click in the Wavelength Range or Intensity Range text boxes to edit the range of each axis Select OK to close the View Axis Attributes dialog box CAChe for Windows User Guide Chapter 18 Investigating Spectra Investigating UV visible spectra NOTE UV visible spectra can be generated only
401. or Windows User Guide 15 19 Chapter 15 Investigating Electron Distribution Viewing dotted surfaces When viewing surfaces as dotted you can choose the density of the surface rendering To display dotted surfaces Viewing wireframe surfaces 15 20 1 Select a surface by clicking on its label with the Select tool 2 Choose Analyze Surface Attributes to display the Surface Attributes dialog box Select the Dotted radio button so that it is enabled 4 Do one of the following a Select the up or down arrow button in the Dot Intensity text box to increase the dot intensity to a maximum of 9 a Click in the Dot Intensity text box and type an integer between 1 and 9 When viewing surfaces as wireframe you have the option of viewing only the portion of the wireframe which is parallel to the x y plane of your chemical sample the y z plane of your chemical sample e the x z plane of your chemical sample To display wireframe surfaces 1 Select a surface by clicking on its label with the Select tool 2 Choose Analyze Surface Attributes to display the Surface Attributes dialog box Select the Wireframe radio button so that it is enabled 4 To view the portion of the wireframe which is parallel to the x y plane select the X Y Planes check box so that it is enabled 5 To view the portion of the wireframe which is parallel to the x y plane select the Y Z Planes check box so that it is enabl
402. or calculations that need high precision MOZYME should not be used BioMedCAChe User Guide Understanding MOPAC BioMedCAChe User Guide Although the SCF uses only a small fraction of the memory needed by an equivalent MOPAC calculation there is no way to reduce the memory needed for geometry optimization The EF method uses a large amount of memory and should therefore not be used in optimizing the geometry of very large systems A better choice is LBFGS although it too uses a lot of memory When the geometry of a large system is optimized the run should be broken into a series of short calculations of 50 200 cycles This is necessary because the geometry might change considerably during the optimization and atoms that were not interacting at the start of the calculation might interact strongly at the end of the run By stopping and restarting the optimization any new interactions are taken into account Failure to break up an optimization in this way can lead to a ruined calculation 20 21 D E i s n i D Chapter 20 CAChe Computational Applications Understanding Tabulator Tabulator concepts 20 22 The Tabulator application converts the results of CAChe computational methods into three dimensional surfaces and properties that you can view from the chemical sample file This operation is needed to visualize electron density molecular orbital electrostatic potential superdel
403. or displaying atoms and bonds so that you can easily change the appearance of your entire chemical sample or selected portions only without changing the molecular structure This allows you to view different representations of your chemical sample at varying stages of your work Choosing a new display style can help you visualize certain aspects or properties of your molecule more clearly CAChe offers the following display options for your chemical sample e shape size and shading options for atoms and bonds e ability to show or hide atoms and bonds of a certain type e ability to display electrons e customizable color palette for workspace objects e labeling options for atoms and bonds e drawing settings for the display of text and lines in the workspace or in files containing graphs Refer to Chapter 19 Investigating Biomolecules for additional information on viewing and displaying biomolecules While you can customize the display of your molecule by combining many different combinations of viewing options for atom and bond properties CAChe also offers the following five built in model styles available from the View menu e Lines displays atoms as their atomic symbol and bonds as multiple lines Colors are not changed The lines are not z buffered improving speed of rotation e Lines Only displays atoms as small circles and bonds as multiple small cylinders scaled to 0 04A Colors are not changed The cyl
404. ormations experiment To use a large number of search labels in a sequence of conformations experiment you can add dihedral angle search labels automatically using the Geometry Label Wizard Refer to Defining search labels automatically p 8 41 for details about using the Geometry Label Wizard Generating a dynamics trajectory 14 10 Dynamics trajectory experiments allow you to visualize the movement of atoms that results from adding thermal energy to the molecule Initially the energy is added in the form of kinetic energy by randomly assigning velocities to atoms As the calculation proceeds however some kinetic energy is transformed into potential energy The total energy in the system is conserved throughout the experiment You do not need to add search labels to a sample before performing a dynamics trajectory experiment so your chemical sample file requires no preparation Therefore a dynamics trajectory experiment is a faster alternative to a rigid map optimized map or sequence of conformations experiment which can take too much time to prepare and generate for large molecules The resulting energy map from a dynamics trajectory allows you to view conformations beside a two dimensional energy graph which can be used to e identify low energy conformations e gain useful information regarding the relative rigidity of a structure The horizontal axis corresponds to the time frame in which the stru
405. ort a worksheet 1 le CU BioMedCAChe User Guide Select the data that you want to export If you want to export the entire worksheet select the worksheet button in the top right hand corner of the worksheet Choose File Export to display the Save As dialog box Click in the File name text box and type a name for the new file Choose Files sdf from the Save as type drop down list Select Save to save the sdf file and to close the Save As dialog box 12 43 Chapter 12 Using ProjectLeader Saving a ProjectLeader project ProjectLeader projects can be saved as project files This enables you to save a project that you have been working on then open it again and continue working on it from where you stopped One ProjectLeader workbook is saved in each project If you have more than one workbook open when you save a workbook as a project ProjectLeader will prompt you to supply a different name for each workbook so that each workbook is saved in a different project Tosavea ProjectLeader project 1 Choose File Save If you have not already defined a name for the project the Save As dialog box is opened 2 Move to the directory in which you want to save the project Enter a name for the project in the File name text box 4 Select Save to save the project If you have more than one workbook that has not been saved as a project the Save as dialog box remains open so that you can save the other proj
406. otential energy changes from conformation to conformation and the resulting kinetic energy is annihilated so that the potential and total energies are the same conserve the kinetic energy of the molecule at every step using a DRC Dynamic Reaction Coordinate calculation Kinetic energy increases as potential energy is lost from conformation to conformation so that total energy is constant The energy of each conformation is plotted in a separate map file where you can view the energy graph alongside each reaction path structure 17 4 CAChe for Windows User Guide Investigating reaction path structures Start a find reaction paths experiment with a transition state structure generated by a search for saddle experiment A ele 4 gt Refer to Investigating transition state structures p 17 2 for further details about generating a transition state structure You can also perform a map reaction experiment which produces an optimized energy map by varying one or two search labels and measuring the energy of each resulting conformation using quantum mechanics NOTE Reaction path experiments are not available with Personal CAChe and BioCAChe Viewing reaction path structures Both a find reaction paths experiment and a map reaction experiment produce an energy map file which you can view in the same way as any other map file lt t gt Refer to Viewing map files p 14 12 for further details about
407. ou can change the following axis attributes for individual axes e edit the range of values along a graph axis change the axis title e hide or display axes axis labels and the range of values for an axis NS To change axis attributes 1 Activate the graph window of the map file by clicking on it 2 Choose View Graph Attributes to display the Graph Attributes dialog box 3 Select Attributes under the box of the axis whose display options you want to change For example if you want to change display options for the X axis choose Attributes under the X box The Axis Attributes dialog box is displayed 14 18 CAChe for Windows User Guide Viewing map files 10 11 12 13 14 CAChe for Windows User Guide Axis Attributes x Title Range Label Axis Title To change an axis title select the Title tab to display the Axis Title text box Click in the Axis Title text box and type a title for the axis To change the range of values displayed on the axis select the Range tab to display the Maximum and Minimum text boxes Click in the Minimum text box and type a minimum value for axis range Click in the Maximum text box and type a maximum value for the axis range To change axis labeling select the Label tab to display a list of check boxes Select the Show Axis check box to hide the graph axis The check mark is no longer displayed in the check box Select the Show Axis Title c
408. ou saved To save an experiment file 1 Select the Experiment dialog box by clicking on it 2 Choose File Save to display the Save As dialog box Save As 2x Save in Cache c App C Btane iso 3 Chem3 io C sopren2 rr Benzen2 io C Btane map E Chem3 iso C lsoprene ic Benzene2 io C Cachetmp C Chemical io C lsoprene rr bin C Chem1 io E Iso io C lsopm2a ic BOND io C Chem1 map C Isoprent io C Isoprm2a r Btane io LA Chem2 io LJ lsopren2 io J lsopm2b ic Save as type Experiments exp x Cancel Help 3 Select a folder in which to save the experiment file from the Save in drop down list or from the scrolling list 4 Click in the File name text box and type a name for the experiment file you are saving 5 Select the arrow button in the Save as type box and choose Experiments exp from the drop down list 6 Select Save to save the experiment file and to close the Save As dialog box The file is saved with the extension exp CAChe for Windows User Guide 10 23 Chapter 10 Performing Workspace Experiments Stopping an experiment 10 24 You can stop an experiment while it is still running before calculations are complete and choose how to deal with any data already produced by the experiment You can stop an experiment from the following dialog boxes e the Experiment Status dialog box displayed automatically while an experiment is running e the Experiments Submitted
409. ow appears 8 Choose the Atom tab and select row 1 The oxygen atom at the center of the cube is selected 9 Inthe workspace choose Edit Select Neighbors The Select Neighbors dialog appears 10 Choose to select nearest atoms by selection radius and set the CAChe for Windows User Guide 19 11 Chapter 19 Investigating Biomolecules 19 12 11 12 13 14 15 16 17 18 19 selection radius to 14 angstroms Select Neighbors 2 x Select Nearest Atoms Selection Radius in A 14 Number of Atoms 1 C Number of Bonds 1 Cancel Choose OK All atoms within a sphere of 14 angstroms from the central oxygen atom are selected Using the Select tool invert the selection by holding down the shift key while clicking on empty space All atoms outside the sphere are selected and those inside the sphere are unselected Choose Edit Delete to remove the atoms outside the droplet A sphere of 515 oxygen atoms remains To retain the spherical shape during optimization lock the outer shell of oxygen atoms In the Sample Properties Window select atom 1 by clicking on the row number In the workspace choose Edit Select Neighbors and select neighbors within 11 5 angstroms of the selected oxygen atom Using the Select tool invert the selection by holding down the shift key while clicking on empty space The outer shell of oxygen atoms is selected Choose Adjust Lock to lo
410. ow that it is selected 2 Hold down the Shift key and select the corresponding atom in the second ring structure by clicking on it with the Select tool The atom is highlighted to show that it is selected The following example shows the order of atom selection in the two rings and the resulting structure when the second selected atom replaces the first When you fuse atoms the second atom you selected will replace the first atom you selected in the first ring structure _ Fuse Atoms BioMedCAChe User Guide 7 21 Chapter 7 Manipulating Molecules 7 22 3 Choose Edit Fuse Atoms The first atom you selected is replaced by the second atom you selected The second atom becomes attached to all connecting bonds and atoms from the first atom Choose Beautify Comprehensive to correct the valence hybridization ring structure and molecular geometry of the resulting structure NS To fuse two bonds 1 Select an atom in the first ring structure by clicking on it with the Select tool The atom is highlighted to show that it is selected Hold down the Shift key and select the corresponding atom in the second ring structure by clicking on it with the Select tool The atom is highlighted to show that it is selected Choose Edit Fuse Atoms The first atom you selected is superimposed over the second atom you selected In the first ring structure select the other atom connected to the bond you want to be
411. own to the left to animate your molecule Depending on which type of window is active one of the following occurs a Fora graph window the conformation window steps through the conformations along the graph axis that is most closely aligned with the horizontal axis based on the graph s current rotation By rotating the graph you can control which axis is animated and which is held constant a Fora conformation window the conformation window steps through each conformation in the map file a For a conformational analysis window the conformation window steps through each conformation listed in the conformational analysis window The molecule in the conformation window moves through each variable value in turn to display the range of conformations At the same time the spherical marker in the graph window moves to each corresponding graph location The Conformation text box in the relevant Animate dialog box displays the position of the current conformation in the range of conformations The box to the right of the Conformation text box displays the total number of conformations in the range To stop the animation at a particular conformation select the stop button shown to the left The molecule stops moving in the conformation window and the marker remains stationary in the graph window The 14 27 Chapter 14 Investigating Low energy Conformations 14 28 cin Conformation text box in the relevant Animate d
412. ows you to include water solvent effects in a current energy experiment by using COSMO 4 gt Refer to Modeling solvent effects with COSMO p 20 19 for more information on experimental procedures that include solvation effects 13 12 CAChe for Windows User Guide 1 4 Investigating Low energy Conformations Overview This chapter describes how to investigate a series of low energy conformations of your molecule by generating and analyzing the following energy maps e arigid energy map e an optimized energy map a sequence of conformations e a dynamics trajectory Contents Generating energy maps 14 2 Viewing map files 14 12 Preparing your chemical sample file 14 5 Map file windows 14 12 Generating a rigid energy map 14 6 Map file display options 14 15 Generating an optimized energy map 14 7 Analyzing map files 14 22 Generating a sequence of conformations 14 9 Animating map files 14 26 Generating a dynamics trajectory 14 10 Saving map files 14 30 Chapter 14 Investigating Low energy Conformations Generating energy maps 14 2 When you optimize a sample the resulting low energy geometry is based on the original geometry that you started with By varying the geometry of your sample into numerous different conformations and measuring the energy of each CAChe can investigate the existence of other low energy conformations for your molecule based on a different geometry CAChe generates energy map files m
413. ox accessed by choosing View Atom Attributes lt t gt Refer to Chapter 6 Viewing Chemical Samples for information about the Atom Attributes dialog box Correcting ring geometry To correct ring geometry 1 Select a workspace selection tool by clicking on it in the tool palette 2 Using the selection tool select the portion of your molecule or the entire molecule for which you want to correct ring geometry The objects you have selected are highlighted in the workspace 3 Choose Beautify Rings CAChe forces selected cyclic structures into either a planar or puckered conformation adjusting bond lengths to their proper values CAChe for Windows User Guide 4 13 Chapter 4 Creating Chemical Samples If the selected structure contains two or more sp atoms the ring is flattened If the selected structure contains fused rings all rings except the first one are flattened Correcting geometry To correct geometry 1 Select a workspace selection tool by clicking on it in the tool palette 2 Using the selection tool select the portion of your molecule or the entire molecule for which you want to correct geometry The objects you have selected are highlighted in the workspace 3 Choose Beautify Geometry CAChe changes the bond angles and bond lengths in the selected objects to chemically sound values based on existing atom valence and hybridization NOTE This menu option does not cl
414. ox and the selected atom or group of atoms changes to the chosen element type CAChe for Windows User Guide 5 19 Chapter 5 Modifying Chemical Samples 5 20 4 If the element you require is not displayed choose Periodic Table from the drop down list to display the Periodic Table dialog box Periodic Table 21 x H i EES B i al 4 JA Na Mg a Si 11 12 13 14 15 16 17 18 K Ca Sc 7 M Cr Mn fe Co Ni Cu Zn Ga Ge As Se Br Kr 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Rb Sr Nb Mo Tc Ru Rh Pd Ag Cd In Sn Sb Te jl Xe 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 Cs Ba la HE Ta W Re Os Ir Pt Au Hg TM Pb Bi Po At Rn 55 56 57 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 fr Ra Ac 97 88 89 Ce Pr Nd Pm Sm Eu Gd Th Dy Ho Er Tm Yb Lu 58 59 60 61 62 63 64 65 66 67 68 69 70 71 Bk 97 Th Pa U Np Pu Am Cm Bk Cf Es Fm Md No Lr 90 31 92 93 94 95 96 Cancel 98 3 100 101 102 103 Select an element by double clicking on it or clicking on it and selecting OK The Periodic Table dialog box closes The element you have chosen is displayed in the Element Type box and the selected atom changes to the chosen element type To change hybridization of an atom using the style bar Select the atom or group of atoms whose hybridization
415. periment Status dialog box 1 When you receive an error message that your disk is full make more storage space available on your local computer 2 Select Retry Output file generation continues and output files are saved as normal To reattempt output file generation from the Experiments Submitted dialog box 1 When you receive an error message that your disk is full make more storage space available on your local computer 2 Choose Experiment Show Submitted Experiments The Experiments Submitted dialog box displays experiments submitted by a user CAChe for Windows User Guide Troubleshooting experiments 3 Select the experiment you want to retry in the Experiments Submitted dialog box 4 Select Retry Output file generation continues and output files are saved as normal Displaying servers on which to run an experiment When you choose Experiment New to display the Experiment dialog box you may find that the server you require is not listed in the Server drop down list For example if you are using CAChe as a standalone program you need to select cache localhost as the server on which to perform your experiment locally If you are using CAChe with CAChe GroupServer you need to select a GroupServer on which to perform your experiment If the server you require is not shown in the Server drop down list of the Experiment dialog box you need to edit your tcpconf txt file which is located in your
416. perties described earlier in Choosing a property and the procedures you can use to run an experiment to calculate each property Properties Available procedures Chemical Sample Properties Optimized Geometry 0 7 19 Heat of Formation 12 15 UV visible transitions 55 59 IR transitions 57 58 Current Energy 0 12 15 CAChe for Windows User Guide 10 15 Chapter 10 Performing Workspace Experiments 10 16 Properties Available procedures Electron Density 1 20 HOMO and LUMO 1 20 HOMO 5 to LUMO 4 1 20 All Molecular Orbitals 1 20 Electrostatic Isopotential 1 20 Susceptibility Electrophilic 1 20 Susceptibility Nucleophilic 1 20 Susceptibility Radical 1 20 Superdelocalizability 1 20 Electrophilic Superdelocalizability 1 20 Nucleophilic Superdelocalizability Radical 1 20 Atom Properties Partial Charge 1 19 Bond Properties Bond Order 1 19 Bond Strain 0 Chemical Sample Conformation Properties Rigid Map 25 33 Optimized Map 25 33 Sequence of Conformations 36 37 Dynamics Trajectory 38 not Personal CAChe CAChe for Windows User Guide Setting up a workspace experiment Properties Available procedures Reaction and Transition State Properties Map Reaction 26 33 not Personal or Bio CAChe Search for Saddle 39 42 not Personal or Bio CAChe Refine Transition State 16 19 not Personal or Bio CAChe Verify Transition State 57 58 not Personal or Bio CAChe Find Reaction Paths 45 52 no
