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Maestro Tutorial

1. selected Figure 2 4 The Project Table panel Maestro 9 0 Tutorial 13 Chapter 2 Starting Maestro and Viewing Molecules Save Project 2lalx PS nfs zonel dy stro tutorial OG O O A E E A eu Nane 7 size ua Type pate Modified 1 Home Directory a Launch Directory ey Working Directory File name tutorial Files of type prj i 7 Cancel Figure 2 5 The Save As Project dialog box 2 7 Saving the Maestro Project Maestro projects are collections of structures and data that you can save in a designated loca tion and then return to later on Because structures that you work with in Maestro are copies that are saved to disk in a designated directory structural changes that you make in Maestro will not affect the actual files that you imported If you ve saved your Maestro project these copies are saved in the project directory that you specified Otherwise the copies are saved in a temporary directory In this exercise you ll save your project so that you can return to it later 1 Click the Save as button on the main toolbar a The Save Project dialog box appears 2 In the File name text box type a name for your project such as tutorial 3 Click the Save button Changes you make in the project are automatically saved so there s no need to save the project again later If you quit Maestro and want to re open this project l
2. 2 A label appears on the chiral atom For the structure that you built it should be R If you can t see the label clearly rotate the molecule Now we ll change the chirality from R to S 2 Choose Chirality from the Adjust button menu on the main toolbar not the Build panel toolbar H To change the chirality you have to pick three atoms the chiral atom then the two that you want to stay where they are The other two atoms are swapped with their attached groups 3 Click on the chiral carbon atom then click on the ring carbon and the carboxylate carbon see Figure 3 22 Figure 3 22 Changing the configuration of ibuprofen from R to S 40 Maestro 9 0 Tutorial Chapter 3 Building Molecules Using Maestro Project Table tutorial Table Select Entry Property Group ePlayer F r small molecule ionized aspirin tylenol ibuprofen _multi structure_ file IEEE WEE IEEE 3D SL h Entries 7 total 7 shown 3 selected 1 included Figure 3 23 The Project Table panel with the three entries selected On the first and second clicks a purple cube appears around the picked atoms On the third click the groups are moved and the chirality label changes from R to S Congratulations You have completed the transformation of aspirin to tylenol to ibuprofen and have learnt how to use most of the tools in the Build panel In the next few chapters you ll see how to use some of the
3. Generally e mail correspondence is best because you can send machine output if necessary When sending e mail messages please include the following information e All relevant user input and machine output e Maestro purchaser company research institution or individual e Primary Maestro user e Computer platform type e Operating system with version number e Maestro version number e Maestro version number e mmshare version number On UNIX you can obtain the machine and system information listed above by entering the following command at a shell prompt SSCHRODINGER utilities postmortem This command generates a file named username host schrodinger tar gz which you should send to help schrodinger com If you have a job that failed enter the following command SSCHRODINGER utilities postmortem jobid where jobid is the job ID of the failed job which you can find in the Monitor panel This command archives job information as well as the machine and system information and includes input and output files but not structure files If you have sensitive data in the job Maestro 9 0 Tutorial Getting Help launch directory you should move those files to another location first The archive is named Jobid archive tar gz and should be sent to help schrodinger com instead If Maestro fails an error report that contains the relevant information is written to the current working directory The report is named maestro_error txt
4. There are also indigo colored links to various sections of the Maestro User Manual These links are provided so you can read more about the feature you are working with if you are interested Clicking on these links takes you to the section referred to Try clicking the words Maestro User Manual in the first sentence of this paragraph then click the Back button Maestro 9 0 Tutorial 1 2 Maestro 9 0 Tutorial Chapter 2 Starting Maestro and Viewing Molecules Maestro is a freely available full featured molecular visualization environment that also serves as the interface to all of Schr dinger s computational chemistry software When coupled with Schr dinger software such as Glide Prime or Phase Maestro is a powerful tool for inter preting managing and sharing the results of computational experiments As a standalone program Maestro is an easy to use tool for building visualizing and sharing 3 dimensional chemical models In this tutorial you ll learn how to perform these simple tasks using Maestro s intuitively designed interface Working through the exercises in this chapter you ll start Maestro import structure files and learn how to view them in the Maestro Workspace Maestro is designed to run on Linux and Windows machines but can be displayed over a network to many commonly used platforms With a little effort Windows users can also install one of many Linux distributions on their PCs Not only do these distr
5. placed in the Workspace or attached to existing structures eliminating the need to manually add every individual atom in a structure 1 Begin by clicking the Clear workspace button on the main toolbar Di This simply excludes any structures that may currently be in the Workspace no atoms or molecules in existing structures are deleted This button is dimmed if there s nothing in the Workspace so you don t need to click it 2 Click the Fragments tab to display a selection of fragment libraries Maestro 9 0 Tutorial 17 Chapter 3 Building Molecules Using Maestro 18 DI Choose Organic from the menu labeled Fragments Click on the phenyl fragment in the library in the center of the panel see Figure 3 2 Q To place the fragment click near the center of the Workspace You ll see the complete phenyl ring appear in wire frame representation Carbon atoms are colored gray and hydrogen atoms are colored white Next we ll add an acid group to the ring There are two acid fragments in the Organic fragment library one for adding at the C H bond and the other for adding at the O H bond The bond that is replaced is indicated by a curved line Click on the carboxylic acid fragment whose C H bond is divided by a curved line LE oa on To place this fragment click on any of the white hydrogen atoms in the Workspace When you move the pointer into the Workspace it turns into a yellow sq
6. 4 Finally click on a carbon atom that is bonded to the atom you picked in the last step After you click on the third atom the purple cubes vanish and a green angle marker appears Maestro 9 0 Tutorial Chapter 5 Measuring Analyzing and Superimposing Structures Figure 5 3 Measuring an angle If you like you can define several other angle measurements on the structure Just like distance measurements multiple angle measurements can appear in the Workspace at any given time and you can measure angles between non bonded atoms Finally delete the angle markers from the Workspace by choosing Delete Measurements from the Measure distances angles dihedrals or coupling button menu The angle markers disappear and the structure remains unchanged in the Workspace 5 4 Measuring Dihedrals Once you know how to measure distances and angles it s a simple matter to measure a dihe dral angle the torsion defined by any four atoms For this example we ll measure the dihedral angles in two different conformations of n propanol We ll begin this exercise by placing one of the n propanol structures in the Workspace 1 Locate the entry n propanol anti in the Project Table 2 Include the n propanol anti entry in the Workspace and exclude all other entries by click ing the square to the left of the title Choose Dihedral from the Measure distances angles dihedrals or coupling button menu Locate the terminal meth
7. HI Polar Hydrogens Membrane Select Figure 2 2 Display only selected atoms and Display only button menus One of the useful features of the Maestro interface is the availability of help features In addi tion to the Auto Help text area in the upper right hand corner of the menu bar you ll see a Help menu that can be used to find information about Maestro features You may have also noticed that when you pause the pointer over one of the buttons in the toolbar a pop up tooltip appears with text that describes the function of the button We ll use this text to refer to the buttons When you move the mouse again it disappears All Maestro windows called panels have a Help button at the bottom that can be used to display relevant information If you can t find the information you need you can also e mail help schrodinger com to get an answer to your questions 2 4 Importing a Maestro File The most common operation within Maestro is the simple manipulation of structures in the Workspace they can be rotated translated and made to appear larger or smaller But before you can experiment with these manipulations you ll need to import some structures To do so 1 Open the Import panel by clicking on the Import Structures button on the toolbar You can also open the panel with the keyboard shortcut CTRL I Take a moment to study the layout of the Import panel At the top is the Look in option menu which
8. Rotate around Y axis by 90 degrees button to rotate 90 degrees to the right eV 4 Click on the Restore view button to return to the view that you saved in Step 1 lt gt Congratulations you re now manipulating structures in the Workspace Feel free to practise these operations until you are familiar with them You can always restore the original view of the molecule by clicking the Reset Workspace button NYE Maestro 9 0 Tutorial 11 Chapter 2 Starting Maestro and Viewing Molecules 12 2 6 Including and Excluding Entries in the Project Table Now that you know how to manipulate structures in the Workspace you re ready to learn how to include and exclude structures from the Workspace using Maestro s Project Table The Project Table is where Maestro stores structures that you ve imported It can also be used to manage the results of computations and store structure associated data For now though we ll just use the Project Table to control which molecules are displayed in the Workspace For more information about the Project Table see Chapter 8 of the Maestro User Manual 1 Open the Import panel by clicking the Import structures button on the toolbar 2 From the Files of type option menu choose MDL SD This action causes all files in SD format with the extension sdf to appear in the list There are many file formats used to store molecular structures and Maestro can read most of the common one
9. We now have a new entry and we will convert the structure in it to ibuprofen 3 13 Changing Bond Orders So far we haven t had to change any of the bond orders The functional groups we added already had the correct bond orders In this exercise the first thing to do is to change some bond orders Maestro has a very easy way of changing bond orders We re going to experiment with adjusting bond orders while we prepare the structure for the next step l On the Build toolbar click the Decrement bond order toolbar button a wa PL 2 In the Workspace click on the carbonyl C O bond The double bond turns into a single bond 3 On the Build toolbar click the Increment bond order toolbar button at Cl Maestro 9 0 Tutorial 31 Chapter 3 Building Molecules Using Maestro Figure 3 15 The incremented C N bond showing the valence violation 4 In the Workspace click on the C N bond between the carbonyl carbon and the nitrogen You ll see the bond order increase and the number of hydrogen atoms is automatically adjusted 5 Click again on the carbon nitrogen bond The bond is now a triple bond but the bonds to the other atoms aren t changed Maestro lets you violate the valences of atoms when adjusting bonds because it s sometimes more convenient to increase the bond order of one bond before decreasing the bond order of other bonds Before you finish changing bond orders don t forget to make sure that the va
10. and should be sent to help schrodinger com A message giving the location of this file 1s written to the terminal window More information on the postmortem command can be found in Appendix A of the Job Control Guide On Windows machine and system information is stored on your desktop in the file schrodinger_machid txt If you have installed software versions for more than one release there will be multiple copies of this file named schrodinger_machid N txt where N is a number In this case you should check that you send the correct version of the file which will usually be the latest version If Maestro fails to start send email to help schrodinger com describing the circumstances and attach the file maestro_error txt If Maestro fails after startup attach this file and the file maestro EXE dmp These files can be found in the following directory LOCALAPPDATA Schrodinger appcrash On Windows XP and Windows 2000 SLOCALAPPDATA is not set by default but should correspond to 3USERPROFILE Local Settings Application Data Maestro 9 0 Tutorial 77 78 Maestro 9 0 Tutorial 120 West 45th Street 17th Floor 101 SW Main Street Suite 1300 8910 University Center Lane Suite 270 New York NY 10036 Portland OR 97204 San Diego CA 92122 Zeppelinstra e 13 Dynamostra e 13 Quatro House Frimley Road 81669 M nchen Germany 68165 Mannheim Germany Camberley GU16 7ER United Kingdom SCHRODINGER