417. played by choosing View Geometry Label Attributes Refer to Chapter 8 Investigating Molecular Geometry for information on this View menu option CAChe for Windows User Guide Saving settings e all settings in the Surface Attributes dialog box displayed by choosing Analyze Surface Attributes Refer to Viewing a surface p 15 9 for information on this View menu option e allsettings in the Select Similar Settings dialog box displayed by choosing Options Select Similar Settings Refer to Chapter 5 Modifying Chemical Samples for information on this Options menu option e all settings in the Drawing Settings dialog box displayed by choosing Options Drawing Settings Refer to Changing view settings p 6 37 for information on this Options menu option e all settings in the Rotation Settings dialog box displayed by choosing Options Rotation Settings Refer to Chapter 7 Manipulating Molecules for information on this Options menu option e all settings in the View Settings dialog box displayed by choosing Options View Settings Refer to Changing view settings earlier in this chapter for information on this Options menu option e all settings in the Valence Settings dialog box displayed by choosing Options Valence Settings Refer to Changing view settings p 6 37 for information on this Options menu option CAChe for Windows User Guide 6 53 Chapter 6 Vie
418. points in vibrational spectrum calculations Electronic property surfaces cannot be tabulated for molecules that contain sparkles atoms BioMedCAChe User Guide Understanding MOPAC Optimizing with MOPAC Stationary geometries are those for which the energy does not change when the atoms are displaced by infinitesimal amounts This means that the net force on each atom is zero Minimum energy geometries are stationary geometries for which the energy increases when the atoms are displaced in any direction This means that the force constants of a molecule at a minimum energy geometry are all positive Because the force constants are all positive the vibrational frequencies are all real The expression optimization refers to finding a minimum energy geometry of the molecule The minimum energy geometry found is usually close to the starting geometry Other molecular geometries besides minimum energy geometries are stationary These include saddle points inflection points and hilltops Of these the saddle point is of greatest interest to chemists Saddle points are also called transition states See the next section for more information about saddle points MOPAC can use search labels to generate maps for optimized geometry A reaction coordinate search uses one search label and a grid search uses two The first label listed in the molecule file will be used All optimize map calculations are done in internal coordinates M
419. pplication in which you want to paste the copied object Open or select the document into which you want to paste the copied object Do one of the following o Choose Edit Paste o Press Ctrl V An image of the selected object is pasted into the document in the format of a Windows bitmap The copied object remains on the Windows Clipboard until you copy or cut another object or quit CAChe so you can continue to paste copies of the object until you have the required number of copies BioMedCAChe User Guide Duplicating molecules Copying objects from ChemDraw or ISIS Draw You can copy any selected object to the Windows Clipboard from ChemDraw or ISIS Draw and paste it into the workspace To copy and paste an object from ChemDraw or ISIS Draw 1 Select the object that you want to copy by clicking on it with a selection tool 2 Do one of the following o Choose Edit Copy o Press Ctrl C 3 Do one of the following o Choose File Open to open the chemical sample file in which you want to paste the copied object o If the chemical sample file in which you want to paste the copied object is already open click on its workspace to make it active NOTE CAChe only transfers chemical samples smaller than 400 atoms to ChemDraw and IsisDraw To transfer information to ChemDraw or IsisDraw CAChe places an SD file on the clipboard The largest chemical sample that can be placed on the clipboard in SD format is
420. quence View window comes to the front and the menus and toolbar change The toolbar The Sequence View toolbar contains a collection of buttons that provide a shortcut to some of the menu options The following diagram shows the toolbar and the corresponding menu options that each button performs when the Sequence View window is at the front er gt x a6 2 52 EB 2 oO zZz 2 S O O ge on OA E 2 50 Seu oaf tri FF ES g L rg g S 5 4 QO ros Experiment Show Submitted Experiments Experiment Show Server Information BioMedCAChe User Guide 9 19 Chapter 9 Manipulating Biomolecules The Sequence View window 9 20 Although you can have many workspaces open at any time there can be only one Sequence View window open at a time Any menu bar or toolbar commands you choose affect the active document window To activate the Sequence View click on it The main components of the Sequence View are e atitle bar that displays the name of the document e a Style bar with drop down lists that enable you to change the residue type secondary structure type and Phi and Psi angles of selected parts of your protein e a Tool palette that provides selection tools and a residue editing tool Title bar Style bar J z Pril Psi B Kumbe a Og PDB Numbe 14 17 18 Tool palette X an B 27 28 29 30 31 32 VAY ma L Tr Ca Ss eRe Bey Sx Hc GLGGLYFY L w ba N l z
421. r 6 Viewing Chemical Samples e calculated bond order colors the selected bonds by the calculated bond order Bond order values are rounded to the nearest integer and the color indexes used are the same as for bond type This option is only useful after a calculated bond order experiment has been run on your chemical sample e specific color colors the selected bonds with a specific color that you choose from a drop down list displaying 12 colors lt t gt Refer to Editing the color palette p 6 38 for information on changing the colors displayed in the drop down list by editing the CAChe color palette To change bond color 1 Select the bonds that you want to change color by clicking on them with a selection tool 2 Choose View Bond Attributes to display the Bond Attributes dialog box Bond Attributes 24x Type Color Shape Color bonds by Atom Element Colors C Bond Type Calculated Bond Strain Calculated Bond Order Specific Color 5 V Display Bonds Cancel Make Default 6 26 CAChe for Windows User Guide Changing the appearance of bonds 3 Select the Color tab to display the following list of color options for bonds o color bonds by atom colors o color bonds by atom element colors o color bonds by bond type o color bonds by calculated bond strain o color bonds by calculated bond order o color bonds by specific color 4 Select the
422. r Area text box to edit the peak width wavelength or area of the selected transitions 3 Select OK to close the View Transition Attributes dialog box NS To change axis attributes 1 Double click either spectral axis to display the View Axis Attributes dialog box 2 Click in the Wavelength Range or Intensity Range text boxes to edit the range of each axis 3 Select OK to close the View Axis Attributes dialog box 18 8 CAChe for Windows User Guide 1 Q Investigating Biomolecules Overview This chapter explains how to use CAChe with biomolecules to e investigate peptide conformations e build a peptide using the Sequence View e explore conformations with CONFLEX e analyze conformations in the workspace e solvate the peptide with water molecules e build a GPCR 3D structure using homology modeling read in the x ray crystal structure of a homolog e use the Sequence View window to modify the seven transmembrane TM helical domains e use the Sequence View window to insert delete and modify loops e solvate the GPCR model with a water shell use mechanics and dynamics to refine the structure e validate the model Contents Investigating peptide conformations 19 3 Viewing bovine rhodopsin 19 16 Building a peptide 19 3 Building a model of MC4R 19 17 Generating peptide conformations 19 6 Docking Agouti Related Protein into the Analyzing peptide conformations 19 8 MC4R 19 22 Including water 19 10 Creating a ho
423. r Guide Setting up a workspace experiment Choosing a procedure Refine transition state Refines a transition state structure using a minimize gradient calculation Verify transition state Verifies the current transition state geometry where a single negative vibration confirms a true transition state Find reaction paths Produces an assemblage file containing the structures a chemical sample in a transition state geometry will pass through on the way to the reactant or product structures The workspace offers a wide range of procedures that you can use to investigate a property Procedures are applied by one or more of the computational applications which apply theories from classical mechanics quantum mechanics and dynamics to your chemical sample Identifying the procedure number Each procedures you can use to run CAChe experiments applications involved in each procedure Each procedure is identified with a number This procedure number can be viewed in CAChe from the Experiment dialog box displayed by choosing Experiment New CAChe for Windows User Guide 10 9 Chapter 10 Performing Workspace Experiments Using the table of procedures 10 10 s Experiment1 O1 x Input List pos ample phenol csf Set Inputs Server Make Default Property of chemical sample bad Property atom count x The number of atoms of a given atomic number in the chemical sample at the time of evalu
424. r Windows User Guide 19 23 Chapter 19 Investigating Biomolecules 19 24 CAChe for Windows User Guide Understanding CAChe ABLSIWSAHIDIOLOH 3 Q 3 The following chapter explains the theories behind the CAChe computational applications and the way each application functions tez gej S n gej D 2 0 CAChe Computational Applications Overview This chapter explains in detail the theories and methods behind the following CAChe computational applications e Mechanics which uses augmented MM2 MM3 parameters e Dynamics which approximates the movement of atoms e MOPAC which determines optimum geometry and electronic properties by solving the Schr dinger equation using MINDO 3 MNDO MNDO d AM PM3 or PM5 semi empirical parameters MOPAC also implements MOZYME a linear scaling method for giant molecules Tabulator which converts CAChe computational results into three dimensional surfaces e DGauss which determines optimum geometry and the electronic properties of molecules by solving the Kohn Sham equations in a self consistent field molecular orbital approximation D E i s N i D e CONFLEX which computes optimum geometry and potential energy maps Contents Understanding Mechanics 20 2 Understanding CONFLEX 20 23 Understanding Dynamics 20 7 Understanding MOPAC 20 11 Understanding Tabulator 20 22 Chapter 20 CAChe
425. r details about creating new experiments modifying procedures and editing parameter data sets Refer to Setting up a workspace experiment p 10 4 for a full list of the properties and procedures that you can use in experiments and which procedures to use for a certain type of experiment Refer to Viewing experimental results p 10 36 for details on file types generated by different experiments and the content of a file type Refer to Chapter 20 CAChe Computational Applications for detailed information on the computational applications that CAChe uses CAChe for Windows User Guide 10 3 Chapter 10 Performing Workspace Experiments Setting up a workspace experiment The following steps outline the process of performing a workspace experiment and the properties and procedures available 1 Prepare a chemical sample file 2 Choose a property class to investigate 3 Choose a property to investigate 4 Choose a procedure to use 5 Ifyou have access to CAChe GroupServer choose a server to run the experiment on Refer to Chapter 11 Using the Procedure Editor for details about creating a new experiment After these steps just listed you are ready to start the experiment Refer to Running an experiment p 10 18 for details about performing an experiment in CAChe Preparing a chemical sample file 10 4 Before you can perform an experiment you need to build and investiga
426. r dialog box a Select the new group package from the right hand Parameter Data Available In drop down list The new package is displayed in the To Group box a From the In User box select the components that you wish to copy to the new group package a Select the Copy button to copy the selected components 11 When all the required components have been added to the new group package select the Close button to close the Organizer dialog box Loading new packages Once the group package has been created all users who share the group package directory are informed of the availability of the new CAChe for Windows User Guide 11 33 Chapter 11 Using the Procedure Editor 11 34 NOTE NOTE package the next time they start the Procedure Editor the Workspace or the ProjectLeader The New Packages Available dialog box is displayed if the package set contains any new packages that were not present the last time the Procedure Editor the Workspace or the ProjectLeader was started You can select the packages that you wish to load The New Packages Available dialog box will inform you in the future if any new packages are added to CAChe as a result of you or a System Administrator installing anew CAChe compute engine To select packages to be loaded 1 In the New Packages Available dialog box select the packages that you wish to be loaded 2 Select OK to confirm your selection and to close the dialog box
427. r on which to run the experiment from the drop down list if you are using CAChe in conjunction with CAChe GroupServer and want to run the experiment on a remote CAChe server Select Start to begin the experiment The Experiment Status dialog box is displayed informing you of the following a the name of the chemical sample file a the time and date when the experiment was submitted a when the experiment began executing a the server on which the experiment is running a the property being calculated a the experiment s progress as the calculations are performed CAChe for Windows User Guide Running an experiment a the current computational application executing and the step it is performing Experiment Status phenol csf St x Submitted Wed Oct 09 1996 16 24 15 Stop Hemy Extract Help raii Soin Started Wed Oct 09 1996 16 24 22 Input List ChemicalS ample phenol cst State Done Server cache localhost Optimize geometry Calculation Done molecular mechanics calculation will be carried out for phenol csf The molecule structure file contains 13 atoms 13 bonds and 82 H connectors IMM2 force field Energy terms for the following interactions are included bond stretch bond angle dihedral angle The scrolling text window at the bottom of the Experiment Status window displays textual output received from the computational applications and information on the progress o
428. r options Examples of buttons are shown below BE NS To select a button 1 Position the cursor over the button you want to select 2 Press the left mouse button An action is performed or another dialog box is displayed 3 26 BioMedCAChe User Guide Using CAChe Tabs Tabs display a list of options radio buttons or check boxes specific to the object on the tab A dialog box can contain two or more tabs Select Similar Settings ix Atoms Bonds Bond tab r Select Similar Atoms By Atom tab IV Hybridization T Charge T Number of Bonded Atoms I Number and Types of Bonds Cancel Help NS To select a tab 1 Move the cursor over the tab you want to select 2 Press the left mouse button The selected tab is displayed Drop down lists Drop down lists display a number of options When you choose one the option you choose is displayed in the relevant text box To choose an option from a drop down list Position the cursor over the drop down list option you require 2 Press the left mouse button The drop down list disappears and the option you chose is displayed in the relevant text box BioMedCAChe User Guide 3 27 Chapter 3 CAChe Basics Scrolling and non scrolling lists 3 28 Lists can be scrolling or non scrolling depending on the number of items being displayed Lists are used to display items that you e select by clicking on the item e open by double clickin
429. radio button next to the coloring option you want to apply to each selected bond so that the relevant radio button is enabled 5 To assign a specific color to selected bonds select the arrow button in the Specific Color box and choose a color from the drop down list 6 Select OK to close the Bond Attributes dialog box The selected bonds are displayed in the colors you chose CAChe for Windows User Guide 6 27 Chapter 6 Viewing Chemical Samples Hiding bonds CAChe allows you to e hide and display selected bonds in your sample You can hide the bonds in your chemical sample in exactly the same way that you can hide atoms The bonds are hidden from view in the workspace but are still present in your molecule Hiding bonds does not affect any experiments you run on your chemical sample while bonds are hidden Hiding and displaying selected bonds A To hide selected bonds 1 Select the bonds that you want to hide by clicking on them with a selection tool Then do one of the following 2 Choose View Hide Selected The selected bonds are not visible in the workspace Alternatively 1 Select the bonds that you want to hide by clicking on them with a selection tool 2 Choose View Bond Attributes to display the Bond Attributes dialog box 3 Select the Display Bonds check box so that it is disabled The Display Bonds check box is displayed no matter which tab is currently selected in the Bond Attributes dial
430. radius size relative to 1A To change atom shape 1 CAChe for Windows User Guide Select the atoms that you want to change shape by clicking on the atoms with a selection tool Choose View Atom Attributes to display the Atom Attributes dialog box Atom Attributes x Type Color Shape Label C Coordination Polyhedra C Thermal Ellipsoid C None Shape Options Scale Sph ch that Shaded Spheres Serie R IES ee Van der Waals Radius of 1A C Wireframe Spheres SN GET AGES MSEINS C Dotted Spheres is displayedas 0 2 A M Display Atoms Cancel Make Default Select the Shape tab Choose one of the following options as the representation for the selected atoms o Spheres radio button proceed to step 5 o Coordination Polyhedra radio button proceed to step 8 o Thermal Ellipsoid radio button proceed to step 9 o None radio button to hide the selected atoms Proceed to step 10 From the following list in the Shape Options panel select the shape option you want to apply to each selected atom o Shaded Spheres radio button o Wireframe Spheres radio button o Dotted Spheres radio button 6 13 Chapter 6 Viewing Chemical Samples Changing atom color 6 10 Select the arrow button in the Scale Spheres such that box and choose a scaling option from the drop down list Enter the factor by which you want to scale the radius in the is displayed as text box Proceed to s
431. ram Files Oxford Molecular CAChe User E xpEnvironment packages Group No group directory has been specified New Package Name NewPackage Package Author Package author Cancel Select the Group radio button to specify that the new package should be available to group users Enter a name for the package in the New Package Name text box Enter the name of the author in the Package Author text box Select OK to create the package and to close the dialog box CAChe for Windows User Guide Creating a group procedure package 8 To copy experiments into the Group package a Select the Experiment tab of the Organizer dialog box a Select the new group package from the right hand Experiments Available In drop down list The new package is displayed in the To Group box a From the In User box select the components that you wish to copy to the new group package a Select the Copy button to copy the selected components 9 To copy procedures into the Group package a Select the Procedures tab of the Organizer dialog box a Select the new group package from the right hand Procedures Available In drop down list The new package is displayed in the To Group box a From the In User box select the components that you wish to copy to the new group package a Select the Copy button to copy the selected components 10 To copy parameter data into the Group package a Select the Parameter Data tab of the Organize
432. random motion at 300K uses MM2 parameters AM1 transition state requires reactant and product as input PM3 transition state requires reactant and product as input AM1 transition state in water requires reactant and product as input PM3 transition state in water requires reactant and product as input AM 1 intrinsic reaction coordinate AM1 intrinsic reaction coordinate reverse direction PM3 intrinsic reaction coordinate PM3 intrinsic reaction coordinate reverse direction AM1 dynamic reaction coordinate AM1 dynamic reaction coordinate reverse direction PM3 dynamic reaction coordinate Computational Applications Mechanics Dynamics MOPAC MOPAC MOPAC MOPAC MOPAC MOPAC MOPAC MOPAC MOPAC MOPAC MOPAC CAChe for Windows User Guide Setting up a workspace experiment Procedure Procedure Computational Number Name Applications 52 PM3 dynamic reaction MOPAC coordinate reverse direction 55 MM PM3 geometry with Mechanics INDO 1 wavefunction MOPAC ZINDO Tabulator 57 AM1 geometry with AM1 MOPAC wavefunction Tabulator 58 PM3 geometry with PM3 MOPAC wavefunction Tabulator 59 Current geometry with ZINDO INDO 1 wavefunction Tabulator NOTE Dynamics MOPAC and ZINDO are not available with Personal CAChe MOPAC ZINDO and Extend Huckel are not available with BioCAChe Matching properties to procedures The following table lists the five classes of pro
433. re For example if you originally used AM1 parameters including the effect of water in your transition state experiment use the same procedure when refining and verifying your transition state structure CAChe for Windows User Guide 17 3 Chapter 17 Investigating Reactions Investigating reaction path structures CAChe calculates structures in a reaction that a chemical sample will pass through as it proceeds from a transition state geometry to either the product or reactant side of the reaction pathway The reaction pathway is the minimum energy path from reactant to transition state structure to product The following types of experiment are available e find reaction paths experiment e map reaction experiment In a find reaction paths experiment CAChe varies two internal coordinates of your chemical sample to form the principal deformations that occur in the course of a reaction A series of reaction path structures are then calculated between the transition state structure to either the product or the reactant You can specify the direction for the reaction path calculation by choosing a vibrational mode for the initial motion of 1 or 1 The direction is purely arbitrary except for the fact that the 1 and 1 modes are in opposite directions When generating reaction path conformations you can e annihilate the kinetic energy of the molecule at every step using an IRC Intrinsic Reaction Coordinate calculation P