11. angle Figure 3 4 Selecting an angle 20 Maestro 9 0 Tutorial Chapter 3 Building Molecules Using Maestro 4 Click and hold on the Adjust button on the main toolbar and choose Delete Adjustments from the button s menu i L mm The lines and the arrow that marked the angles disappear from the Workspace 5 Finally click the Adjust button click and release immediately not click and hold to leave adjustment mode 3 4 Deleting and Labeling Atoms and Adjusting Formal Charge Acetylsalicylic acid is partially ionized in solution In this exercise you ll delete the acidic hydrogen label atoms with structural information and adjust the formal charge of an atom 1 Choose Atoms from the Delete button menu on the main toolbar x If you don t remember how to do this see the explanation on page 7 When you move the pointer into the Workspace it turns into a square with an A beside it to show that you are picking atoms which will be deleted 2 Click on the acidic hydrogen atom in the Workspace The hydrogen atom is removed If you make a mistake when you delete an atom you can always click the Undo button to restore it 3 Next choose Formal charge from the Label atoms button menu on the main toolbar 7 You ll notice that no new information appears in the Workspace that s because the formal charge of all the atoms is still zero The oxy gen atom of the acidic group needs to
12. are rotating around the z axis the one perpendicular to the screen Translating the molecule e To translate the molecule in the Workspace change its position in the Workspace place the pointer anywhere in the Workspace hold down the right mouse button and move the mouse left right up or down The pointer changes to a pair of double headed arrows perpendicular to each other to show that you are translating the Workspace structure Maestro 9 0 Tutorial Chapter 2 Starting Maestro and Viewing Molecules Zooming in or out e To zoom in on the structure place the pointer anywhere in the Workspace hold down the middle and right mouse buttons and move the mouse to the right If your mouse has a scroll wheel for a middle button you can also use it to zoom in and out The pointer changes to a magnifying glass to indicate that you are zooming e To zoom out on the structure repeat the above step but move the mouse to the left instead of to the right e It s also possible to automatically fit the structure to the Workspace so that it fills the screen To do so simply click the Fit to screen button on the toolbar Saving the view You can also save the orientation of the Workspace and return to it later Here s an example 1 First click the Save view button on the toolbar i gt 2 Next rotate the structure toward you by clicking on the Rotate around X axis by 90 degrees button oot 3 Click
13. done using the Display residues within N A of currently displayed atoms toolbar button which we ll shorten to Display residues within N A This exercise demonstrates how the Also display Undisplay and Display residues within N A toolbar buttons can be used to selectively display the structural features that you are interested in 1 Choose All from the Also display button menu This is to make sure that all atoms are displayed Note that this operation will have no apparent effect if you displayed all atoms at the end of the previous step 2 Choose Protein Side Chains from the Undisplay button menu Observe that the protein backbone ligand and water molecules are now visible but the side chains have disappeared 3 Choose Protein Backbone from the Undisplay button menu The protein backbone has disappeared and only the water molecules and the ligand remain visible in the Workspace Maestro 9 0 Tutorial 47 Chapter 4 Changing the Appearance of Structures 48 Figure 4 5 Ligand only left and ligand with residues within 4A right 4 Choose Waters from the Undisplay button menu to undisplay the water molecules Only the ligand remains visible in the Workspace Now that the ligand is the only molecule displayed in the Workspace we can use the Display residues within N angstroms toolbar button to display the active site features 5 Choose 4 A from the Display residues within N A button menu Re
14. dyall glidestutorial structures O ocg EJ lfjs_prep_lig mae gz lfjs_prep_recep mae gz Home Directo ta 50ligs mae gz HOl recmae Xx HO6_altered mae en Des refine_xp entries mae gz BL en sar_reference mae gz sar_series mae gz neo fi Working Directory Options lt lt Help _ Import all structures Xx Replace Workspace Start 1 x Fit to screen following import C End Total 1 Include in Workspace First Imported Structure ina x For Desmond files import only first structure Create groups for Files with multiple structures For SD files create titles from SD molecule name gt SD property _ Import associated data files For PDB files read alternate locations File name 1tpb mae Files of type Figure 2 3 The Import panel Maestro 9 0 Tutorial 9 Chapter 2 Starting Maestro and Viewing Molecules 10 2 5 Viewing a Structure in the Workspace After importing a molecule into Maestro you re ready to manipulate the structure in the Work space In this exercise you ll learn how to translate rotate and zoom in or out on a molecule You ll also want to note that these manipulations require the use of a three button mouse If you don t have a three button mouse or a two button mouse capable of three button emula tion you may want to consider obtaining one But first a word about the axis system used by Mae
15. guides researchers through the process of creating a pharmacophore model creating a 3D database and screening databases for matches to the pharmacophore model Prime An accurate program for protein structure prediction Prime boasts an intuitive easily mastered step by step Maestro interface that leads researchers from sequence data to finished protein models PrimeX PrimeX uses the OPLS AA force field along with state of the art technologies to refine protein crystal structures for computational drug discovery QikProp The Maestro QikProp panel allows researchers to perform extremely rapid ADME property predictions for hundreds of thousands of compounds per hour QSite Using the Maestro interface for QSite researchers can easily set up and interpret the results of QM MM calculations where reactive centers are modeled using Jaguar s accurate ab initio methodologies SiteMap SiteMap characterizes the regions near a protein binding site so that research ers can identify sites that are likely to be good targets for potential new drugs Strike Strike is closely integrated within Maestro and affords researchers a chemically aware package of statistics tools facilitating QSAR and statistical modeling Maestro 9 0 Tutorial 73 74 Maestro 9 0 Tutorial Getting Help Schr dinger software is distributed with documentation in PDF format If the documentation is not installed in SCHRODINGER docs on a computer that you have a
16. have experience with Maestro s ribbon rendering options you may wish to further customize the look and feel of protein ribbons For more information on doing so see Section 6 2 4 of the Maestro User Manual Maestro 9 0 Tutorial 53 Chapter 4 Changing the Appearance of Structures Show Ribbons for Selected Residues Show Ribbons for Displayed Residues Display Atoms Undisplay Atoms Display Side Chains and Portion of Backbone Only Delete Ribbons Secondary Structure Chain Name CA Atom Color Residue Charge Residue Property Color schemes for ribbons Residue Type Residue Position Entry Constant Color Figure 4 6 Show hide or color ribbons button menu Figure 4 7 Ribbon representation of protein with atoms right and without left 54 Maestro 9 0 Tutorial Chapter 4 Changing the Appearance of Structures 4 6 Creating and Displaying a Molecular Surface In addition to custom rendering for higher level structural features like protein backbones Maestro can also represent the surfaces that are created by groups of molecules Surfaces can represent the volume of a molecule as approximated by van der Waals radii Surfaces can also display properties such as the electron density created by programs like Jaguar In this example we ll create and visualize a molecular surface which is a smooth contiguous surface that represents the solvent accessible area presented by a structure We ll use th
17. is also capable of generating several other surface types The interfaces used to create these surfaces are generally similar to the Molecular Surfaces panel and all settings for the generated surfaces are controlled via the Manage Surfaces panel For more information on creating and viewing surfaces using Maestro see Chapter 11 of the Maestro User Manual Maestro 9 0 Tutorial Chapter 5 Measuring Analyzing and Superimposing Structures Once you re satisfied with the way that your structures appear in the Workspace you can go on to examine the structures and their properties For example you can examine the geometric differences between two conformations of a molecule by superimposing them or you can have Maestro display the hydrogen bonding interactions between a ligand and a receptor In this chapter we ll start with basic operations like measuring distances and angles before performing more complicated structural analyses For more information on the full extent of Maestro s analysis capabilities see Chapter 9 of the Maestro User Manual 5 1 Getting Ready for the Exercises in this Chapter To perform the exercises in this chapter you ll need to import the structure file analysis _exercises mae This is a multi structure file that includes several small mole cules a set of conformations created by MacroModel and a ligand that has been docked to a protein structure using Glide If you haven t already copied this file fr
18. of building these structures and is designed to introduce most of the useful facets of the Build panel rather than demonstrate the quickest possible way to build this particular molecule After you complete the exercises in this chapter feel free to rebuild these molecules without the aid of the tutorial and see how the process can differ O Y OH OH O OH O N O Figure 3 1 Aspirin tylenol and ibuprofen Maestro 9 0 Tutorial 15 Chapter 3 Building Molecules Using Maestro 16 If you make an error while working through the exercises in this chapter keep in mind that you can always undo your last action by clicking on the Undo button in Maestro s toolbar JE 3 1 Opening the Build Panel To begin the exercises in this chapter we ll display the Build toolbar then open the Build panel and survey its contents 1 Click on the Show Hide the Build toolbar button on the main toolbar A row of buttons is displayed across the top of the Workspace Some of them have icons some of them have chemical structures on them a I a i gt _ i H 0 LA H Peg LO mi E A CL RLRE Se a ee AO UIL The ones with chemical structures can be used to build molecules but you can also build molecules with a much larger variety of fragments in the Build panel which we ll now open 2 Choose Edit gt Fragments from the main window You ll see the Build Panel open along with the main toolbar and the Build toolbar it contains al
19. other capabilities of Maestro 3 19 Exporting Structures to a File Now that you ve created these three molecules you can share them by exporting them to a disk file SD format is used by a number of other programs so we ll export them in this format 1 In the Project Table click the aspirin entry then shift click the ibuprofen entry The three structures should be highlighted in yellow which means they are selected 2 In the Project Table panel click the Export Structures button on the toolbar to open the Export panel gt You can also open this panel by choosing Table gt Export gt Structures in the Project Table panel or by choosing Project gt Export Structures in the main window Notice that the Files of type option menu setting is By Extension This means that Maestro will use the extension of the file name the part after the dot to determine what kind of file to write It can recognize many of the common formats If you want to be sure that it s the right type you can always make a choice from this option menu Maestro 9 0 Tutorial 41 Chapter 3 Building Molecules Using Maestro Pm nfs zonel dy stro tutorial G O 0 A e tutorial prj B multi structure file sdf Home Directory K Launch Director S Working Director Options File name analgesics sdf Files of type MDL SD uncompressed sdf sd mol NM Cancel Figure 3 24 The Export panel 3 If y
20. the color and transparency of this surface These properties can be changed in the Display Options dialog box 7 Click the Display Options button near the bottom of the Manage Surfaces panel The Surface Display Options dialog box opens 8 Use the Transparency slider to set the transparency to 50 fifty percent transparent 9 Select Light Blue from the Color option menu 10 Click OK to accept and view the changes see Figure 4 10 The dialog box closes and the changes are applied If you want to experiment more with the display options click Apply instead The dialog box remains open and you can make whatever other changes you would like to make 11 Once you ve viewed the surface control click the square in the leftmost column of the Manage Surfaces panel to undisplay the surface 12 Close the Manage Surfaces panel by clicking the Close button Maestro 9 0 Tutorial 57 Chapter 4 Changing the Appearance of Structures 58 _ Surface Display Options Transparency Front surface j 0 Back surface J a Style Solid Mesh Dot RK Adjust together Color scheme O Property Partial Charge Constant Color Light Blue M _ Set as default Negative color Red NM Set as default O Map values from volume data Color ramp Red White Blue Minimum _ Reset Full Range Maximum Show legend in workspace Figure 4 11 The Surface Display Options dialog box Maestro