434. re information on the Beautify menu To check an atom s valence using the Beautify menu 1 Select the atom or group of atoms whose valence you want to change by clicking on the atoms with a selection tool The atom or group of atoms are highlighted to show that they are selected 2 Choose Beautify Check Valence CAChe checks the atomic valence of the selected atom or group of atoms to match bond type and atomic charge If the valence is correct CAChe displays a dialog with the message Valence OK Otherwise CAChe highlights the atoms which do not satisfy the valence rules Choose Beautify Valence to correct the valence of the selected atoms Changing an atom s radius for a particular atomic charge You can specify atomic radius for a particular atomic charge for any element in the periodic table To specify atomic radius for a particular atomic charge 1 Choose Options Periodic Table Settings to display the 5 26 CAChe for Windows User Guide Changing atom and bond properties Periodic Table Settings dialog box Periodic Table Settings xi Charge Color Beautify Charge VDW Radius H Hydrogen N Nitrogen Add 0 Oxygen Change F Fluorine CI Chlorine Fe Iron Periodic Table Cancel Factory Settings for All 2 Do one of the following o Choose the element for which you want to specify a radius associated with atomic charge from the element list by clicking
435. re the insertion is to take place The insertion position is shown with an I beam cursor between residues If the workspace is open on this structure the workspace display remains unchanged Do one of the following o Type the 1 letter code for new residue o Choose Edit Insert to insert the residue shown in the Residue Type box in the style bar The new residue is inserted at the insertion position and the I beam moves to the right BioMedCAChe User Guide Changing biomolecules NOTE When you insert a residue the Psi and Phi angles used are the same as specified in the style bar In addition the next residue in the sequence is moved to make room for the insertion only if the peptide bond is shorter than 2 A Deleting residues NS To delete residues Do one of the following 1 Use the Select tool to select the residues you want to delete The selected residues are highlighted If the workspace is open on this structure the atoms belonging to the selected residues are highlighted in the workspace 2 Type the Delete key The selected residues are deleted and a single asterisk appears in place of the deleted residues The chain is broken unless the deleted residues were at the end of a chain Or 1 Use the Residue tool to place the I beam to the right of the residue you want to delete 2 Type the backspace key The residue to the left of the I beam is deleted the I beam is moved to the left and a single a
436. re type and then enter the sequence After you have entered the sequence set the turns create any disulfide linkages and add terminal atoms Toentera peptide from its sequence 1 Open anew chemical sample file 2 Choose Analyze Sequence to display the Sequence View window Refer to Working in the Sequence View window p 9 18 for information on using the Sequence View 3 Choose Window Tile to show both the Sequence View window and the workspace simultaneously 4 Choose the insert Residue tool From the style bar set the secondary style to beta anti parallel ALA Beta anti parallel Phil 39 Pai 35 CAChe for Windows User Guide 19 3 Chapter 19 Investigating Biomolecules 19 4 TIP TIP Oxytocin is a small 9 residue cyclic peptide with the sequence Cys Tyr Ile Gln Asn Cys Pro Leu Gly NH C Y I Q N C P L G NH2 with a disulfide bond between the cystine residues Oxytocin is a hormone secreted by the posterior pituitary that stimulates uterine contractions Note that it has an unusual amino group on the C terminal glycine 6 Do one of the following a Type the 1 letter code for each residue a From the style bar choose the first residue Then choose Edit Insert Continue typing or inserting until the sequence is entered ALA x Beta anti parallel Phi 139 F iy PDB Number i 8 9 The residues appear connected in the workspace as the peptide is built You can choo
437. rease the current dihedral angle value to the value that you require 4 Select Apply to view the results of the new dihedral angle value in the workspace The first atom that you selected moves to increase or decrease the dihedral angle to the value that you specified in the Angle text box 5 Select OK to accept the new atom distance value and close the Set Dihedral Angle dialog box Specifying improper torsion angles View an improper torsion angle by selecting four atoms and then measuring the angle between the bond connecting the first and second atoms and the projection of that same bond on to the plane formed by the first third and fourth atoms The following two examples show improper torsion angles with the atoms labeled in the order of selection in each example To measure and adjust improper torsion 1 Select the four atoms that form the improper torsion angle by clicking on the first atom with the Select tool then holding down the Shift key and clicking on the second third and fourth atom CAChe for Windows User Guide 8 17 Chapter 8 Investigating Molecular Geometry 8 18 If you are adjusting the improper torsion angle ensure that the first atom you select is the atom that you want to move Choose Adjust Improper Torsion to display the Set Improper Torsion dialog box Set Improper Torsion 27 x Angle 145 206 degree OK Cancel e h Apply Unlock Geometry C Lock Geome
438. rge or calculated bond order experiment on your chemical sample file 2 Choose View Partial Chg and Calc Bond Order CAChe colors atoms by partial charge polarity where positively charged atoms are red and negatively charged atoms are yellow Atoms are also labeled with partial charge and scaled to reflect partial charge Bonds are colored by calculated bond order according to the CAChe color tables A gt Refer to CAChe color tables p 15 13 for further details about bond colors Displaying bond order with color S To view bond order with colored bonds 1 Run an atomic partial charge or calculated bond order experiment on your chemical sample file 2 Choose View Bond Attributes to display the Bond Attributes dialog box CAChe for Windows User Guide 16 11 Chapter 16 Investigating Atom and Bond Properties Bond Attributes 27 x Type Color Shape Color bonds by C Atom Element Colors C Bond Type Calculated Bond Strain C Calculated Bond Order Specific Color 5 BEE J V Display Bonds Cancel Make Defaut Select the Color tab to display a list of color options for bonds 4 Select the Calculated Bond Order radio button so that it is enabled 5 Select OK to close the Bond Attributes dialog box Bonds are colored to reflect bond order according to the CAChe color tables t Refer to CAChe color tables p 15 13 for further details about bo
439. rive in which you want to save the file from the drop down list 4 Do one of the following c a To create a new folder in which to save the file select the dialog box button shown to the left a To move up a level of folders to locate the folder in which you want to save the file select the dialog box button shown to the left a To save the file in a subfolder click and drag the scroll bar in the scrolling list to locate the folder in which you want to save the file and double click on the folder to open it 5 Do one of the following a Clickin the File name text box and type the file name that you want to use to save the file a Click and drag the scroll bar in the scrolling list to display a file that you want to replace and click on it to select it That file name is now displayed in the File name text box 4 18 CAChe for Windows User Guide Saving files 6 Select the arrow button in the Save as type box and choose the file type you require from the drop down list 7 Select Save to close the Save As dialog box and to save the file Saving an existing file To save an existing file without changing the name type or location 1 Do one of the following a Choose File Save m a Press Ctrl S a Select the toolbar button shown to the left The file is saved To save an existing file with a new file name as a different file type or in a new location 1 Choose File Save As to display th
440. rking with chemical sample files 4 2 Drawing a molecule in the workspace 4 4 Completing your molecule 4 9 Perfecting your molecule 4 10 Saving files 4 16 Printing files 4 21 Modifying Chemical Samples 5 1 Modifying atoms and bonds 5 2 Selecting workspace objects 5 3 Changing atom and bond properties 5 17 Viewing Chemical Samples 6 1 CAChe display options 6 2 Using CAChe model types 6 4 Changing the appearance of atoms 6 8 BioMedCAChe User Guide Hiding atoms 6 18 Changing the appearance of bonds 6 21 Hiding bonds 6 28 Viewing selection only 6 30 Coloring by molecules 6 31 Viewing multiple windows 6 32 Viewing chemical sample data 6 33 Changing view settings 6 37 Saving settings 6 51 Building crystal structures 6 54 Manipulating Molecules 7 1 Using the manipulation tools 7 2 Manipulating portions of your molecule 7 9 Using faster motion mode 7 12 Duplicating molecules 7 13 Deleting portions of your molecule 7 18 Fusing ring structures 7 21 Grouping atoms 7 24 Investigating Molecular Geometry 8 1 Working with chiral centers 8 2 Mirroring a molecule 8 5 Superimposing molecules 8 6 Specifying angles and distances 8 12 Working with geometry labels 8 19 Locking geometry labels 8 28 Locking atoms 8 31 Disabling locked geometry 8 34 Working with search labels 8 36 Manipulating Biomolecules 9 1 Viewing biomolecules 9 2 Working in the Sequence View window 9 10 Changing biomolecules 9 23 Comparing biomolecules 9 31 Performing Wo
441. rkspace Experiments 10 1 Introduction to workspace experiments 10 2 Setting up a workspace experiment 10 4 Running an experiment 10 17 Viewing active experiments 10 26 Viewing server information 10 28 Size and element limitations 10 30 Troubleshooting experiments 10 31 BioMedCAChe User Guide Viewing experimental results 10 35 Viewing log files and output files 10 39 Using the Procedure Editor 11 1 The Procedure Editor 11 2 Starting the Procedure Editor 11 3 The Procedure Editor interface 11 4 Managing the experiment environment 11 8 Showing properties of a component 11 13 Modifying a procedure 11 17 Editing the settings of a compute engine 11 23 Creating experiments 11 25 Expert modification 11 30 Creating a group procedure package 11 31 Exporting environment components 11 37 Quitting the Procedure Editor 11 38 Using ProjectLeader 12 1 Introduction to ProjectLeader 12 2 Starting ProjectLeader 12 4 Using the ProjectLeader workbook 12 6 Opening a ProjectLeader project 12 10 Adding chemical samples 12 11 Viewing sample properties 12 15 Running a ProjectLeader experiment 12 18 Using scatter plots 12 25 Changing workbook display options 12 31 Viewing cell information 12 37 Printing files 12 38 Exporting a ProjectLeader worksheet 12 41 Saving a ProjectLeader project 12 42 Quitting ProjectLeader 12 43 Optimization and Energy Calculations 13 1 Optimizing chemical samples 13 2 Selective optimization 13 5 Viewing optimized structures 13
442. rkspace objects For example to move your chemical sample to the bottom of the workspace click and drag downwards Workspace objects are moved in the direction that you drag the Translate tool Recentering workspace objects When you use the Translate tool workspace objects move away from the center of the workspace This means that the next time you rotate your chemical sample using the Rotate tool your chemical sample rotates in an arc around the x y or z axes instead of rotating around its center It is possible to translate a molecule so far from the center of the workspace that when you rotate it the molecule s motion takes it off the edge of the screen You can return your molecule to the center of the workspace or resize it to fit the workspace window to recover workspace objects that have disappeared from view Centering workspace objects You can center selected portions of your chemical sample in the workspace window The size of the selected objects is not changed BioMedCAChe User Guide Using the manipulation tools To center objects in the workspace 1 Select the workspace object that you want to center by clicking on it with a selection tool The object is highlighted to show that it is selected 2 Choose View Center in Window The selected workspace object is moved to the center of the workspace Scaling and centering workspace objects You can center selected portions of your chemical
443. rnatively select Original Settings to return to the default machine settings for the compute engine NOTE You can remove user defined settings from a compute engine step at any time by selecting the Original Settings button To edit the settings of an existing compute engine step 1 From the Procedure window select the compute engine step that you wish to modify For details about displaying the Procedure window refer to Modifying a procedure p 11 17 2 Select the View button to display the Settings dialog box Modify the settings for the compute engine as required Refer to the on line Help system for CAChe for details of the settings available for each compute engine 4 Select OK to save the changes to the compute engine Alternatively select Original Settings to return to the default machine settings for the compute engine lt t gt Refer to the CAChe on line Help system for details about the settings available for each compute engine 11 24 CAChe for Windows User Guide Creating experiments Creating experiments There are three ways to create an experiment using the Procedure Editor e create a new experiment from scratch e clone an existing experiment and edit it e import an existing CAChe experiment Creating a new experiment You can create a new experiment in the Procedure Editor and save it in the experiment environment Use the Properties dialog box to create a new experiment T
444. rocedures numbered 1 19 has already been run on it choose procedure 20 Procedure 20 takes advantage of geometry and wavefunction data generated already during the first experiment Procedure Procedure Computational Number Name Applications 0 MM geometry Mechanics 1 MM geometry with AM1 Mechanics wavefunction MOPAC Tabulator 2 MM geometry with PM3 Mechanics wavefunction MOPAC Tabulator 3 MM geometry with EHT Mechanics wavefunction ExtH ckel Tabulator 4 MM geometry with AM1 Mechanics wavefunction in water MOPAC Tabulator 5 MM geometry with PM3 Mechanics wavefunction in water MOPAC Tabulator 6 MM geometry with INDO 1 Mechanics wavefunction ZINDO Tabulator 10 11 Chapter 10 Performing Workspace Experiments Procedure Number 7 10 11 12 13 14 15 16 17 10 12 Procedure Name MM AM1 geometry with AM 1 wavefunction MM PM3 geometry with PM3 wavefunction MM INDO 1 geometry with INDO 1 wavefunction MM AM1 geometry with AM 1 wavefunction in water MM PM3 geometry with PM3 wavefunction in water AM1 geometry with AM1 wavefunction PM3 geometry with PM3 wavefunction AM1 geometry with AM1 wavefunction in water PM3 geometry with PM3 wavefunction in water AM1 transition state geometry with AM1 wavefunction PM3 transition state geometry with PM3 wavefunction Computational Applications Mechanics MOPAC Tabulator Mechanics MOPAC Tabulator M
445. roperty of radio button 3 Select an option from the Property of drop down list then select Next The available properties are displayed in a scrolling list A brief description of the selected property is displayed underneath the list Selecting a property displays its description 4 Select a property to investigate from the Kind of property 12 21 Chapter 12 Using ProjectLeader 12 22 TIP scrolling list then select Next 5 Select a procedure from the Kind of procedure scrolling list 6 If required choose Edit to edit the procedure The Procedure Editor is opened Refer to Chapter 11 Using the Procedure Editor for information on the Procedure Editor 7 Select OK If you have more than one Chemical Sample column in a worksheet you will be prompted to select a column 8 From the Column Select dialog box do one of the following a select a column from the list and choose OK to perform the calculation on that column a select Automatic to perform the calculation on the Chemical Sample column to the nearest left of the new column The property is displayed in the column title cell at the top of the relevant column When you evaluate any cell in this column the chosen property is calculated To undo a command choose Edit Undo Toadda sample component to a worksheet 1 Double click on an empty column title cell to display the Enter Property dialog box 2 Select the Sample Compone
446. rties Different properties are available for each type of environment component Each different type of property is displayed on a different tab of the Property dialog box Experiment environment properties You cannot edit the attributes of the General tab for the experiment environment component You can edit the Packages tab to specify which packages to load when refreshing the experiment environment lt t gt Refer to Refreshing the experiment environment p 11 35 for full details of using the Packages tab to define which packages are loaded into the experiment environment Property component properties For Workspace property components the Property dialog box features a General tab For ProjectLeader property components the Property dialog box also features a Property tab Properties 21x General Property r Name r Retum Value Special Value Type Object Class and Property Object Class atom hd Object Property pehrg F Retum Value Units Value Units charge_au Cancel Original Settings 11 14 CAChe for Windows User Guide Showing properties of a component ProjectLeader experiment component properties The ProjectLeader experiment component Properties dialog box contains an Experiment tab that allows you to select from the four classes of ProjectLeader experiment Properties i Lx General Experiment Name q Experiment name HOMO dens at AM1 H20
447. rties window is a workbook view of your chemical sample As you work with the chemical sample using either the 3D Structure workspace or the Chemical Properties workbook you add or change chemical sample information The changes are immediately updated in the 3D Structure windows and Chemical Properties workbook sample properties window Save the workspace as a chemical sample file csf to preserve all of the information you have added If you save chemical samples in other formats information such as rendering style and computed atom properties will be lost Selecting chemical sample data 6 34 You can select objects in the chemical sample file such as atoms bonds labels and groups directly from a spreadsheet in the workbook Selection from a worksheet is often the easiest way to choose specific atoms bonds groups labels or other objects To select all chemical sample objects 1 In the Chemical Properties Spreadsheet choose Edit Select All All objects in the chemical sample on all worksheets are selected and displayed as greyed Objects displayed in any workspaces of the same chemical sample are highlighted To select a chemical sample object 1 Inthe Chemical Properties workbook choose the tab for the kind of object e g Atoms or Bonds 2 Click on the row number The row number is contained in the first column of the spreadsheet The row background is greyed all other objects are deselected and the objec
448. ry to assign bonding and charges in HET groups This file changes with each new update to the PDB You should download the new version of this file from the PDB with each new release of the PDB to ensure that your HET group definitions are up to date If the PDB file contains HETATM records you should use the Sequence View to select the HET residues and you should check them to see that the bond types and atom valencies are as expected for that structure Chapter 9 Manipulating Biomolecules A new workspace opens and the structure displays CAChe E Molecules 1A9T pdb BEES 1 File Edt View Adjust Beautify Analyze Options Experiment Window Help la x Oe ta slale alze all e pele le xis I z E A a 7 A a ERNIS etir AAAA q i hg OS aie For Help press F1 Net chig 5 2295 atoms C1410 N393 0475 P1 S16 NOTE Itmay take afew seconds to load the PDB file depending on its size or the number of atoms it contains At this point you should save the file as chemical sample with the appropriate name All of the information in the PDB file has been stored in the CAChe chemical sample format For example residues have been stored as Groups and you can use the Select Group tool to select residues To view this information choose Analyze Chemical Properties Spreadsheet The chemical sample properties window appears BioMedCAChe User Guide Viewing biomolecules E
449. s p 8 29 for information on locked geometry labels and broken geometry label locks Refer to Disabling locked geometry p 8 35 for information on disabling locks Changing geometry label color Color geometry labels in one of two ways by label type by the standard text color defined in the color palette To color geometry labels by label type 1 CAChe for Windows User Guide Select the geometry label whose color you want to change by clicking on the label with the Select tool Choose View Geometry Label Attributes to display the Geometry Label Attributes dialog box Geometry Label Attributes 20x Label Color Color Geometry Labels with Standard Text Color V Display Geometry Label Cancel Make Default Select the Color tab Select the Geometry Label Type Color radio button in the Color Geometry Labels with section to enable it Select OK to close the Geometry Label Attributes dialog box The geometry label you selected is displayed in the color assigned to its geometry label type 8 25 Chapter 8 Investigating Molecular Geometry To color geometry labels by standard text color 1 Select the geometry label whose color you want to change by clicking on the numeral portion of the label with the Select tool 2 Choose View Geometry Label Attributes to display the Geometry Label Attributes dialog box 3 Select the Color tab Select the Standard
450. s appear on dialog boxes such as the Open and Save As dialog boxes The two directory buttons perform the following functions the directory level button shown to the left takes you up one directory level to display the contents of the next folder up in your directory structure ee e the new folder button shown to the left which creates a new folder within the folder whose contents the dialog box is currently displaying To select a directory button 1 Position the cursor over the button you want to select 2 Press the left mouse button The scrolling list in the dialog box either displays the contents of the next directory up or a new folder is created in the current directory BioMedCAChe User Guide 3 25 Chapter 3 CAChe Basics Details buttons Details buttons appear on some dialog boxes such as the Open and Save As dialog boxes Toggle between the two details buttons shown to the left to view lial e file names only displayed in the dialog box scrolling list e file details such as type and size in the dialog box scrolling list To select a details button 1 Position the cursor over the button you want to select 2 Press the left mouse button Files in the scrolling list are either displayed with file name and icon only or with file name icon file type and size and the date that the file was last modified Buttons Buttons perform an action or display another dialog box containing furthe