21. the structure It s marked in yellow with a magenta circle with crossed lines in it This circle marks the center around which you can rotate the frag Maestro 9 0 Tutorial 25 Chapter 3 Building Molecules Using Maestro ment if you want If you don t want to see these markers deselect Show Markers on the Local transformation button menu For now we are only going to translate the fragment 6 Drag the fragment with the right mouse button so that the oxygen atom that was attached to the ring is near the para hydrogen of the ring see Figure 3 9 If you see a menu appear in the Workspace it means that you were a bit too slow in drag ging the fragment Just release the right mouse button and press it again to drag If you pressed it while the pointer was over an atom a yellow dot appears on the atom To get rid of the dot click the Workspace selection toolbar button then click in the Workspace if you didn t finish moving the fragment click again on the Local transformation button These menus are shortcuts to various commands that you can apply to the Workspace or to the selected atoms We won t be using them but feel free to explore them Now we ll reconnect the acetate fragment to the ring 7 From the Edit menu choose Connect amp Fuse The Connect amp Fuse panel opens docked into the Workspace If you want to move it out click the button at the top right that has two rectangles in it You can then move it to
22. third party software or linked sites do not constitute an endorsement by Schr dinger LLC Use of such other third party software and linked sites may be subject to third party license agreements and fees Schr dinger LLC and its affiliates have no responsibility or liability directly or indirectly for such other third party software and linked sites or for damage resulting from the use thereof Any warranties that we make regarding Schr dinger products and services do not apply to such other third party software or linked sites or to the interaction between or interoperability of Schr dinger products and services and such other third party software Revision A October 2009 Contents Document CONVENTIONS nta eee I V Chapter 1 About This TUN ne 1 Chapter 2 Starting Maestro and Viewing MOIECUlES 3 2 1 Copying the Files You Need To Run this Tutorial no 3 2 2 Starting Maestro 5 2 3 Features of the Maestro Main WINdoW i 5 2 4 Importing a Maestro File onnnsnrssssssssssssserssrssssssssnsenrsrerenrrnnnnnnrnnn rn rr rn nr nn rr nr rn rr rn nr nr nen 8 2 5 Viewing a Structure in the Workspace rr rr nn rn arna 10 2 6 Including and Excluding Entries in the Project Table 12 2 7 Saving the Maestro Project 14 Chapter 3 Building Molecules Using Maestro 15 3 1 Opening the B
23. 02 is included in the Workspace This is the normal behavior including one entry in the Workspace excludes all others To include both sd_molecule_02 and sd_molecule_03 in the Workspace control click the square next to the entry for sd_molecule_03 Holding down the control key when including an entry just affects that entry other included entries remain included To clear the Workspace control click the square next to sd_molecule_02 and then control click the square next to sd_molecule_03 Control clicking the square for an entry that is already included in the Workspace excludes it from the Workspace This only affects whether or not the structure appears in the Workspace no atoms are deleted when excluding an entry To include sd molecule 01 sd molecule 02 and sd molecule 03 in the Work space click the square next to sd molecule 01 then shift click the square next to sd molecule 03 Shift clicking includes all entries between the two most recently clicked entries in the Workspace Clear the Workspace by clicking the Clear Workspace button on the main toolbar EB This automatically excludes all entries from the Workspace Later on we ll just say Clear the Workspace MM Project Table Scratch Project Table Select Entry Property Group ePlayer ft N bx By bl OR oe ar He Z small molecule _multi structure file Eis E sd molecule 01 T sd molecule 02 sd molecule 03 2D structure height si
24. 3 8 Adding Hydrogen Atoms to a Structure Now that the acetate group is joined back on we need to add a hydrogen atom to the place where it was removed Although you can add hydrogen atoms one by one to a structure this is unnecessarily tedious Maestro allows you to automatically add hydrogen atoms wherever they re needed with just a few clicks of the mouse In this exercise we ll add the missing hydrogen atom to the ring where we cut off the acetate group Missing hydrogen atoms can be added to any structure in the Workspace by double clicking the Add hydrogens button on the main Maestro toolbar e Double click the Add hydrogens button to build the necessary hydrogen atoms H The ring carbon atom now has a hydrogen atom attached to it For more information on the Add Hydrogens feature see Section 4 9 of the Maestro User Manual 3 9 Substituting Functional Groups in Place Mode When you built the aspirin structure you added functional groups by clicking on hydrogen atoms The new group replaced the hydrogen atom You can also substitute functional groups in the middle of a molecule provided they have similar sorts of connections For example you can convert a hydrocarbon into an ether by replacing a CH2 group with an O group In this exercise you ll convert the acetate group into an acetamide group This time you ll use the fragment on the Build toolbar These fragments can be placed in Place mode 1 On the Build too
25. 50 Another property that can be visualized using color is the B factor that was experimentally determined when the protein structure was resolved The B factor is a measure of how mobile a particular region of a protein is Side chains and loops for example tend to have higher B factors while the relatively rigid helix and sheet regions of the protein backbone tend to have lower B factors 2 To view the B factors choose Atom PDB B Factor Temperature Factor from the Color Scheme button menu The color scheme used by Maestro ranges from blue for low values through white at values in the mid 30s to red for high values above about 60 Color schemes can be useful for identifying parts of the displayed structure In a big molecule like this protein ligand complex it s hard to tell what s the protein what s the ligand and what s something else Each of these pieces is usually a separate molecule so you can color them by molecule number to tell which is which 3 Choose Molecule Number from the Color Scheme button menu 4 To return to the element based coloring scheme choose Element from the Color Scheme button menu Using the Atom Coloring panel it s possible to apply custom color schemes to structures For more information on using the Atom Coloring panel see Section 6 1 of the Maestro User Manual Maestro 9 0 Tutorial Chapter 4 Changing the Appearance of Structures 4 4 Changing the Appearanc