451. s for managing worksheets 12 10 BioMedCAChe User Guide Opening a ProjectLeader project Opening a ProjectLeader project ProjectLeader projects can be saved as project files so that you can continue working on a project at a later time ProjectLeader project files are saved with the extension plp To open an existing ProjectLeader project 1 Choose File Open to display a dialog box 2 Move to the directory that contains the project that you want to open The files are filtered so that only files that have the extension plp are displayed Select the project that you want to open 4 Select Open The project is opened in a ProjectLeader workbook BioMedCAChe User Guide 12 11 Chapter 12 Using ProjectLeader Adding chemical samples 12 12 Chemical samples can be added to the ProjectLeader worksheet from e CAChe Chemical Sample files csf files e MDL SD files sd sdf_ files e MDL MOL files mol files Multiple files of each format can be added simultaneously Chemical samples can be added straight to ProjectLeader from file Alternatively you can open the Workspace from the worksheet draw a new Chemical Sample file save it then add the new file to the worksheet NS To add existing files 1 Double click on a cell in the Chemical Sample column to display the Open dialog box From the Files of type drop down list choose the format of the files that you want to import S
452. s normal optimizing would cause structural adjustments throughout the whole chemical sample The following example shows a molecular structure where the core atoms of a molecule could be locked while allowing the pendant groups to optimize CAChe for Windows User Guide Selective optimization Follow the steps below to perform a selective optimization To optimize selected portions only of a molecule 1 CAChe for Windows User Guide Select all the atoms you want to remain unchanged by clicking on the first one with the Select tool holding down the Shift key and clicking on the rest of the atoms you do not want to optimize Choose Adjust Lock An L is displayed in the workspace to indicate that the atoms are locked Use the Atom Bond tool to draw the atoms and bonds that comprise the substituted portion of the molecule by clicking and dragging in the workspace This is the portion that you want to optimize Choose File Save to save the chemical sample file Run the optimization experiment of your choice The locked atoms remain fixed at their workspace coordinates while the rest of the chemical sample is optimized 13 7 Chapter 13 Optimization and Energy Calculations Investigating reactive sites at the surface of enzymes Selectively locking geometry attributes can also be helpful when you are investigating reactive sites at the surface of enzymes The only difference between this example and t
453. s you want to print by clicking on the window 2 Do one of the following a Choose File Print a Press Ctrl P a Select the toolbar button shown to the left The Print dialog box is displayed CAChe for Windows User Guide 4 25 Chapter 4 Creating Chemical Samples 3 To use a different printer from the one displayed in the Printer panel select the arrow button in the Name box and choose a printer from the drop down list The printer s status type and location are displayed in the Printer panel of the dialog box 4 To change the properties of the printer select Properties to display a dialog box containing specific options for your printer type HP LaserJet 474M Plus PS Properties 4 26 CAChe for Windows User Guide Printing files 5 Select the Paper Graphics Device Options or Postscript tab to display and select the options relevant to your printer NOTE The bitmap created depends on the resolution set for your printer Therefore high printer resolution will create a smoother print but will take longer to print Lower printer resolution will be faster to print and can be useful for very large shaded spheres e g large atoms 6 Select OK to close the dialog box of printer properties and to return to the Print dialog box 7 Inthe Copies panel of the Print dialog box do one of the following a Select the up arrow button in the Number of Copies text box to increase the number of cop
454. sample in the workspace and scale the selected portion so that it fits into the currently sized workspace To scale and center objects in the workspace 1 Select the workspace object that you want to center and scale relative to the size of the workspace window by clicking on the object with a selection tool The object is highlighted to show that it is selected 2 Do one of the following gt Choose View Fit in Window o Select the toolbar button shown to the left o Press Ctrl F The selected workspace object is rescaled and moved to the center of the workspace Other ways to move workspace objects Apart from using the Translate tool you can also move workspace objects by e selecting one or more objects with a selection tool and dragging across the workspace The selected objects move to the location to which you dragged the selection tool BioMedCAChe User Guide 7 7 Chapter 7 Manipulating Molecules using geometry labels to accurately adjust the geometrical relationship between atoms in the workspace A t gt Refer to Chapter 8 Investigating Molecular Geometry for more information on geometry labels and how to adjust them Using the Scale tool Scaling lets you zoom into and out from workspace objects along the eg z axis of the workspace NS To select the Scale tool 1 Select the Scale tool by clicking on it in the tool palette Q The mouse cursor changes to the Scale tool shown t
455. se Edit Select All and View Fit in Window from the workspace to show the peptide as you build it Finally you add the terminal groups so that the peptide ends with NH and CO as expected in water solution S To add terminal atoms 1 In the workspace choose the Select tool 2 Select the N terminal atom Change the charge on the style bar to 1 The charge on N changes to 1 4 Choose Beautify Valence The group is now NH3 Select the C terminal atom 6 Choose Beautify Valence The group should now be CH O CAChe for Windows User Guide Investigating peptide conformations NOTE If you are building oxytocin which has an unusual amino group on its C terminal glycine change the H to N and Beautify Valence Then skip to To create a turn Otherwise for standard C terminal CO groups follow the following steps 7 Select the newly created H atom 8 Using the style bar change the atom type to O and the charge to 1 The H atom is replaced by O 9 Select the CO7 group 10 Choose Beautify Hybridization The hybridization changes to sp 11 With only the CO group selected choose Beautify Geometry Only the CO group changes 12 Choose File Save and save the peptide as a chemical sample The peptide now terminates in NH3 and CO terminal groups the structure expected in aqeuous solution As you build a peptide you may need to enter turns for example if the peptide is
456. select similar atoms or bonds NS To select similar atoms 1 Position the Select Similar tool over an atom of the type that you want to select 2 Press the left mouse button to select the atom and all other atoms of the same type All similar atoms are highlighted in the workspace to show that they are selected NS To select similar bonds 1 Position the Select Similar tool over a bond of the type that you want to select 2 Press the left mouse button to select the bond and all other bonds of the same type All similar bonds are highlighted in the workspace to show that they are selected 5 10 CAChe for Windows User Guide Selecting workspace objects Using the Select Similar tools to deselect similar atoms or bonds S To deselect similar atoms 1 Position the Select Similar tool over a selected atom of the type that you want to deselect 2 Hold down either the Shift or Ctrl key and press the left mouse button to deselect the atom and all other atoms of the same type All similar atoms are grayed out in the workspace to show that they are deselected NSS To deselect similar bonds 1 Position the Select Similar tool over a selected bond of the type that you want to deselect 2 Hold down either the Shift or Ctrl key and press the left mouse button to select the bond and all other bonds of the same type All similar bonds are highlighted in the workspace to show that they are selected Defining Similarity
457. ser Guide Comparing biomolecules The Match Sequence Selection dialog appears Match Sequence Selection 21x m Select Master Sequence and Sequence for New Selection Master Sequence New Selection 2 Chose one sequence from each list The Master Sequence contains the selection you wish to match in the New Selection The OK button highlights 3 Select OK The dialog closes and residues in the New Selection sequence adjacent to selected residues in the Master Sequence highlight and all other residues dim Select conserved The active sites in homologous proteins are often conserved When you have many aligned homologous proteins you may be able to identify the active site residues in them protein by selecting the conserved residues NS To select conserved residues 1 From the Sequence View choose Edit Select Conserved BioMedCAChe User Guide 9 41 Chapter 9 Manipulating Biomolecules The Select Conserved Residues dialog appears Select Conserved Residues 21x r Select Master Sequences and Sequence for New Selection Master Sequences New Selection ChemicalS ample1 ChemicalS ample1 2 Chose one or more sequences from each list Choose the sequences whose residues are to be matched from the Master Sequence and choose the sequences that will have the conserved residues highlighted from the New Selection list You may choose the same sequences in each list The OK button high
458. ser Guide Investigating electron density surfaces Generating electron density colored by electrostatic potential You can generate an electron density surface colored by electrostatic potential to view charge distribution in a molecule The three dimensional electron density isosurface that is produced gives a more accurate representation of the true shape of your chemical sample An electron density isosurface for an electron probability density of 0 01 e A3 is generated This surface is colored to reflect the electrostatic potential at every point on the surface Surface color changes to reflect the magnitude and polarity of the electrostatic potential The following example shows a line drawing of a furan molecule and an electron density surface for the same molecule colored to show electrostatic potential which indicates furan s charge distribution legative electrostatic IY 7 potential Positive electrostatic potentia The colors displayed depend on the current colors assigned to each of the color indexes lt t gt Refer to CAChe color tables p 15 13 for details about assigned colors CAChe for Windows User Guide 15 3 Chapter 15 Investigating Electron Distribution Generating an electron density surface colored by susceptibility NOTE 15 4 You can generate an electron density surface colored by nucleophilic susceptibility e electrophilic susceptibility e radical susceptibility
459. settings dialog box 6 48 Van der Waals 20 2 radius 5 27 Variables plotting 14 16 Verify transition experiment 17 1 Verify transition state 2 17 10 9 Vibrational frequencies 20 11 spectra 18 2 View active experiments 10 27 bond order 16 11 change settings 6 37 change valence settings 6 48 chemical sample by partial charge and calculated bond order 6 6 chemical samples 6 1 chemical samples as a line only drawings 6 4 chemical samples as ball and cylinder models 6 5 chemical samples as line drawings 6 4 chemical samples as space filling models 6 5 chiral centers 8 2 color palette 6 40 color threshold values 15 12 Cory Pauling and Koltun model 6 3 electrons settings 6 48 experimental results 18 1 hydrogens settings 6 48 log and output files 10 40 multiple windows 6 32 PDB atom names 9 7 sample properties 12 17 server information 10 29 surfaces 15 9 View atom and bond properties 3 42 View settings dialog box 6 45 Viewing energy maps 14 2 BioMedCAChe User Guide 15 i ic o 3 b 5 W Water solvent effects 14 9 Wavefunction 20 22 Weak bonds 5 33 Window menu 3 16 Windows viewing multiple 6 32 Wireframe 15 20 Wireframe spheres 6 12 Wizard geometry label 8 41 Workspace 3 8 changing perspective and distance 6 44 style bar 3 9 title bar 3 9 Workspace selection tools 3 29 5 3 5 14 Z Zooming in and out on objects 7 8 16 BioMedCAChe User Guide
460. sible Transitions window indicated by a legend which is automatically displayed The following shows an example of a UV visible Transitions window U visible Transitions Molar Absorptivity 1 mol cm 200 300 400 600 600 700 800 900 1000 Wavelength nm H NS To view molecular orbital transitions 1 Using the Select tool click a transition in the graph function which is indicated by a triangle The selected transition is highlighted in red to show that it is selected Molecular orbital surfaces for the transition are displayed superimposed on the relevant atoms in the workspace HOMO and LUMO energy values are also displayed CAChe for Windows User Guide 18 7 Chapter 18 Investigating Spectra 2 Hold down Shift and click repeatedly on the graph function to select several transitions The selected transitions are highlighted in red and molecular orbital surfaces belonging to all the selected transitions are displayed for each atom in the workspace The following example shows a display of molecular orbital surfaces from several selected transitions To edit transition properties 1 Fora single transition double click the transition For more than one transition select the transitions for which you want to edit properties then choose View Transition Attributes The View Transition Attributes dialog box is displayed 2 Click in the Wavelength Width o
461. sidues in the middle of a sequence will shift the right most portion of the chain changing the 3D coordinates of all atoms in the right subchain e Changing the Phi or Psi value of a residue may change the global 3D structure Mutating residues Replacing residues causes a point mutation NS To mutate residues 1 Use the select tool to select the residues you want to mutate to a particular residue The residues are highlighted If the workspace is open on this structure the atoms belonging to the selected residues are highlighted in the workspace BioMedCAChe User Guide 9 31 Chapter 9 Manipulating Biomolecules NOTE Inserting residues 9 32 2 Choose the new residue from the Residue Type drop down SER z MET z PHE PRO THR TRP TYR VAL 7 The selected residues are replaced with the newly chosen residue When you mutate a residue the backbone atoms of both residues are superimposed and then the original residue is removed The residue in the workspace and the residue in the repository must contain the three crucial backbone atoms given by the PDB names C CA N If the backbone atoms are not present a dialog appears that explains which residue was missing the backbone PDB names To insert a residue 1 Select the name of a protein to activate it for modification The name is highlighted in yellow 2 Inthe Sequence View window use the residue tool to select the position whe
462. sing the Beautify menu A way to check atom hybridizations is to select the atoms and choose Beautify Check Hybridization This menu option employs valence rules to check atomic hybridization to match the existing bond type and atomic charge A lt 4 Refer to Chapter 4 Creating Chemical Samples for more information on the Beautify menu To check an atom s hybridization using the Beautify menu 1 Select the atom or group of atoms whose hybridization you want to change by clicking on the atoms with a selection tool The atom or group of atoms are highlighted to show that they are selected 2 Choose Beautify Check Hybridization CAChe checks the atomic hybridization of the selected atom or group of atoms to match bond type and atomic charge If the hybridization is correct CAChe displays a dialog with the message Hybridization OK Otherwise CAChe highlights the atoms which do not satisfy the hybridization rules Choose Beautify Hybridization to correct the hybridization of the selected atoms CAChe for Windows User Guide 5 25 Chapter 5 Modifying Chemical Samples Checking an atom s valence using the Beautify menu A way to check atom valences is to select the atoms and choose Beautify Check Valence This menu option employs valence rules to check atomic valence to match the existing bond type and atomic charge A lt 4 Refer to Chapter 4 Creating Chemical Samples for mo
463. some care In CAChe Dynamics simulations the molecule is alone in a vacuum Thus it never collides with another molecule and as a result never changes energy or the pattern of motion Once the initial random velocities have been selected the fate of the simulation is established In simple molecules this may be easily noticeable as a somewhat limited range of motions For larger BioMedCAChe User Guide Understanding Dynamics molecules the larger number of degrees of freedom will lead to more complex motions but will still not cover every configuration One application of Dynamics simulations is to search for nearby energy conformations We may know that in real molecules a particular rotational barrier is easily crossed at a given temperature However the probability of catching a molecule in the process of crossing the barrier may not be very high CAChe Dynamics simulations should behave similarly but as in real life will require some repeated simulations Normally you should start with a minimized structure for a simulation Sometimes the random velocities given to the individual atoms partially cancel each other and do not lead to the rotational motion expected This is especially a problem with symmetrical groups like methyl and in small molecules A simple approach to obtaining greater rotational motion is to start the simulation with the group rotated somewhat away from the minimum conformation This does have the e
464. ss relaxation that is possible during optimization Each combination of search labels and steps is computed when you generate an exhaustive map That is if you define two search labels each with ten steps your potential energy map will contain 121 conformations 112 because ten steps result in eleven conformations and each one is tested in combination with all other possibilities You can examine an energy map for up to eight search labels at one time but it is impractical to employ this computation for more than three or four search labels in one molecule file because of the time required to perform the calculations a i i s N i D Generating a sequential search with Mechanics Search labels you define in the workspace also serve as the basis for performing sequential searches with Mechanics When you compute the potential energy of multiple conformations of your molecule using the sequence of conformations experiment the conformations defined by search labels are examined in sequence A new assemblage file called seqsrch map is created and saved in the automatically generated map folder BioMedCAChe User Guide 20 5 Chapter 20 CAChe Computational Applications 20 6 Mechanics begins this computation by performing a rigid energy search to find the best starting structure among those defined by the search label steps and ranges To do so it traverses each search label one step at a
465. stances in your molecule are examined and compared to the classical mechanical ideal geometry Deviations from the ideal accumulate potential energy which is measured and plotted in an energy graph for each conformation CAChe for Windows User Guide Generating energy maps You can add up to eight search labels to generate a rigid energy map using classical mechanical procedures However because of the time required to complete the calculations it is more practical to add a maximum of three or four search labels to one molecule Generating a rigid energy map with quantum mechanics NOTE Quantum mechanical procedures measure the heat of formation of each conformation of a molecule formed by varying the search labels The presence and position of electrons between atoms is measured in every conformation formed by the search labels and heat of formation is calculated based on the Schr dinger equation You are limited to a maximum of two search labels in your molecule If you use one search label the result is a reaction coordinate search If you use two search labels the result is a grid search Energy maps generated using quantum mechanics are useful for mapping bond breaking and bond formation in a molecule You cannot generate a rigid energy map using quantum mechanics with Personal CAChe or BioCAChe Generating an optimized energy map An optimized energy map is similar to a rigid map except that each conformati
466. sterisk appears in the place of the deleted residue The chain is broken unless the deleted residues were at the end of a chain Joining chains Chains are broken when you delete residues NS To join two chains 1 With the Select tool choose the two residues you want to join One residue must be at the start of a chain and the other at the BioMedCAChe User Guide 9 33 Chapter 9 Manipulating Biomolecules end of a chain The residues can be in the same chain The selected residues are highlighted If the workspace is open on this structure the atoms belonging to the selected residues are highlighted in the workspace 2 Choose Edit Connect Chains The selected residues are joined and the original chains are connected into one chain No atoms are moved and since the geometry is unchanged unusually long bonds may be created To clean up the structure after all modifications are made run an experiment that optimizes the geometry To join adjacent chains 1 With the Residue tool place the I beam to the right of the asterisk separating the chains you intend to join 2 Type the Backspace key The asterisk disappears and two chains are joined forming one chain No atoms are moved and since the geometry is unchanged unusually long bonds may be created To clean up the structure after all modifications are made run an experiment that optimizes the geometry Copying and pasting sequences You can copy and paste se