26. Maestro 9 0 Tutorial O Schrodinger Press Maestro Tutorial Copyright 2009 Schr dinger LLC All rights reserved While care has been taken in the preparation of this publication Schr dinger assumes no responsibility for errors or omissions or for damages resulting from the use of the information contained herein Canvas CombiGlide ConfGen Epik Glide Impact Jaguar Liaison LigPrep Maestro Phase Prime PrimeX QikProp QikFit QikSim QSite SiteMap Strike and WaterMap are trademarks of Schr dinger LLC Schr dinger and MacroModel are registered trademarks of Schr dinger LLC MCPRO is a trademark of William L Jorgensen Desmond is a trademark of D E Shaw Research Desmond is used with the permission of D E Shaw Research All rights reserved This publication may contain the trademarks of other companies Schr dinger software includes software and libraries provided by third parties For details of the copyrights and terms and conditions associated with such included third party software see the Legal Notices for Third Party Software in your product installation at SSCHRODINGER docs html third_party_legal html Linux OS or SCHRODINGER docs html third_party_legal html Windows OS This publication may refer to other third party software not included in or with Schr dinger software such other third party software and provide links to third party Web sites linked sites References to such other
27. Next we ll move one of the methyl group out of the plane Maestro 9 0 Tutorial 37 Chapter 3 Building Molecules Using Maestro 3 Choose Z from the Move button menu on the Build toolbar 4 Click twice on the methyl carbon atom in the CH CH COOH group 5 Now rotate the structure middle mouse button to see what happened Notice that the methyl hydrogens moved with the carbon atoms Groups that are attached to an atom move with the atom 6 Click the Reset Workspace button after you have looked at the rotated structure XYI Finally we ll move one of the CH hydrogen atoms in plane 7 Choose XY from the Move button menu on the Build toolbar t x a 8 Click on the CH hydrogen atom in the CH CH CH group see Figure 3 20 A purple cube appears around the atom to show that it has been selected for movement in the xy plane 9 Click somewhere between the two methyl groups The hydrogen atom moves to the new location Figure 3 20 Moving the CH hydrogen in the xy plane 38 Maestro 9 0 Tutorial Chapter 3 Building Molecules Using Maestro Moving atoms with these tools is useful when you are drawing a structure so that you get approximately the right geometry but it doesn t give structures that are close to the real structure In the next exercise you ll see how to improve the structure 3 17 Cleaning Up Structures Maestro s fragment libraries allow you to build molecules out of f
28. amp Stick button menu page 52 upper left Double clicking applies the action of the button to all atoms in the Workspace You can use a double click for all four representation buttons 4 Choose Molecule from the Draw bonds in wire button menu and click on a protein atom Observe that both the protein backbone and active site residues are displayed as wires but the ligand and the water molecule remain unchanged page 52 upper right The ligand and water molecules are now much easier to distinguish from the protein Next we ll change the representation of the ligand and the residues in the active site 5 To represent the ligand using space filling CPK atoms choose Molecules from the Draw atoms in CPK button menu and click on any atom in the ligand page 52 lower left 6 To represent active site residues as tubes choose Residues from the Draw bonds in tube button menu and click on an atom in each active site residue page 52 lower right Maestro 9 0 Tutorial 51 Chapter 4 Changing the Appearance of Structures 52 CIA Maestro 9 0 Tutorial Chapter 4 Changing the Appearance of Structures Beyond the options in the Maestro toolbar it is also possible to customize settings such as the width of tubes the size of spheres and so on For more information on changing these settings refer to Section 6 2 of the Maestro User Manual In addition the Workspace Style toolbar can be used to au
29. an select residues in the Workspace 5 Click on any one atom in the Workspace Maestro displays only the residue that contains the atom you clicked on All other atoms are undisplayed 6 Choose Protein Backbone from the Display only button menu Now only the protein backbone is visible and all other atoms are invisible 7 Choose All from the Display only button menu to redisplay all atoms The toolbar buttons behave similarly when other modes are selected from the button menus For example if you choose Molecules from the Display only selected atoms button menu you can click on any molecule in the Workspace and all other molecules will be undisplayed 4 2 2 Using the Other Display Buttons In the previous section we saw how to display only a certain set of atoms in a single operation However Maestro also allows you to display subsets of invisible atoms without undisplaying any currently visible atoms and to selectively undisplay a subset of currently visible atoms These actions can be performed using the Also display and Undisplay toolbar buttons Maestro 9 0 Tutorial Chapter 4 Changing the Appearance of Structures Fr A ad pe x T ll om Ei M k Aa ur En i 0 f i Sa ft A zi Li Figure 4 4 Protein side chains undisplayed left and entire protein undisplayed right Maestro also allows you to display atoms within a given distance of any currently displayed atoms This can be
30. ater click the Open a project button on the Maestro toolbar This will open a file chooser so you can select a project 14 Maestro 9 0 Tutorial Chapter 3 Building Molecules Using Maestro Once you ve mastered the process of starting Maestro and importing structures you re ready to begin building structures of your own Maestro s Build panel supports a wide variety of 3D building operations that can be used to easily create any reasonably sized chemical structure that you re interested in You can even build polypeptides and DNA sequences although experimentally resolved structures of proteins and other macromolecules are freely available online at http www rcsb org For protein sequences without experimentally resolved struc tures Schr dinger s Prime program can be used to predict the naturally occurring low energy protein structure In this chapter you ll work through the process of creating three familiar analgesic drugs aspirin tylenol and ibuprofen using Maestro s Build panel For a full description of the Build panel and all its various features see Chapter 4 of the Maestro User Manual If you d like to learn about using Schr dinger software to prepare experimentally resolved protein structures for calculations see the Protein Preparation Guide Building 3D structures is a multi step process and for any given structure there are many different ways to create it This tutorial suggests just one way
31. ccess to you should install it or ask your system administrator to install it For help installing and setting up licenses for Schr dinger software and installing documenta tion see the Installation Guide For information on running jobs see the Job Control Guide Maestro has automatic context sensitive help Auto Help and Balloon Help or tooltips and an online help system To get help follow the steps below e Check the Auto Help text box which is located at the foot of the main window If help is available for the task you are performing it is automatically displayed there Auto Help contains a single line of information For more detailed information use the online help e If you want information about a GUI element such as a button or option there may be Balloon Help for the item Pause the cursor over the element If the Balloon Help does not appear check that Show Balloon Help is selected in the Maestro menu of the main window If there is Balloon Help for the element it appears within a few seconds e For information about a panel or the tab that is displayed in a panel click the Help button in the panel or press F1 The help topic is displayed in your browser e For other information in the online help open the default help topic by choosing Online Help from the Help menu on the main menu bar or by pressing CTRL H This topic is dis played in your browser You can navigate to topics in the navigation bar The Help m
32. details Viewing vibration animations Both Jaguar and MacroModel allow chemists to visual ize vibrational modes using Maestro For more information on calculations see Section 3 11 of the Jaguar User Manual For information on viewing MacroModel vibra tion animations see Section 18 4 of the MacroModel User Manual Viewing electronic structure Beyond the molecular structure representations described in this tutorial Maestro also allows chemists to view the electronic structure of a mole cule as determined by Jaguar using surfaces For more information on viewing elec tronic structure information see Section3 12 of the Jaguar User Manual and Section 11 3 of the Maestro User Manual Visualizing active site properties In addition to the shape based volumetric surfaces that Maestro can calculate Maestro can also map regions of space that correspond to active site properties such as hydrophobicity For more information on mapping active sites with Maestro see Section 11 2 of the Maestro User Manual Command Scripting You can automate repetitive tasks using Maestro s command scripting tools Because all actions in the Maestro interface are automatically logged by the Command Script Editor there s no need to learn the actual commands themselves just perform the desired actions using the Maestro interface and save the command log for future use For more information see Section 13 3 of the Maestro User Manual Python Scripting Ma
33. displays the location of the directory that you ll be importing structures from By default the path is first set to your current working directory To the left are but tons to quickly change directory to either your Home Directory the Launch Directory or Maestro 9 0 Tutorial Chapter 2 Starting Maestro and Viewing Molecules the Working Directory At the center of the Import panel is a list that displays all of the files in the selected directory of the format selected in the Files of type option menu If you correctly copied the tutorial structure files to your current working directory you should see the file small_molecule mae in the list Note that as you type a complete filename in the File name text box Maestro offers selec tions and the option for auto complete 2 To import the file small_molecule mae either double click on the file name or click the file name and click Open The Import panel closes and a structure appears in the Workspace Take a moment to observe the color scheme used Carbon atoms are colored gray nitrogen atoms are col ored blue oxygen atoms are colored red and hydrogen atoms are colored white This commonly used color scheme makes it easy to identify the elements in the Workspace If you re curious about some of the options in the Import panel that weren t used you can either click on the Help button in the Import panel or see Section 3 1 of the Maestro User Manual Look in FB scr
34. e protein from the previous exercise so leave the structure in the Workspace 1 Choose Display gt Surface gt Molecular Surface in the main window The Molecular Surface panel opens docked into the Workspace 2 Delete the text in the Name text box at the top of the panel and type Tutorial Surface This text box contains the text Molecular Surface by default Molecular Surface Name Molecular Surface Atoms for surface display A Ea All Selection Previous Select Pick Entries Ir Show markers Boolean operation None Union Intersection Difference ro X All Selection Previous Select LI Pick Entries 2 L Show markers Surface context Entry Molecule Selected atoms Image quality Low Medium High Custom Probe radius 1 A Create Surface Figure 4 8 The Molecular Surface panel Maestro 9 0 Tutorial 55 Chapter 4 Changing the Appearance of Structures Below the Name text box is an area titled Atoms for surface display This is used to define the structure for which Maestro creates a surface For this exercise we ll select the protein struc ture only 3 Choose Molecules from the Pick option menu 4 Click on any atom in the protein to select the entire protein The wire bonds in the protein are temporarily colored a purple color to show that they have been selected for the surface Note that the text in th
35. e ASL text box is automatically filled in once you click on the protein ASL stands for Atom Specification Language and is a way of describing which atoms have been selected If you want to be more selec tive in the atoms you choose you can click the Select button which opens the Atom Selection dialog box For more information see Section 5 3 of the Maestro User Manual The rest of the settings can be left at their default values For large molecules such as pro teins the default image quality setting of Low is usually appropriate For small molecules higher quality settings may be useful 5 Click Create Surface to generate the molecular surface Once the surface is created the Manage Surfaces panel automatically appears Notice that you can see inside the surface where the ligand atoms are This is because the surface doesn t cover these atoms we chose to put a surface on only the protein 6 Click Close to close the Molecular Surface panel __7 Manage Surfaces Tutorial Surface molecular s5 16106 4 a SS u Import Duplicate Delete Limit Export to Map Display Options Isovalue C Display at most A CA Figure 4 9 The Manage Surfaces panel 56 Maestro 9 0 Tutorial Chapter 4 Changing the Appearance of Structures Figure 4 10 Molecular surface green at 100 transparency left and light blue at 50 transparency right Next we ll experiment with