467. straints on unit cell parameters values for the cell parameters will be automatically entered 4 Select Apply to view the crystal structure in the workspace Select OK to accept the changes and to close the Crystal Shape dialog box Defining fractional coordinates You can use the Fractional Coordinates tab of the Crystal Shape dialog box to e enter asymmetric atoms and their fractional coordinates before you build a crystal enter and edit atoms and their fractional coordinates after you build a crystal Crystal Shape Lix Main Fractional Coordinates Multiplier a Atom Symbol x Y Zz 1 C 1 22252 0 64427 0 00010 2 c 0 02628 1 36522 0 00010 Bac 1 19621 0 68973 0 00010 4 C 1 22244 0 70673 0 00010 5 c 0 02618 1 42769 0 00010 6 C 1 19630 0 75218 0 00010 a L 2 17148 1 16862 0 00010 8 H 0 04664 2 44922 0 00010 9 jH 2 12481 1 24936 0 00010 10 H 2 17141 1 23110 0 00010 11 a 0 04655 2 51171 0 00010 12_ H 2 12488 1 31183 0 00010 13 Redefine All Atoms as Asymmetric Cni Apa 6 58 CAChe for Windows User Guide Building crystal structures NS To define the fractional coordinates NOTE Ifyou are entering asymmetric atoms before you build the crystal enter the space group and cell parameters first 1 Choose Edit Crystal Shape to display the Crystal Shape dialog box Select the Fractional Coordinates tab Select the arrow button in th
468. structure that moves to accomplish the superimposition is the one that contains the first atom you select To superimpose two molecules 1 Select the atoms that you want to be superimposed on another structure s atoms by clicking on the atoms with the Select tool 2 Do one of the following o Select the same number of corresponding atoms in the second structure in exactly the same order that you selected the atoms in the first structure CAChe for Windows User Guide Superimposing molecules o Select one atom in the first molecule and then select the corresponding atom in the second molecule then select another atom in the first structure and the corresponding atom in the second structure until you select the required number of atoms 3 Choose Analyze Superimpose The molecule that contains the first atom that you selected moves to overlap the other molecule The selected atoms are highlighted to show that they are still selected An RMS error is displayed which indicates the error in molecular geometry between the two structures 4 Do one of the following to move the molecules apart again o Choose Edit Undo o Press Ctrl Z o Select one molecule by clicking on it with the Select Molecule tool and click and drag to move the selected molecule to one side Superimposing with ordered atom groups You can compare the molecular geometry of two structures by superimposing an ordered group in one structure on
469. t Crystal Shape The Crystal Shape dialog opens Choose the Fractional Coordinates tab in the Crystal Shape dialog Enter O for oxygen and set the fractional coordinates at 0 0 0 so that the dialog looks like this Crystal Shape 2 xi Main Fractional Coordinates Multiplier N z 0 00000 0 00000 0 00000 Redeine All Atoms as Aspmmetic Cancel Apply After typing the last coordinate press the Enter key to complete CAChe for Windows User Guide Investigating peptide conformations the row 5 Choose the Main tab and set the space group to P1 the Lattice Boundaries to 5 0 to 5 0 and the a b and c lengths to 2 8 angstroms Finally choose to build an Infinite lattice The Crystal Shape dialog should look like this Crystal Shape 2 x Main Fractional Coordinates m Space Groups Space Group T Identification mooo Space Group Name P1 Number 1 Descriptor Crystal System Triclinic MA Specific Name PI m Build p Angles C Asymmetric atoms only C Molecule c Lattice Boundaries 5 000 to 5 000 in the a direction A g a so 000 a 28 A 5 000 to 5 000 in the b direction a s0 000 we pe A f5 000 to 5 000 in the c direction y so 000 i S28 A Cancel Apply 6 Choose OK A 28 angstrom cube of 1326 oxygen atoms appears in the workspace 7 Choose Window New Sample Properties Window The sample properties wind
470. t display the Crystal Shape dialog box and select either OK or Apply To display the asymmetric cell 1 Select the asymmetric atom using the Select Tool 2 Choose Edit Crystal Boundaries Draw Asymmetric Cell An outline of the asymmetric cell is displayed To display the unit cell 1 Select the asymmetric atom using the Select Tool 2 Choose Edit Crystal Boundaries Draw Unit Cell An outline of the unit cell is displayed To display the lattice boundaries 1 Select the asymmetric atom using the Select Tool 2 Choose Edit Crystal Boundaries Draw Lattice Boundaries An outline of the crystal lattice is displayed Creating CrystalStructure files You can build crystal structures by opening a CrystalStructure file A CrystalStructure file is an ASCII text file that you create with a word processing application This file enables you to enter fractional coordinates and thermal tensor parameters for atoms derived from theoretical or experimental data CAChe for Windows User Guide 6 63 Chapter 6 Viewing Chemical Samples 6 64 CrystalStructure files have the following format and information Line OMANI DUN PWN RWNr CO nwWN format CrystalStructure spelled exactly as shown Comments must be present Comments must be present Comments must be present a length of a axis in angstroms b length of b axis in angstroms c length of c axis in angstroms alph
471. t molecule The following types of experiment are available search for saddle experiment e refine transition state experiment e verify transition state experiment The search for saddle experiment locates a stationary point between the reactant and product that corresponds to the transition state for the reaction A stationary point is a structure where small geometry changes do not affect overall molecular energy Before generating a transition state structure you must specify a reactant molecule and a product molecule two chemical sample files for input The product molecule must have all the atoms of the reactant molecule and each atom must have the same atom number The only differences between reactant and product that are allowed are positions of atoms and bonds Once you have generated a transition state structure you can refine it using a minimize gradient calculation in the refine transition state experiment You can then calculate the molecule s vibrational transitions to verify the current transition state geometry using the verify transition state experiment A single negative vibration confirms a true transition state CAChe also allows you to include water solvent effects in a transition state experiment Refer to Modeling solvent effects with COSMO p 20 19 for more information on experimental procedures that include solvation effects Transition state experiments are not available with Personal
472. t List box is not the chemical sample file on which you want to perform the experiment select the currently displayed file in the Input List file name and select Set Inputs to display the Open dialog box CAChe for Windows User Guide Running an experiment CAChe for Windows User Guide Open 24x Look in i Cache gt c 3 benzenel 2 Chem3 B isopren2 E isprn2ts 22 benzene2 2 chem4 2 isoprene 3 ispm3 2 BOND 2 Chemical isopm2a 2 jaw 2 btane 3 display 2 isopm2b 23 maptest 2 Chem1 3 gold 2 isopm2c 2 methan1 2 Chem2 2 isoprent E isprent 28 methan2 File name A Files of type E EAS Cancel Select the arrow button in the Look in box and choose Cache from the drop down list to open the Cache folder Select the arrow button in the Files of type box and choose Chemical Sample csf from the drop down list to display all chemical sample files in the Cache folder Do one of the following a Click and drag on the scroll bar at the bottom of the scrolling list to locate the chemical sample file on which you want to experiment and select it by clicking on it a Click in the File name text box and type the name of the chemical sample file on which you want to experiment Select Open to close the Open dialog box The selected chemical sample file is now displayed in the Input List box in the Experiment dialog box Select the arrow button in the Pr
473. t Personal or Bio CAChe Choosing a server If you are using your CAChe product as a standalone program experiments are performed locally on your computer However if you are using CAChe in conjunction with CAChe GroupServer you may have access to multiple Unix servers on which you can run experiments If this is the case you need to choose a server before you run an experiment CAChe for Windows User Guide 10 17 Chapter 10 Performing Workspace Experiments Running an experiment 10 18 This section describes how to run a CAChe experiment from the workspace and how to use the menu options and dialog boxes involved in performing an experiment You do not need to open the chemical sample file that you want to experiment on before running an experiment S To perform an experiment 1 Do one of the following a Choose Experiment New a Select the toolbar button shown to the left The Experiment dialog box is displayed Experiment1 Of x Input List ee phenol cst Get Inputs Server cache localhost Make Default Property of chemical sample x Property atom count be The number of atoms of a given atomic number in the chemical a sample at the time of evaluation x Using all atoms x The number of atoms of all elements present in the chemical a sample xi The Input List box displays the name of the currently active chemical sample file If the file displayed in the Inpu
474. t box and type the energy value for the range of low energy conformations that you want to view To display a selected number only of low energy conformations do the following a Select the Show radio button so that it is enabled a Click in the lowest value minima text box and type the number of conformations with the lowest energy value that you want to view To eliminate minima occurring in shallow energy wells separated from adjacent lower minima by low energy barriers do the following a Select the Coalesce minima which are separated by barriers smaller than radio button so that it is enabled a Click in the adjacent text box and type a value for the energy barrier Energy wells separated by barriers smaller than the specified value result in the higher energy minimum being ignored Select Analyze to apply the specified analysis criteria to the map file windows and to close the Analysis Settings dialog box 14 25 Chapter 14 Investigating Low energy Conformations Animating map files Animating a map file runs through each conformation in the map file while indicating the corresponding location on the energy graph for each location You can visualize the following properties in each type of map file e animating a rigid or optimized map shows how the conformation defined by each step in a search label affects energy animating a sequence file shows a series of optimized structures animating a reaction
475. t calculates isosurfaces for all of your sample s molecular orbitals CAChe for Windows User Guide 15 17 Chapter 15 Investigating Electron Distribution Electrostatic potential The MO surface files created by all three of these experiments depict surfaces with an electron probability amplitude of 0 07 a u The default molecular orbital colors for occupied orbitals are green and blue and the defaults for unoccupied orbitals are red and yellow Color assignment with respect to positive and negative phase is arbitrary so identical calculations can result in surfaces with opposite colors You can switch these colors using the color palette accessed by choosing View Color Palette If you change green and blue in the color palette to two different colors the occupied orbital surfaces are displayed in the nearest colors to green and blue You can open the surfaces of several molecular orbitals at the same time by choosing Analyze Show Surfaces An electrostatic potential surface represents the distance from your sample at which a proton experiences a set attraction or repulsion The value of the electrostatic potential on the surface is 0 03 a u 18 kCals mol 75 kJ mol Electrostatic potential is normally represented by red and blue to indicate positive and negative potential respectively You can switch these colors using the color palette accessed by choosing View Color Palette Changing display options for surfa
476. t element Refer to Using the workspace style bar p 3 40 for information on using the Element Type drop down list 3 10 BioMedCAChe User Guide The workspace The Hybridization box The Hybridization box provides a drop down list of hybridization or electronic configuration alternatives which you can apply to e the next atom you draw e a selected atom sp3 tetrahedron sp2 trigonal plane isp3 tetrahedron d3 tetrahedron d2sp3 octahedron dzsp3 trigonal pyramid dxysp3 square pyramid p3 trigonal pyramid dsp3 square plane Uneconfigured lt t gt Refer to Using the workspace style bar p 3 40 for information The Charge box BioMedCAChe User Guide on using the Hybridization drop down list The Charge box is a text box which you can use to enter a charge value or select a negative or positive charge value provided by CAChe by using the up or down arrow button next to the text box E Ei Once you have selected or entered a charge value you can e draw an atom with the specified charge value e change the charge of a selected atom Refer to Using the workspace style bar p 3 40 for information on using the Charge text box 3 11 Chapter 3 CAChe Basics The Bond Type box The Bond Type box lists up to six bond types Once you choose a bond type from the drop down list you can e draw a bond of the specified bond type e change a selected bond to th
477. t is selected The same object displayed in any workspaces of the same chemical sample are highlighted To toggle the selection of a chemical sample object 1 Inthe Chemical Properties workbook choose the tab for the kind CAChe for Windows User Guide Viewing chemical sample data of object e g Atoms or Bonds 2 While holding the Ctrl key click on the row number The row number is contained in the first column of the spreadsheet The selection state of the object is inverted and its display in any workspaces of the same chemical sample are updated The selection of other objects is unchanged To extend the selection of chemical sample objects 1 Inthe Chemical Properties workbook choose the tab for the kind of object that is currently selected e g Atoms or Bonds 2 While holding the Shift key click on the row number The row background is greyed from the first selected object to the current row all other objects are deselected and the greyed objects are selected Selected objects displayed in any workspaces of the same chemical sample are highlighted Editing chemical sample data You can enter specific data into the chemical sample file such as precise atom coordinates or experimental UV visible absorption spectra TIP Editing the value of atom IDs renumbers atoms in a molecule To enter chemical sample properties 1 Inthe Chemical Properties workbook choose Edit Edit Property Values E
478. t to view part or all of your chemical sample without displaying its atoms so that you can view other aspects of your molecule more clearly Hiding atoms simplifies the appearance of your chemical sample and increases the speed of manipulating the molecule around the workspace CAChe allows you to e hide and display selected atoms in your sample e hide and display all of the hydrogen atoms in your sample Hiding and displaying selected atoms When you hide selected atoms the atoms are hidden in the workspace but remain part of your chemical sample Hiding atoms does not affect any experiments you subsequently run on the chemical sample NS To hide selected atoms 1 Select the atoms that you want to hide by clicking on them with a selection tool 2 Do one of the following o Choose View Hide Selected o OF o Choose View Atom Attributes to display the Atom Attributes dialog box Select the Display Atoms check box so that it is not checked The Display Atoms check box is displayed no matter which tab is currently selected in the Atom Attributes dialog box Select OK to close the Atom Attributes dialog box The selected atoms are hidden and then the visible objects are selected NS To hide unselected atoms 6 18 CAChe for Windows User Guide Hiding atoms 1 Select the atoms that you want to remain visible by clicking on them with a selection tool 2 Choose View Hide Unselected The atoms that are not se
479. t you can use to enter values for the attachment angles for the residue Phi 180 Psi f 180 Once you have selected or entered angles you can insert a residue with the specified Phi and Psi values e change the Phi or Psi values of a selected residue Hiding the style bar You can display or hide the sequence style bar To hide the sequence style bar 1 When the style bar is visible choose Options Show Ribbon The style bar is no longer displayed at the top of the workspace The check mark next to the Show Ribbon drop down item on the Options menu no longer appears indicating that the style bar is currently hidden To redisplay the sequence style bar 1 When the style bar is hidden choose Options Show Ribbon The style bar is displayed at the top of the workspace A check mark appears next to the Show Ribbon drop down item on the Options menu indicating that the style bar is currently visible The tool palette The sequence tool palette provides two types of tools selection tools BioMedCAChe User Guide 9 23 Chapter 9 Manipulating Biomolecules e aresidue tool for inserting residues Select Select Molecule Chain _ Selection tools R Select Similar Residue Residue tool The selection tools The tool palette contains the following selection tools e the Select tool default which selects individual residues or sequences e the Select Molecule tool which sele
480. t you want to participate in a group by clicking on them with a selection tool If you are using the Select tool hold down the Shift key when selecting more than one atom The atoms are highlighted to show that they are selected 2 Choose Edit Group Atoms to display the Group Atoms dialog box Group Atoms 2 x m Define groups from the current selection Defined Groups M Show Residues Group Type Zil none x Group Name A m Combine the current selection S with group G to form a new selection D D D PL Cancel 3 Choose the Group Type from the pulldown A group can be an active site ligand water amino acid nucleic acid hetero type or none of these 4 Click in the Group Name text box and type a name for the group of selected atoms 5 Select gt gt Group gt gt to display the new group name in the Defined Groups list BioMedCAChe User Guide Grouping atoms When you select a new or existing group in the Defined Groups list the buttons in the section Combine the current selection S with group G to form a new selection are enabled Selecting groups and portions of groups W The Group Atoms dialog box refers to the atoms you selected in the workspace as S and previously defined groups of atoms as G Using set operator buttons in the dialog box you can combine atoms from both S and G to e form new groups of atoms select portions of an existing group
481. tLeader Changing the display of the plot Selecting data points 12 28 To scale the plot 1 Hold down Ctrl the left mouse button and the right mouse button then do one of the following a drag the cursor up and to the left to make the plot smaller a drag the cursor down and to the right to make the plot larger 2 To zoom in on a particular part of the plot hold down Ctrl and the left mouse button and drag the cursor over the area that you want to zoom in on A rectangular box is drawn around the section then the display is zoomed in on that section 3 To reset the view choose View Reset graph To translate the plot 1 Hold down Shift the left mouse button and the right mouse button then drag the cursor in the direction that you want to translate the graph 2 To reset the view choose View Reset graph You can select single data points entire data sets or combinations of points Menu actions apply to all selected data points To select data points 1 Use the left mouse button to select a single data point The label of the selected data point is boxed to indicate that the point is selected 2 Use the right mouse button to display the popup menu for the selected data point The menu options are activated but only relate to the selected point Regression is still grayed out because an entire data set must be selected before a regression analysis can be performed BioMedCAChe User Gu
482. tLeader The Procedure Editor allows you to edit procedures and other components of the experiment environment e create new procedures and components of the experiment environment e clone existing procedures e share procedures with other CAChe users e perform expert modification to individual property parameters e create a new package of experiments procedures and parameter data for use by other users 11 2 CAChe for Windows User Guide Starting the Procedure Editor Starting the Procedure Editor You can start the Procedure Editor in any of the following ways e manually from the Start menu e from the Experiment Definition dialog box in the Workspace e from the Property Wizard in the ProjectLeader Y To start the Procedure Editor 1 Perform one of the following a From Windows choose Start CAChe Procedure Editor a From the Workspace select the Edit button in the Experiment Definition dialog box a From the ProjectLeader select the Edit button in the Property Wizard The Navigator window of the Procedure Editor is displayed If you started the Procedure Editor from either the Workspace or the ProjectLeader the Procedure Editor opens with the currently active experiment visible in the Navigator window and the referenced procedure visible in a Procedure window For experiments that are unique to the ProjectLeader the Property dialog box is displayed instead CAChe for Windows User Guide 11 3
483. tLeader workbook 1 In the Sample Properties workbook select the cells that you want to copy to the ProjectLeader workbook 2 To display the Select Columns dialog box do one of the 12 18 BioMedCAChe User Guide Viewing sample properties following a choose Edit Copy to Main Workbook a click the right mouse button to display a popup menu and choose Copy to Main Workbook It prompts you to choose the first column in the ProjectLeader workbook to which the sample property data should be copied 3 In the Select Columns dialog box choose the first column to which the cells should be copied You must choose a column in the ProjectLeader workbook for each of the rows in the Sample Properties workbook from which you are copying data 4 Ifyou are copying data from more than one row in the Sample Properties workbook select Next then choose a ProjectLeader workbook column for the next row of data until you have chosen a column for each of the rows 5 Select OK The cells are copied into the ProjectLeader workbook lt t gt Refer to Running a ProjectLeader experiment p 12 20 for details about performing experiments on sample properties when they are in the main ProjectLeader workbook Select Columns x Action Select the column to store the Atom List component C1 The available columns are displayed in this list G New Column Atom List 3 Description This column will store the Atom List c
484. te an object BioMedCAChe User Guide 1 Select the object that you want to duplicate by clicking on it with a selection tool The object is highlighted to show that it is selected Do one of the following gt Choose Edit Duplicate o Press Ctrl D A copy of the selected object is displayed in the workspace above and to one side of the original object The copy is highlighted in the workspace to show that it is selected while all other workspace objects are grayed out Do one of the following o Click and drag in the workspace with a selection tool to move the selected copy to the location you want o Click and drag the Translate tool across the workspace to the location where you want to place the duplicated object The duplicate moves to the location where you dragged it 7 13 Chapter 7 Manipulating Molecules Copying workspace objects 7 14 You can copy any selected object to the Windows Clipboard and paste it into the active workspace or into a different workspace When you paste an object it appears as a selected object in the center of the workspace You can paste the same object repeatedly You can also copy and paste a workspace object into another Windows application for example ChemDraw ISIS Draw The image is pasted as a Windows bitmap To copy and paste an object in the active workspace 1 Select the object that you want to copy by clicking on it with a selection tool The
485. te the geometry of your molecule in a chemical sample file Perfect the geometry of the molecule as much as possible by using the tools and menu options in the workspace before running an experiment Some CAChe experiments such as generating an energy map also require the addition of search labels Refer to Chapter 4 Creating Chemical Samples and Chapter 5 Modifying Chemical Samples for details about building and perfecting your molecule Refer to Chapter 8 Investigating Molecular Geometry for details about adding geometry search labels to your molecule CAChe for Windows User Guide Setting up a workspace experiment Choosing a property class Choosing a property Chemical sample properties Choose from the following five classes of properties on which to experiment and investigate further for your chemical sample e chemical sample properties atom properties bond properties sample conformation properties e reaction and transition state properties The workspace provides a range of properties on which you can experiment for each class of property Properties for each property class are described in the following sections Choose from the following properties for a chemical sample Optimized geometry Optimizes the geometry of your chemical sample using procedures from either classical molecular mechanics or semi empirical quantum mechanics Procedures that use classical methods
486. tend the repository by adding nonstandard amino acids and assigning shortcuts to them After adding the nonstandard amino acid to the repository you can used it for building peptide sequences in the same way as the standard amino acids You add nonstandard amino acids to the repository in one of two different ways directly from the Sequence View of a PDB file from the Sequence View of a nonstandard amino acid you have drawn in the CAChe Workspace Nonstandard amino acid in a PDB file With CAChe you can easily add nonstandard residues that appear in PDB files NS To add a nonstandard residue from a PDB file 1 From the 3D Structure window choose File Open and select the PDB file containing nonstandard amino acids The PDB file opens in a new 3D Structure window Tip Tf you need a trial case 4hvp ent contains the following hetero groups ABA ALPHA AMINO N BUTYRIC ACID NLE NORLEUCINE 2 Choose Analyze Sequence The Sequence View window comes to the front and the sequence from the PDB file appears BioMedCAChe User Guide 9 45 Chapter 9 Manipulating Biomolecules 9 46 3 Choose Options Amino Acids Repository The Amino Acids Repository dialog appears Amino Acid Repository 4 Inthe Amino Acids Repository dialog press the New button The New Amino Acids dialog appears New Amino Acids 5 Select one amino acid e g ABA67 from the New Amino Acid list and choose Add
487. tep 10 Enter a value in the Polyhedra Scale Factor text box in the Shape Options panel Proceed to step 10 The coordination polyhedra will be scaled by the factor you have entered Enter a value in the Probability text box in the Shape Options panel to determine the probability at which the ellipsoid is represented Select OK to apply the changes and to close the Atom Attributes dialog box The selected atoms are displayed as the spheres you specified with a radius representing the scaling options you chose Color atoms by e element colors the selected atoms with the element color from the periodic table settings e partial charge polarity colors the selected atoms by the calculated partial charge polarity Atoms with a positive partial charge are colored with color index 2 usually red Atoms with a negative partial charge are colored with color index 3 usually yellow An experiment which produces partial charge must have been run on your chemical sample before this choice produces useful results e specific color colors the selected atoms with a specific color that you choose from a drop down list displaying 12 colors A t gt Refer to Changing view settings p 6 37 for information on how to edit element color settings for the periodic table 6 14 Use the following options to change the color of atom labels CAChe for Windows User Guide Changing the appearance of atoms atom color co
488. tes of the asymmetric atoms NS To build an infinite lattice 1 i hE Choose Edit Crystal Shape to display the Crystal Shape dialog box Select the Fractional Coordinates tab and enter the fractional coordinates of asymmetric atoms Select the Main tab Choose the appropriate Space Group from the drop down list Enter the cell parameters using the Angles panel In the Build panel select Infinite Lattice Select Apply to view the infinite lattice in the workspace Bonds are based on the distance criteria as molecular crystals Infinite lattices are trimmed to lattice boundaries Select OK to accept the changes and to close the Crystal Shape dialog box To change the lattice boundaries 1 2 Select the infinite lattice using the Select Molecule Tool Choose Edit Crystal Shape to display the Crystal Shape dialog box In the Lattice Boundaries panel enter the lattice boundaries in both positive and negative a b and c directions Select Apply to view the changes in the workspace The size of the crystal is changed accordingly Select OK to accept the changes and to close the Crystal Shape dialog box CAChe for Windows User Guide Building crystal structures Displaying and hiding crystal boundaries NOTE You can display or hide outlines of the asymmetric cell unit cell and crystal lattice To enable the display of crystal boundaries the structure requires crystal information firs
489. th the Select tool The surface is highlighted in the workspace to show that it is selected 2 Choose Analyze Surface Legend to display the Surface Legend dialog box Surface Legend 2x Values at the color boundaries for FURAN CSF EFonD _ a a a es LJ 0 005 0 003 0 002 0 002 0 001 0 001 0 000 The Surface Legend dialog box displays the threshold value of transition from one surface color to another for the selected surface The colors displayed depend on the current colors assigned to each of the color indexes listed in the following CAChe color tables NOTE Any color indexes you selected previously using the View Color Palette option will replace the default colors 15 12 CAChe for Windows User Guide Viewing a surface CAChe color tables The following tables list colors and color index values for properties calculated by CAChe experiments The colors listed are the default colors present when you install the software If you have changed colors using the color palette only the indexes in the table below will be accurate You can reset colors to the default values by deleting the cache ini file located in the same folder as cache exe Deleting cache ini returns all CAChe defaults to their original settings Electron density surfaces The following applies to electron density surfaces colored by electrostatic potential superdelocalizability or susceptibility Color
490. that the structure is correct Are double bonds where they are expected Is the valence correct Are charges correct 4 Choose File Save and name the file AGRP csf To dock AGRP into MC4R Open MC4R final csf and AGRP csf Choose Analyze Sequence from each workspace Select R24 F25 F26 in the AGRP sequence Select G92 C189 V186 in the MC4R sequence Choose Edit Superimpose Sequence Choose Superimpose Target and Probe in New Window Choose OK SE Ao oe Nia A new workspace opens with AGRP superimposed on top of the receptor in MCAR Choose File Save and name the file ACRP MC4R csf 7 Define distance labels between the a C alpha atoms in R24 and G92 a C alpha atoms in F25 and C189 a C alpha atoms in F26 and V186 CAChe for Windows User Guide Docking Agouti Related Protein into the MC4R 10 11 12 With the Select Molecule tool select AGRP and choose Edit Move Selected With the Rotate and the Drag tools adjust the position of AGRP until the distance labels each are approximately 2 angstroms and atoms in AGRP are clear of the MC4R atoms Place a sphere of explicit water molecules about the extracellular regions as described in Including water p 19 10 Start an experiment to optimize the geometry using MM3 Continue the refinement with dynamics experiments at 300 K for 200 ps You have created a 3D structural model for the complex between Agouti Related Protein and MC4R CAChe fo
491. the ProjectLeader worksheet to display a pop up menu listing actions that can be performed for that cell A different pop up menu is displayed if you click the right mouse button on a sheet tab in the ProjectLeader workbook on a cell in the Sample Properties workbook and yet another from a right mouse click on a scatter plot Each workbook can contain many worksheets Select the sheet tabs to move from one worksheet to another ProjectLeader enables you to insert a sheet e delete a sheet rename a sheet move a sheet NS To insert a sheet a Choose Edit Insert Sheet A new sheet is inserted to the immediate left of the currently selected sheet NS To delete a sheet 1 Select the sheet tab that you want to delete 2 Choose Edit Delete Sheet The sheet is deleted from the workbook NS To rename a sheet BioMedCAChe User Guide 1 Select the sheet tab that you want to rename 12 9 Chapter 12 Using ProjectLeader 2 Choose Edit Rename Sheet 3 Enter anew name in the Rename Sheet dialog box and select OK The sheet is renamed NS To move a sheet 1 Select the sheet that you want to move 2 Choose Edit Move Sheet to display the Move Sheets dialog box 3 As required select either a Move Up a Move Down 4 Select OK when the sheet has been reordered to your requirements TIP Select a sheet tab using the right mouse button to display a pop up menu listing the command
492. the Rotation Settings dialog box Rotation Settings EEG Rotation Center Window center Cancel C Curent selection center Make Default 2 To rotate workspace objects around the center of the workspace select the Window Center radio button so that it is enabled 3 To rotate workspace objects around the center of any currently selected object select the Current Selection Center radio button so that it is enabled 4 Select OK to close the Rotation Settings dialog box and to save the rotation settings for the Rotate tool Using the Translate tool The Translate tool allows you to move the chemical sample sideways and up and down in the workspace relative to the x and y coordinates of the workspace Use the Translate tool to e move workspace objects around the workspace A lt 4 Refer to Other ways to move workspace objects p 7 7 for further details about moving your molecule and its components around the workspace BioMedCAChe User Guide 7 5 Chapter 7 Manipulating Molecules NS To select the Translate tool 1 Select the Translate tool by clicking on it in the tool palette 2 The mouse cursor changes to the Translate tool shown to the left Moving objects around the workspace To move workspace objects relative to the x and y axes 1 Position the Translate tool anywhere in the workspace 2 Click and drag with the Translate tool in the direction that you want to move wo
493. ther atoms belonging to the group chosen in the Group Atoms dialog box are selected in the workspace To select grouped atoms among selected workspace atoms 1 Select a number of atoms or everything in the workspace by clicking on the atoms or the workspace background with a selection tool The selected atoms are highlighted Choose Edit Group Atoms to display the Group Atoms dialog box Select the group that contains the atoms you want to remain selected in the workspace by clicking on the group in the Defined Groups list Select S and G Select OK to close the Group Atoms dialog box Any atoms that were previously selected before opening the Group Atoms dialog box and which belong to the group chosen in the Group Atoms dialog box remain selected in the workspace To select non grouped atoms among selected workspace atoms 1 Select a number of atoms or everything in the workspace by clicking on the atoms or the workspace background with a selection tool The selected atoms are highlighted 7 27 Chapter 7 Manipulating Molecules 2 Choose Edit Group Atoms to display the Group Atoms dialog box 3 Select the group that contains the atoms you do not want selected in the workspace by clicking on the group in the Defined Groups list 4 Select S but not G 5 Select OK to close the Group Atoms dialog box Any atoms that were previously selected before opening the Group Atoms dialog box and
494. they rotate To change stereo display in the workspace 1 Choose Options View Settings 2 Select the OpenGL tab to display the following dialog box View OpenGL m View Quality mi g I Specular Highlights T High Quality Spheres Eye Settings Cancel Make Default 3 Select the required features from the following list of options in the View Quality panel o Texture Mapping o Spectral Highlights o High Quality Spheres Texture Mapping and Spectral Highlights cannot be chosen together High Quality Spheres can be chosen with either option 4 Inthe Eye Settings panel select Swap Left Right Eyes to correctly view the workspace while wearing the stereo glasses 5 To adjust the stereoscopic view for your eyes do one of the following o Click and drag the Eye Separation slider to the right to make objects appear deeper o Click and drag the Eye Separation slider to the left to make objects appear flatter CAChe for Windows User Guide 6 47 Chapter 6 Viewing Chemical Samples The stereo view in the workspace changes when you release the mouse button so that you can find the best separation for your eyes 6 Select OK to close the View Settings dialog box Changing view settings for valence You can choose to keep hydrogens and electrons displayed if they are attached to atoms with valence exceptions You can also choose to keep locked hydrogen atoms displayed When you h
495. time Beginning with the first search label it determines the lowest energy position and holds it there while the lowest energy position of the second label is determined and held and continues down the line of search labels That first pass through all the search labels provides a starting structure for the sequential search In the fastest procedure and MM one pass procedures the computation returns to the first search label and for each step optimizes the structure while holding the internal coordinates defined for that step of that search label constant The optimized structure that results from each step in each search label is saved in the seqsrch map file To examine view the map file The seqsrch map file is an assemblage file that contains a number of conformations equal to the number of steps plus one multiplied by the number of search labels For example if your structure contains eight search labels each with five steps the seqsrch map file includes 6x8 48 conformations five steps results in six conformations As a result the sequential search is a more economical computation than the optimized map when your goal is to look for low energy structures If you choose the MM multiple passes option you can reduce the bias caused by the sequential search traversing the structure once in a single direction The multiple pass option examines the multiple minima that occurred in traversing the search labels The multiple pass
496. tional selected objects while continuing to hold down the Shift or Ctrl key deselects those selected objects NOTE You cannot deselect everything in the workspace because CAChe requires that at least one object must be selected If you attempt to do this all objects become selected Using the Select tool Use the Select tool to e select one or more objects such as individual atoms or bonds e deselect one or more objects D Refer to Chapter 3 CAChe Basics for further details about how to use the Select tool The Select Molecule tool Use the Select Molecule tool to E e select one or more molecules by clicking on them e select one or more molecules by clicking and dragging around them e select a group of molecules by clicking on them while holding down either the Shift or Ctrl key deselect a selected molecule by clicking on it deselect a group of selected molecules by clicking and dragging around them while holding down either the Shift or Ctrl key 5 6 CAChe for Windows User Guide Selecting workspace objects e deselect a group of selected molecules by clicking on them while holding down either the Shift or Ctrl key NS To select the Select Molecule tool 1 Select the Select Molecule tool by clicking on it in the tool palette ke The mouse cursor changes to the Select Molecule tool shown to the left Using the Select Molecule tool to select a molecule Use the Select Molecule too
497. tom and bond properties using the color palette e single bonds e double bonds e triple bonds e ionic bonds e weak bonds e surface labels e atom distance geometry labels e bond angle geometry labels e dihedral angle geometry labels e improper torsion geometry labels You can change the color of the following workspace properties using the color palette e standard text color e workspace background color When you edit the color palette all the objects represented by that color will change to the new color For example the color assigned to the index number 8 represents triple bonds and improper torsion geometry labels and may CAChe for Windows User Guide 6 39 Chapter 6 Viewing Chemical Samples represent some elements and parts of a calculated 3D surface generated by experiments When you edit this color all objects represented by this color will change in the active workspace lt t gt Refer to Changing the appearance of atoms p 6 8 and Changing the appearance of bonds p 6 21 for details about changing the color of selected atoms or bonds Refer to Changing element color p 6 37 for details about changing the color of particular elements without affecting other objects that share the same color Viewing the color palette To view the color palette 1 Choose View Color Palette The Define Colors dialog box is displayed A scrolling list displays a color index number
498. top an Experiment dialog box The experiment is aborted and output data already generated is either discarded or saved depending on the option you selected If you chose to save output files data already generated is also displayed in the Experiment Status dialog box To stop an experiment from the Experiments Submitted dialog box 1 Choose one of the following a Experiment Show Submitted Experiments The Experiments Submitted dialog box is displayed which shows experiments submitted by a user a Experiment Show Server Information The Select a Server dialog box is displayed which shows a list of servers Select the server on which the experiment you want to stop is running and select OK The Experiments Submitted dialog box is displayed which shows experiments running on that server 2 Select the experiment you want to stop in the Experiments Submitted dialog box Select Stop to display the Stop an Experiment dialog box 4 Select the required radio button as described in the previous procedure To stop an experiment from the Experiment Status dialog box 5 Select OK to close the Stop an Experiment dialog box and to close the Experiments Submitted dialog box The experiment is aborted and output data already generated is either discarded or saved depending on the option you selected CAChe for Windows User Guide 10 25 Chapter 10 Performing Workspace Experiments Running experiments si
499. try Search between and 180 00000 using 24 steps of 15 000000 degree The current improper torsion value in degrees is displayed in the Angle text box Do one of the following o Click in the Angle text box and type the new improper torsion value that you require o Select the Angle text box arrow buttons to increase or decrease the current improper torsion value to the value that you require Select Apply to view the results of the new improper torsion angle value in the workspace The first atom that you selected moves to increase or decrease the improper torsion angle to the value that you specified in the Angle text box Select OK to accept the new improper torsion value and close the Set Improper Torsion dialog box CAChe for Windows User Guide Working with geometry labels Working with geometry labels Geometry labels identify the participating atoms and the current value of a specific angle or distance Use geometry labels to e identify specific geometry attributes of your chemical sample e display existing values of your chemical sample s internal coordinates e lock atom distances and bond angles at their current values lt t gt Refer to Locking geometry labels p 8 29 for further details You can define geometry labels in three ways e when viewing and adjusting values for atom distance bond angle improper torsion and dihedral angles e directly from the Adjust
500. ttons appear as follows Select Start Menu items are described as follows Choose File Open i e Choose File from the menu bar then choose the Open menu option from the File menu Text that you need to type in or text that is displayed in a window appears as follows cache localhost The following symbols appear throughout the user guide Indicates step by step instructions for a task Indicates a note Indicates a tip hint or shortcut Indicates a reference to another part of the user guide or another book BioMedCAChe User Guide Conventions in this user guide lt t gt Refer to Chapter 3 CAChe Basics for a description of the components of the CAChe interface and an explanation of the conventions used for mouse actions such as choosing menu options selecting tools and using dialog boxes i 2 o gt 3 b 5 BioMedCAChe User Guide 1 7 Chapter I Introduction to the User Guide Navigation aids 1 8 There is a full table of contents for this user guide on page iii As explained earlier this user guide is divided into parts where each part contains one or more chapters Each chapter has a short table of contents and an overview that explains exactly what information is in the chapter The user guide contains many cross references that direct you to further relevant information on a topic However where possible information on any particular top
501. tures even though there may be considerable variation in their amino acid sequences due to their different biological functions On the other hand since the mechanisms of GPCR activation are identical a small number of amino acids in each TM helix are conserved and can be used to align the sequence with rhodopsin using algorithms such as CLUSTAL W Starting with an aligned sequence you can use the Sequence View Window to modify the rhodopsin sequences to match the GPCR you want to model and then refine it with mechanics and dynamics following the protocols described in the following discussion 1 Palczewski K Kumasaka T Hori T Behnke C A Motoshima H Fox B A Le Trong I Teller D C Okada T Stenkamp R E Yamamoto M and Miyano M Crystal structure of rhodopsin A G protein coupled receptor Science 2000 289 739 745 CAChe for Windows User Guide 19 15 Chapter 19 Investigating Biomolecules Viewing bovine rhodopsin To view bovine rhodopsin 1 Open the bovine rhodopsin crystal structure 1F88 pdb from the Protein Data Bank http www rcsb org pdb Choose Analyzel Sequence In the Sequence View choose the Select Molecule tool NOTE 1F88 contains two copies of bovine rhodopsin in the asymmetric unit They are called chain A and chain B 4 19 16 Select chain A Copy it Close the Sequence View Window Note that you have selected only the sequence chain The covalently modif
502. u need to create an ordered group using all the atoms in a residue select that residue and then create a new group with a different name see Defining a group p 7 24 The new group will not be classified as a residue and you can reorder the atoms in the new group 7 30 BioMedCAChe User Guide Investigating Molecular Geometry Overview This chapter describes how to measure and adjust aspects of the geometry of your chemical sample including how to e identify and invert any chiral centers in your chemical sample e generate a mirror image of your molecule e compare the molecular geometry of two structures e measure atom distance and bond angle values using geometry labels e lock geometry labels e lock atoms e disable locked geometry and repair broken locked geometry labels e add search labels to create varying conformations of the structure Contents Working with chiral centers 8 2 Changing geometry label appearance 8 21 Viewing chiral centers 8 2 Deleting geometry labels 8 26 Inverting chiral centers 8 3 Labeling H Bonds 8 27 Mirroring a molecule 8 5 Labeling Bumps 8 28 Superimposing molecules 8 6 Locking geometry labels 8 29 Superimposing by atoms 8 6 Broken geometry locks 8 31 Superimposing with ordered atom groups 8 7 Locking atoms 8 32 Calculating the RMS error 8 10 Hiding locked atom labels 8 33 Specifying angles and distances 8 12 Selecting locked atoms 8 34 Specifying atom distance 8 13 Disabling locked geometry 8 35 Spec
503. uivalent to each toolbar button T HPA plp al c 8 aao x a sc 9 5 D 33e r ESS E25 BSFESE FEBE a o O O o 2 cs ce 0 oon Of eET Z 2S SHSPFEBOCHR EE 8 TEE se3e2ee 2 g oO o x o 5 OD O oOo D E oO 8 o L iu see Fes 5 t oo 2 scc 5H Bw Ss kerk uo L oo x c ee 8S a JO 2 Ww ro EWU s FS EF SF TS BO ao So 8 amp 8 uw oO z amp e oOo KA D x E eo gt S m 7p a o zZ E a St n e SsS2z 5 ESS 2 gt Oo 70 URS gt 0 O 3 wn g oo et g D D 5 E o oD E S 5 H 2 x lt Lu BioMedCAChe User Guide 3 2 Chapter 3 CAChe Basics Using dialog boxes 3 22 The following section describes how to use the scrolling lists buttons and text boxes in a sample CAChe dialog box Dialog boxes in CAChe are used to create open save or print files change display attributes of objects add and define geometry labels and search labels change settings for menu options and workspace tools initiate experiments choose chemical properties on which to base an experiment choose procedures used in an experiment display experimental results display more detailed information about an experimental output file scrolling or non scrolling lists from which you can select an item scrolling or non scrolling windows that display information BioMedCAChe User Guide Using CAChe The following diagram shows examples
504. ulating atomic partial charge for your sample NOTE You cannot use procedures that involve MOPAC or ZINDO with Personal CAChe CAChe for Windows User Guide 16 3 Chapter 16 Investigating Atom and Bond Properties Calculating bond properties Calculating bond order 16 4 NOTE CAChe offers the following bond property experiments e calculated bond order e calculated bond strain You can calculate bond order using one of the quantum mechanical applications CAChe determines the experimental bond order of each bond in your chemical sample Both bond order and partial charge are calculated at the same time so you do not need to run separate experiments to get both properties If you have run an experiment that employed a quantum mechanical procedure previously this information is already present in the chemical sample file and you do not need to re compute it unless you have changed the geometry of the molecule CAChe procedures for calculating bond order also enable you to optimize the geometry of the molecule first using classical mechanics quantum mechanics or a combination of both You can combine all of the optimization procedures with calculating bond order for your sample You cannot use procedures that involve MOPAC or ZINDO with Personal CAChe After you run a calculated bond order experiment you can view bonds that are scaled to reflect calculated bond order You can change the disp
505. umn the regression is evaluated Columns with no predictive power that is those without any variance are omitted from the regression The regression equation for each cross validation step can be distinctly different for each model even if the overall regression equation is the same for a given set of data to predict one variable To add an equation to a worksheet BioMedCAChe User Guide 1 Double click on an empty column title cell to display the Enter Property dialog box Select the Analysis radio button then select Next Select Algebraic Equation then select Next Type an algebraic equation into the Equation panel Start the equation with an equals sign and use letters to refer to the worksheet columns Select OK The equation is displayed in the column title cell at the top of the 12 23 Chapter 12 Using ProjectLeader Selecting a server Selecting cells 12 24 TIP column When you evaluate any cell in this column the chosen equation is evaluated To add a comment to a worksheet 1 Double click on an empty column title cell to display the Enter Property dialog box 2 Select the Comment radio button then select Next 3 Type the title for the column in the Comment panel then select OK The title is displayed in the column title cell at the top of the relevant column Edit the cells individually to add comments To select a server on which to run the experiment 1 Choose Evalu
506. ure to use conjugate gradient for geometry optimization Refer to 19 19 Chapter 19 Investigating Biomolecules 19 20 13 14 15 16 17 18 19 Modifying a procedure p 11 17 The energy is minimized for 300 cycles with the locked atoms using the conjugate gradient method After the experiment completes choose File Save As and rename the file MC4R 1 csf Next choose Experiment New Choose a Property of chemical sample conformations a Property dynamics trajectory and a Using MD simulation MM3 Choose Start to do dynamics at 1000 K with the locked atoms for 50 ps After the experiment completes choose File Save As Chemical Sample and name the file MC4R 2 csf Choose Experiment New The Experiment dialog appears Choose a Property of chemical sample a Property optimized geometry and a Using MM geometry MM3 Choose Edit and change the procedure to use steepest descent for geometry optimization Refer to Modifying a procedure p 11 17 Choose Start The energy is minimized using conjugate gradient After the experiment completes select one turn 4 residues at each end of each helix and then choose Adjust Unlock Then start a dynamics experiment at 600K for 50 ps Save the last structure from the trajectory and energy minimize Repeat the unlocking and the dynamics and optimization experiments at 600 Kelvin until all helices have been unlocked a
507. us using MM3 is performed CAChe for Windows User Guide Creating a homology model of the MC4R Creating a homology model of the MC4R During 2000 the first high resolution x ray crystal structure of a G protein coupled receptor GPCR bovine rhodopsin was determined GPCRs form a superfamily of homologous membrane bound proteins important in cellular signaling and are targets for 60 of drugs in use or development Design of more active selective and safe drugs that target GPCRs requires knowledge of other GPCR 3D structures Unfortunately because there are often relatively few molecules of a specific GPCR in each cell and because of the difficulty in growing the crystals it is unlikely that the x ray structure of other GPCRs will be determined GPCRs are membrane bound proteins that are characterized by seven helical regions that traverse the lipid bilayer of the cell membrane These transmembrane TM helices not only define the binding sites for ligands that can interact with the GPCR such as hormones and neuropeptides but also undergo conformational rearrangements that are an essential element of signal transduction and intercellular communication Since all GPCRs likely share a common ancestor you can use the recent crystal structure of rhodopsin as the basis for building a high quality model of other GPCRs using well established homology modeling methods In this GPCR have very similar core TM helical struc
508. using experimental results to calibrate the calculated predictions The calibration holds true for other samples in the same class So how do you calibrate CAChe Simply plot experimental data from similar chemical systems against calculated results and fit the plot Computer aided chemistry matches a mathematical model to your chemical sample The following table shows the level of accuracy that you can expect when you use models of molecular structures and computational chemistry Keep in mind that even the most accurate experimental techniques are challenged to measure bond lengths with greater accuracy than 0 002A Molecular Semi empirical Mechanics MM2 Quantum Mechanics PM3 Bond lengths 0 005A 0 036A Bond angles 1 3 9 Dihedral angles 5 14 9 Heats of formation 0 7 kcal mol 7 8 kcal mol BioMedCAChe User Guide The advantages of CAChe a N L Allinger comments made during a lecture at the QCPE Workshop on semi empirical and ab initio techniques July 1986 at the University of Oxford England b James J P Stewart J Comp Chem 1989 10 209 220 i 2 o 3 b 5 BioMedCAChe User Guide 2 11 Chapter 2 Introduction to CAChe Performing experiments with CAChe The following process is a summary of how to run an experiment in CAChe 1 Build your molecule in a chemical sample file and view it from different perspectives by moving it around the screen rotating
509. utput file containing experimental details are also generated when an experiment is performed with Dynamics Trajectory information is stored graphically in a separate energy map file MOPAC is a semi empirical quantum mechanical computational tool that provides optimization and wavefunction electron distribution data to search for optimized geometry transition state geometry and molecular properties such as bond order partial charges and orbital energies MOPAC includes several sets of parameters from which you can choose MINDO 3 MNDO MNDO d PM3 and AM1 MOPAC also implements MOZYME a linear scaling method for giant molecules MOPAC generates a log data file and an output file containing experimental details and alters the structure of the molecule in your chemical sample file to correspond to the calculated optimum geometry Tabulator converts the solved wavefunction from MOPAC into three dimensional graphical representations of several properties including susceptibility electron density molecular orbitals and electrostatic potential Information generated by Tabulator can be viewed superimposed on the molecule in the chemical sample file 2 21 i uo 5 o 3 b 5 Chapter 2 Introduction to CAChe DGauss is a density funtional theory program It can determine an optimum geometry and compute electronic properties such as bond order atom partial charges and potential energy maps NOTE DGauss is av
510. ved in the conformer storage The algorithms for searching conformational space or a torsional hypersurface involve repeated sampling from the vast conformational space The process which is illustrated on the following page a curved arrow indicates a looping subprocess has the following steps 1 generation of an appropriate starting structure 2 geometry optimization of the starting structure 3 comparison of the optimized structure with the stored conformers Finally a structure passing all comparisons is added to the list of stored conformers In the advanced conformational space search algorithms the first step consists of two subprocesses 1 1 selection of an initial structure from among the stored conformers 1 2 assignment of appropriate structural perturbation to the initial structure to produce the coordinates of a starting structure Whereas the overall scheme is similar to most of the known conformation generators new strategies have been implemented for each step In the following sections these strategies are described BioMedCAChe User Guide Understanding CONFLEX Conformational Space Search 3 Comparison Selection of Initial Structure PeMturbation The structures used in each process are Input and Output Structures Process Input Output 1 None Starting 1 1 None or Stored Initial S 1 2 Initial Starting A 1 3 None Stored E 2 Starting
511. viewing adjustment such as rotate until another viewing command is received Return view of molecular structure to initial conditions including no rotation or translation scale factor of 0 1 and x y and z axes aligned with origin Enter the keyboard view rotation mode and set the rate of change to 90 per rotation No adjustments occur until you choose a direction of rotation x X y Y z Z CAChe for Windows User Guide Keyboard shortcuts Keys rorR tor T sors CAChe for Windows User Guide Action Enter the keyboard view rotation mode No adjustments occur until you choose a direction of rotation x X y Y z Z Enter the keyboard view translation mode No adjustments occur until you choose a direction of translation x X y Y z Z Enter the keyboard view scale mode No adjustments occur until you choose a direction of scaling x X y Y z Z Assign a negative x direction to the current view adjustment mode Rotate about minus x axis Translate in the negative x direction Decrease scale Assign a positive x direction to the current view adjustment mode Rotate about positive x axis Translate in the positive x direction Increase scale Assign a negative y direction to the current view adjustment mode Rotate about minus y axis Translate in the negative y direction Decrease scale Assign a positive y direction to the current view adjustment mode Rotate about positive y axis
512. w samples A lt t gt Y Contents Introduction to ProjectLeader 12 2 ProjectLeader experiments 12 3 Starting ProjectLeader 12 5 Using the ProjectLeader workbook 12 7 Opening a ProjectLeader project 12 11 Adding chemical samples 12 12 Using the CAChe Workspace from a worksheet 12 14 Copying objects from ChemDraw ISIS Draw or ChemFrontier 12 15 Viewing sample properties 12 17 Editing sample properties 12 18 Copying sample properties 12 18 Running a ProjectLeader experiment 12 20 Adding a chemical sample column property sample component analysis or comment to a worksheet 12 21 Selecting a server 12 24 Selecting cells 12 24 Evaluating the cells 12 25 Editing data 12 26 Using scatter plots 12 27 Changing workbook display options 12 33 Changing the chemical sample display 12 33 Sorting rows 12 34 Changing the grid line display 12 35 Changing the text display 12 36 Changing the numerical display 12 36 Hiding and displaying worksheet features 12 37 Using worksheet footnotes 12 37 Viewing cell information 12 39 Printing files 12 40 Previewing a printout 12 40 Choosing print options 12 40 Printing a ProjectLeader window 12 42 Exporting a ProjectLeader worksheet 12 43 Saving a ProjectLeader project 12 44 Quitting ProjectLeader 12 45 Chapter 12 Using ProjectLeader Introduction to ProjectLeader NOTE ProjectLeader is a separate application from the CAChe Workspace ProjectLeader simplifies the applicati
513. w experiments Chapter 12 Using ProjectLeader for an overview of performing experiments using ProjectLeader and Workspace versus ProjectLeader p 2 21 for a comparison of the two Contents Introduction to workspace experiments 10 2 Viewing server information 10 29 Setting up a workspace experiment 10 4 Size and element limitations 10 31 Preparing a chemical sample file 10 4 Troubleshooting experiments 10 32 Choosing a property class 10 5 Reattempting output file generation 10 32 Choosing a property 10 5 Displaying servers on which to run an Choosing a procedure 10 9 experiment 10 33 Choosing a server 10 17 Displaying experimental details 10 35 Running an experiment 10 18 Viewing experimental results 10 36 Saving an experiment file 10 23 Sample io folder 10 37 Stopping an experiment 10 24 Sample iso folder 10 37 Running experiments simultaneously 10 26 Sample map folder 10 39 Viewing active experiments 10 27 Viewing log files and output files 10 40 Chapter 10 Performing Workspace Experiments Introduction to workspace experiments 10 2 CAChe runs experiments by performing calculations based on the geometry or molecular properties of a chemical sample in the workspace Workspace experiments allow you to visualize experimental results in a variety of ways such as e viewing low energy conformations alongside a three dimensional energy graph e animating a series of low energy structures superimposing surfaces
514. want the experiment to be available in the ProjectLeader 2 Choose File Import Experiments to display the Open dialog box Note that if you have not selected the Workspace or ProjectLeader folder this option will not be available 3 Select the Property Index file that you wish to import and select the Open button to import the file CAChe for Windows User Guide Creating experiments This file contains the experiment The experiment is added to the tree view lt t Refer to steps two to eight of Creating a new experiment p 11 25 for details about changing the settings of an experiment NOTE The import facility always creates new environment components with unique names The currently selected components are not overwritten A lt t Refer to Exporting environment components p 11 37 for details about exporting experiments procedures and parameter data CAChe for Windows User Guide 11 29 Chapter 11 Using the Procedure Editor Expert modification 11 30 NOTE You can modify the parameter data of a compute engine The modified parameter data is used for all experiments that use that compute engine with that set of parameter data A Parameter Data window is used to modify parameter data To modify parameter data 1 In the tree view of the Navigator window move to the Parameter Data folder Double click on the parameter data set that you wish to modify e g the
515. want to view from the drop down list The right hand parameter bar box displays the value for the currently selected graph position To increase or decrease the value of the selected parameter select the up or down arrow buttons in the right hand parameter bar box The value jumps incrementally to the next value in the range The conformation window displays the conformation with the corresponding increased or decreased value and the spherical marker moves to the graph location of the increased or decreased value As you step through the range of values using the parameter bar the marker in the graph window moves to the graph position that corresponds with the current value and the conformation window displays the structure corresponding to the current parameter value CAChe enables you to change the display of components of the two map file windows including CAChe for Windows User Guide e each window s parameter bar e variables plotted along each graph axis e graph color options e axis attributes e graph attributes 14 15 Chapter 14 Investigating Low energy Conformations Hiding the parameter bar You can choose to hide the parameter bar on either a conformation or a graph window To hide the parameter bar 1 Activate the window whose parameter bar you want to hide 2 Choose Options Show Parameter Bar The check mark next to the drop down list option disappears to show that this option is
516. water molecules are selected CAChe for Windows User Guide Changing atom and bond properties Changing atom and bond properties Once you have selected the atom bond or molecule that you want to change you choose its new values or properties from e the style bar boxes at the top of the workspace e dialog boxes accessed from the menu that provide further options for modifying your molecule s atoms and bonds e Beautify menu options that correct an atom s hybridization e an Edit menu option that changes bond type while connecting two atoms participating in the bond Changing an atom using the style bar The quickest way to change the element type hybridization or charge of an atom involves using the Element Type Hybridization and Charge style bar boxes at the top of the workspace E Carbon x meee Charge a Single 7 Element Type box Hybridization box Charge box Bond Type box To change an atom s element type using the style bar boxes 1 Select the atom or group of atoms whose element type you want to change by clicking on the atoms with a selection tool The atom or group of atoms are highlighted to show that they are selected 2 Select the arrow button in the Element Type box A drop down list is displayed listing the last seven element types you have used 3 Ifthe element you require is displayed choose it from the drop down list The element is displayed in the Element Type b
517. which don t belong to the group chosen in the Group Atoms dialog box remain selected in the workspace amp To ungroup a previously named group 1 Choose Edit Group Atoms to display the Group Atoms dialog box 2 Select the group that you want to ungroup by clicking on the group in the Defined Groups list 3 Select lt lt Ungroup lt lt 4 The group is no longer displayed in the Defined Groups list 5 Select OK to close the Group Atoms dialog box Any atoms belonging to that group still remain in your molecule but the association between them is broken Changing atom order in groups Atoms in atom groups have an order Atom order is important when superimposing atom groups as explained in Superimposing with ordered atom groups p 8 7 To change atom order in an existing group of atoms 1 Choose Edit Group Atoms to display the Group Atoms dialog box 2 In the Defined Groups list click on the plus symbol next to the group that you want to reorder The group expands to display 7 28 BioMedCAChe User Guide Grouping atoms the name of each atom in the group Group Atoms _2 xj Define groups from the current selection Defined Groups I Show Residues Group 5 TN CA lt lt Ungroup lt lt C360 CA Group Name C336 CA PROBE E e TARGET C3198 CA xl m Combine the current selection S with group G to form a new selection G only All but G SoG G but not 5
518. which you want to measure atom distance by clicking on an atom with the Select tool then holding down the Shift key and clicking on the second atom If you are adjusting atom distance ensure that the first atom you select is the atom that you want to move 2 Choose Adjust Atom Distance to display the Set Atom Distance dialog box Set Atom Distance BEI Distance 2 489 4 angstrom Cancel Apply C Unlock Geometry C Lock Geometry gt amp Search between 2 24 and 2 737 using E stepsof 0 082833 angstrom The current atom distance value in angstroms is displayed in the Distance text box 3 Do one of the following o Clickin the Distance text box and type the new atom distance value that you require o Select the Distance text box arrow buttons to increase or decrease the current atom distance value to the value that you require 4 Select Apply to view the results of the new atom distance value in the workspace CAChe for Windows User Guide 8 13 Chapter 8 Investigating Molecular Geometry Specifying bond angle 8 14 The first atom that you selected moves to increase or decrease the atom distance to the value that you specified in the Distance text box Select OK to accept the new atom distance value and to close the Set Atom Distance dialog box Measure and adjust the angle between two bonds by selecting the three participating atoms in the order in which the atoms span the angl
519. wing Chemical Samples Building crystal structures CAChe enables you to build models of infinite lattice and molecular crystal structures within the workspace CAChe enables you to e select a space group e define cell parameters e define fractional coordinates of the asymmetric atoms build a structure containing only the asymmetric atoms and bonds build the molecular structure from asymmetric atoms which can then be used to build a molecular crystal e build an infinite lattice e display and hide crystal boundaries e open CrystalStructure and ShelX file types e import data from a text file into the Crystal Shape dialog box There are five ways that you can add asymmetric atoms from which the crystal structure is built e add atoms to a workspace using the Atom tool lt t gt Refer to Using the Atom Bond tool p 4 4 for further details e add atoms to a workspace by opening a chemical sample file A gt Refer to Working with chemical sample files p 4 2 for further details e use the Crystal Shape dialog box to enter the atomic symbols and their fractional coordinates e create an ASCII text file of data using a specified file format when you open this file the asymmetric atoms and bonds are added to the workspace 6 54 CAChe for Windows User Guide Building crystal structures e copy data from a text file and paste it into a fractional coordinates table From the asymmetric atoms space
520. wing distance of your molecule click and drag the Viewing Distance slider to the left To increase the viewing distance of your molecule click and drag the Viewing Distance slider to the right To shrink the front of the three dimensional viewing box to clip your molecule click and drag the Near Clipping slider to the left To expand the front of the three dimensional viewing box to clip your molecule click and drag the Near Clipping slider to the right To shrink the back of the three dimensional viewing box to clip your molecule click and drag the Far Clipping slider to the left To expand the back of the three dimensional viewing box to clip your molecule click and drag the Far Clipping slider to the right Changing workspace stereo display 6 46 If you have a Stereo license you can improve the way in which your chemical sample is displayed in the workspace by using the following options texture mapping enables you to improve the texture quality of your sample specular highlights enables you to add specular highlights to the atoms in your sample e high quality spheres enables you to improve the precision of the atoms in your sample CAChe for Windows User Guide Changing view settings You can alter the eye settings while wearing the stereo glasses using the following option e eye separation controls the stereo disparity so that as you rotate the trackball objects seem not to stretch as
521. with a partial charge of 1 a u scaled to 1 0 and colored by partial charge polarity Bonds are displayed as single cylinders scaled to 0 1A for a calculated bond order of 1 colored by calculated bond order Refer to Chapter 16 Investigating Atom and Bond Properties for information on running both a partial charge experiment and a calculated bond order experiment CAChe for Windows User Guide Using CAChe model types The following example shows a molecule displaying partial charge and calculated bond order CAChe for Windows User Guide 6 7 Chapter 6 Viewing Chemical Samples Changing the appearance of atoms Atoms can be represented by a variety of symbols that depict different kinds of information such as spheres and space filling spheres or as combinations of symbols and spheres NOTE The display style you choose to represent your chemical sample has no impact on its structure or on any experiments you run using that chemical sample CAChe allows you to change the following aspects of an atom s appearance e atom labeling e atom shape e atom color e the electrons of an atom Changing atom labeling Choose from the following selection of atom labels e atomic symbol displays the atom symbol e g C for carbon e hybridization displays the atom hybridization e g sp charge displays the atomic charge e g 1 e partial charge displays the calculated partial ch
522. ws User Guide Manipulating Biomolecules Overview This chapter describes how to open Protein Data Bank PDB files view protein structures and sequences and build proteins and peptides from their sequence You ll learn how to open and view PDB molecules build peptides and proteins by sequence mutate residues e display secondary structure color sequences and structure by property e compare and align sequences in separate proteins superimpose structures from sequences e map protein and active site surfaces Contents Viewing biomolecules 9 2 Wrapping and hiding sequences Saving a PDB molecule 9 6 Changing biomolecules Displaying proteins 9 6 Mutating residues Viewing PDB atom names 9 7 Inserting residues Highlighting residues 9 8 Deleting residues Coloring residues 9 8 Joining chains Highlighting and displaying the backbone 9 9 Copying and pasting sequences Displaying the backbone N C C trace 9 10 Building peptides and proteins Displaying ribbons 9 10 Building by homology Displaying surfaces 9 11 Changing secondary structure Working in the Sequence View window9 18 Comparing biomolecules Viewing sequence residues 9 18 Aligning sequences The toolbar 9 19 Matching selections The Sequence View window 9 20 Select conserved The style bar 9 21 Superimposing biomolecules The tool palette 9 23 Removing superposition Changing the sequence style 9 25 Extending the amino acid repository Computing and viewing secondary structure Nonstan
523. x The atoms belonging to the chosen group are highlighted in the workspace to show that they are selected To select an existing group of atoms plus additional atoms 1 Select the additional atoms that you want to select by clicking on them with a selection tool The atoms are highlighted to show that they are selected 2 Choose Edit Group Atoms to display the Group Atoms dialog box 3 Select the group whose atoms you also want to select in the workspace by clicking on the group in the Defined Groups list 4 Select S or G Select OK to close the Group Atoms dialog box The atoms that you selected before opening the Group Atoms dialog box are still selected and the atoms belonging to the chosen group in the Group Atoms dialog box are also selected in the workspace To select an existing group of atoms minus additional atoms 1 Select the grouped atoms that you do not want selected by clicking on them with a selection tool The atoms are highlighted to show that they are selected 7 26 BioMedCAChe User Guide Grouping atoms BioMedCAChe User Guide Choose Edit Group Atoms to display the Group Atoms dialog box Select the group that contains the atoms you selected in the workspace by clicking on the group in the Defined Groups list Select G but not S Select OK to close the Group Atoms dialog box The atoms that you selected before opening the Group Atoms dialog box are no longer selected while all o
524. xperiment you can display bond strain represented by colors that indicate the order of magnitude of the CAChe for Windows User Guide 16 5 Chapter 16 Investigating Atom and Bond Properties 16 6 strain energy Tension and compression can both lead to strain and are indistinguishable For example red indicates a high bond strain value and is indicative of a structure that has high potential or steric energy Refer to CAChe color tables p 15 13 for details of the bond strain colors and energy values they represent CAChe for Windows User Guide Viewing atom and bond properties Viewing atom and bond properties After you run a partial charge or bond order experiment you can view atomic partial charge in your chemical sample file by choosing a CAChe modeling style or customizing the display of partial charge using one of the following two view options atoms labeled with partial charge atoms sized and colored to reflect partial charge Similarly you can view bond order in your chemical sample file by choosing a CAChe modeling style or customizing display of bond order by choosing one of the following two view options bonds colored by bond order e scale the radius of bonds by bond order When bonds are colored by bond order CAChe determines which of the standard bond types is closest to the bond order of each bond in your sample A calculated bond order of 1 5 is rounded to 1 0 and is color
525. xperiment environment Using the list view The list view can be used to e edit the name of an entry edit the description of an entry sort entries lt t Refer to Using the tree view p 11 8 for details about selecting an object and displaying Procedure and Parameter Data windows from the list view Expanding the list view You can display the contents of a folder in the list view NS To expand a folder in the list view a Inthe list view move the cursor over the folder that you wish to expand and double click the left mouse button The contents of the selected folder are displayed in the list view and the tree view is updated to ensure that the selected folder is visible Editing an entry You can edit the name of an object in the list view or change its description To edit the name of an object 1 Select the entry in the list view that you wish to change 2 Choose File Rename The object name is highlighted 3 Enter the new name CAChe for Windows User Guide 11 11 Chapter 11 Using the Procedure Editor Sorting entries 11 12 To edit the description of an object 1 2 3 4 Select the entry in the list view that you wish to change Choose File Properties to display the Properties dialog box Enter the new description in the Description text box Select OK to confirm the changes and to close the dialog box You can sort the entries in the list view into ascend
526. xt files via the clipboard into the fractional coordinates table of the Crystal Shape dialog box CAChe for Windows User Guide 6 65 Chapter 6 Viewing Chemical Samples 6 66 NS To import data from a text file Open the file using a text editor Select the rows you want to copy and copy the data to your clipboard by pressing Ctrl C Choose Edit Crystal Shape to open the Crystal Shape dialog box Select the Fractional Coordinates tab Select one or more rows by clicking on a row in the Atom column and holding down the Shift key Press Ctrl V to paste the data from your clipboard to the table Select Apply to view the structure in the workspace Select OK to accept the changes and to close the Crystal Shape dialog box CAChe for Windows User Guide i Manipulating Molecules Overview This chapter describes how to manipulate molecules in the CAChe workspace including how to use the manipulation tools to rotate translate and scale workspace objects e rotate translate and scale only selected portions of your molecule e duplicate copy cut delete and paste selected portions of your molecule superimpose one molecule over another to visualize geometrical differences e fuse atoms and bonds from one cyclic structure with atoms and bonds from another cyclic structure e name and define groups of atoms e select atom groups and portions of atom groups Contents Using the manipulation tools 7 2 Deleting port
527. xt to the drop down list option to show that it is disabled The axis labels of the graph are no longer displayed in the graph window To display axis labels 1 Activate the graph window of the map file by clicking on it CAChe for Windows User Guide Viewing map files 2 When axis labels are hidden choose View Show Axes Text A check mark is displayed next to the drop down list option to show that it is enabled The axis labels of the graph are displayed in the graph window To hide the graph function 1 Activate the graph window of the map file by clicking on it 2 When the graph function is visible choose View Show Graph Function A check mark is no longer displayed next to the drop down list option to show that it is disabled The graph function is no longer displayed in the graph window To display the graph function 1 Activate the graph window of the map file by clicking on it 2 When the graph function is hidden choose View Show Graph Function A check mark is displayed next to the drop down list option to show that it is enabled The graph function is displayed in the graph window To hide the graph marker 1 Activate the graph window of the map file by clicking on it 2 When the graph marker is visible choose View Show Marker A check mark is no longer displayed next to the drop down list option to show that it is disabled The spherical graph marker is no longer displa
528. y Specifying angles and distances CAChe allows you to measure and adjust distances and angles in a molecule so that you can view and change the exact internal coordinates of a structure You can also measure and adjust angle and distance values between atoms belonging to different molecules You can measure and change the following angles and distances e atom distance e bond angle e dihedral angle improper torsion When measuring angles and distances the order in which you select the participating atoms is crucial to the resulting geometry adjustment In all cases the atom you select first is the atom that moves to achieve the new value of the angle or distance The values you can measure and adjust depend on the number of selected atoms e if two atoms are selected you can measure and adjust atom distance e if three atoms are selected you can measure and adjust bond angles e if four atoms are selected you can measure and adjust dihedral angles and improper torsion You can also choose to label bond angles and atom distances in the workspace by applying geometry labels Refer to Working with geometry labels p 8 19 for information on applying geometry labels CAChe for Windows User Guide Specifying angles and distances Specifying atom distance You can view and adjust the distance between two atoms in the same workspace To measure and adjust atom distance 1 Select the two atoms between
529. y e calculate molecular properties such as bond order and atomic partial charge Introducing the computational applications 2 20 While mostly invisible to the user CAChe uses a number of computational applications which use classical and quantum mechanical methods to perform experiments on your chemical sample This section gives an overview of each computational application BioMedCAChe User Guide Computational chemistry and CAChe lt t gt Refer to Chapter 20 CAChe Computational Applications for BioMedCAChe User Guide more detailed information Mechanics optimizes molecular geometry using classical molecular mechanics Mechanics finds an optimum geometry by systematically moving all atoms in a chemical sample until the net force acting on each atom approaches zero Mechanics generates a log data file and an output file containing experimental details and alters the structure of the molecule in your chemical sample file to correspond to the calculated optimum geometry CONFLEX generates low energy conformers of a molecule of any shape It can be used to compute an optimum geometry and potential energy maps Dynamics simulates the normal motion of atoms according to time temperature and the calculated forces on the atoms Dynamics generates a trajectory or collection of structures over time where each structure has an associated potential and kinetic energy as well as temperature A log data file and an o
530. y Open the chemical sample file and choose the relevant menu options to view the data stored in isosurface files BioMedCAChe User Guide Understanding CONFLEX Understanding CONFLEX CONFLEX generates low energy conformers of a molecule of any shape CONFLEX incorporates several unique strategies to complete a conformational space search e down stream reservoir filling e a variable search limit three modes of perturbation unique corner flap edge flip and stepwise rotation e pre check This section provides reference information about the kinds of computations possible using CONFLEX theory and specific information about the CAChe computational application CONFLEX Use CONFLEX to compute optimum geometry e conformations e potential energy maps D i i s N i D BioMedCAChe User Guide 20 23 Chapter 20 CAChe Computational Applications CONFLEX concepts 20 24 For convenience the structures being processed are given different names as follows input structure is the input at the beginning of a search e initial structure is called in from the conformer storage at the beginning of each perturbation cycle e starting trial structure is the perturbed structure before geometry optimization optimized structure is the structure after geometry optimization stored structure is the optimized structure that survived the redundancy test and it is sa
531. y conformations e eliminate low energy conformations if they belong to shallow energy wells that are separated from adjacent lower minima by low energy barriers To specify analysis criteria 1 Activate a conformational analysis window by clicking on it 2 Choose Options Analysis Settings to display the Analysis Settings dialog box Analysis Settings BE Variable Energy x Range 6 8172 to 47 4561 kcal mole Cancel Show minima in the lowest foo of the range C Show all minima with Value less than fio kcal mole I Coalesce minima which C Show Tio tres are separated by Melia Carel barriers smaller than 0 Make Default kcal mole 3 Select the arrow button in the Variable box to display a drop down list of variables for which you can change settings 14 24 CAChe for Windows User Guide Viewing map files CAChe for Windows User Guide To display a certain percentage only of low energy conformations in the conformational analysis window conformation window and graph window do the following Select the Show minima in the lowest radio button so that it is enabled Click in the text box and type the percentage value for the range of low energy conformations that you want to view To display only those low energy conformations with a specified energy value do the following Select the Show all minima with value less than radio button so that it is enabled Click in the keal mole tex
532. y individual conformation view the conformations step by step or in a range of steps NS To animate search labels 1 Select the search labels that you want to animate in one of the following ways o Select a molecule and its search label by clicking in the workspace background using a selection tool o Select individual search labels by clicking on one label with the Select tool holding down the Shift key and clicking on the other search labels that you want to animate 2 Choose Adjust Animate Geometry Labels to display the Animate Geometry Labels dialog box Animate Geometry Labels Controls KORA Cancel Conformation 7 of faz Help Step by fi conformations W 3 Select the forward button shown to the left to animate your molecule from the first to the last conformation The molecule in the workspace moves through each search label value in turn to create a range of conformations The Conformation text box displays the position of the current 8 44 CAChe for Windows User Guide Working with search labels conformation in the range of conformations The box to the right of the Conformation text box displays the total number of conformations in the range To stop the animation at a particular conformation select the stop button shown to the left The molecule stops moving and the Conformation text box displays the position of the current conformation in the range of conformati
533. yed in the graph window To display the graph marker 1 Activate the graph window of the map file by clicking on it 2 When the graph marker is hidden choose View Show Marker CAChe for Windows User Guide A check mark is displayed next to the drop down list option to show that it is enabled The spherical graph marker is displayed in the graph window 14 21 Chapter 14 Investigating Low energy Conformations Analyzing map files 14 22 CAChe uses a conformational analysis window to list all of the conformations in your map file in ascending order of energy values You can view the energy value of a conformation plus the value of any other variable for that conformation NS To open a conformational analysis window E C CACHE CHEM1 MAP ENERGY MAP 3 1 Activate a graph window or conformation window by clicking on it Choose Window New Conformational Analysis Window A conformational analysis window is displayed The window lists the energies of the map file s conformations in order of ascending energy The first energy value listed corresponds to the lowest energy minimum in the analysis The conformational analysis window is interactive with the graph and conformation window Marker Rank Energy kcal mole BondAngle1 16 602440 17 173389 20 491859 23 016891 25 258429 31 108000 39 581776 40 927017 47 963909 50 953728 53 302963 80 821152 94 879013 35 266 degree

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