36. e of Atoms and Bonds Prior to this section the tutorial operations were all performed using a simple wire frame representation for molecular structures In this section you ll learn how to represent atoms and bonds as spheres and tubes Not only can you make it easier to view the structure by changing the way that atoms and bonds appear but you can also use various representation modes to differentiate substructures in the Maestro Workspace The Maestro toolbar includes several buttons used to control the representation of atoms and bonds in the Workspace Structures can be represented as wires space filling CPK atoms balls and sticks or tubes Draw bonds in wire button i yy Draw atoms in CPK button a GE Draw atoms in Ball amp Stick button Draw bonds in tube button To begin this exercise you will need to ensure that you can see the ligand and the water mole cules clearly Follow the instructions below to set up the Workspace for this exercise 1 Zoom in on the ligand until it occupies a large part of the Workspace Drag horizontally with the middle and right mouse buttons 2 Right click on an atom in the middle of the ligand to center the ligand in the Workspace Now we ll start changing the representation First we ll display the structure in Ball amp Stick representation instead of wire frame and then convert the protein back to wire frame 3 Double click the Draw atoms in Ball
37. e this file manager to copy the files instead of typing the commands 4 Maestro 9 0 Tutorial Chapter 2 Starting Maestro and Viewing Molecules 2 2 Starting Maestro After you ve installed Maestro starting the program is a simple matter To start Maestro under Windows e Simply double click the Maestro icon on your desktop The Maestro interface should appear after a short delay To start Maestro under UNIX 1 Make sure that you ve set the SCHRODINGER environment variable and moved to the directory you want to work in If you haven t done this follow the instructions under To copy the files under UNIX in the previous section 2 Start Maestro by entering the following command SSCHRODINGER maestro amp The Maestro interface should appear after a short delay The amp atthe end of the line means that Maestro is run in the background and you can continue to use the terminal window Without it you would have to wait until Maestro has finished running to type any other commands This has no effect on how well Mae stro runs Here version s the 5 digit Maestro version number for example 70113 From here on the terminal and the command line are no longer used all tasks can be performed within the Maestro interface 2 3 Features of the Maestro Main Window Once you ve started Maestro you ll want to take note of various features in the Maestro main window as shown in Figure 2 1 e At the cen
38. element in the periodic table by clicking on it Clicking on an atom in the Work space then changes it to the selected element Maestro 9 0 Tutorial 33 Chapter 3 Building Molecules Using Maestro 3 15 Adding Atoms by Freehand Drawing Although the Build panel contains a variety of common fragments that can be combined to form complex molecules it is sometimes useful to build parts of your structure manually In freehand drawing mode Maestro allows you to do just that This exercise will introduce you to the freehand drawing tool as you continue to convert tylenol to ibuprofen For more informa tion on freehand drawing in Maestro see Section 4 4 of the Maestro User Manual 1 Click and hold the Draw structures button on the Build toolbar and choose C from the menu that appears f La This action sets the element type to carbon The menu allows you to choose from a vari ety of common elements including hydrogen oxygen nitrogen sulfur and phosphorous 2 Click on the carbon atom attached to the ring that only has a hydrogen attached to it see Figure 3 17 A purple box appears around the atom indicating that you ve selected this atom the active atom as the starting point for the next drawing operation 3 Click near the hydrogen atom to place a new carbon atom see Figure 3 17 You ll see that a new carbon atom is placed and bonded to the first carbon atom It s only a carbon atom it doesn t have any h
39. en Close Project Table button in the toolbar it should be indented or by clicking the Close button in the bottom right hand corner of the Project Table panel Congratulations you ve just completed a quick survey of Maestro s analys s capabilities In addition to the analys s tasks covered in this chapter Maestro can also display intermolecular steric contacts add H bond counts to the project table and align protein structures For more information on Maestro s analysis tasks see Chapter 9 of the Maestro User Manual In the next chapter you ll see an overview of some of Maestro s more advanced visualization and analysis capabilities and a brief description of other Schr dinger products Maestro 9 0 Tutorial 69 70 Maestro 9 0 Tutorial Chapter 6 Beyond the Basics 6 1 Advanced Maestro Features Beyond the Maestro operations surveyed in the previous chapters there are other advanced tasks that Maestro can perform This section offers an overview of a few such tasks explaining when they might come in handy and where to go for more information Plotting Data Using Maestro s plotting tools it s possible to examine relationships between structure related data that s saved in the Project Table For more information on Maestro s plotting tools see Chapter 10 of the Maestro User Manual For more advanced statistical analysis the program Strike is integrated into Maestro see the Strike User Manual for
40. enu also provides access to the manuals including a full text search the FAQ pages the New Features pages and several other topics If you do not find the information you need in the Maestro help system check the following sources e Maestro User Manual for detailed information on using Maestro e Maestro Command Reference Manual for information on Maestro commands e Maestro Overview for an overview of the main features of Maestro e Maestro Frequently Asked Questions pages at https www schrodinger com Maestro FAQ html e Known Issues pages available on the Support Center Maestro 9 0 Tutorial 75 Getting Help 76 The manuals are also available in PDF format from the Schr dinger Support Center Local copies of the FAQs and Known Issues pages can be viewed by opening the file Suite_2009_Index html which is in the docs directory of the software installation and following the links to the relevant index pages Information on available scripts can be found on the Script Center Information on available software updates can be obtained by choosing Check for Updates from the Maestro menu If you have questions that are not answered from any of the above sources contact Schr dinger using the information below E mail help schrodinger com USPS Schr dinger 101 SW Main Street Suite 1300 Portland OR 97204 Phone 503 299 1150 Fax 503 299 4532 WWW http www schrodinger com FTP ftp ftp schrodinger com
41. ers are excluded 3 Choose Distance from the Measure distances angles dihedrals or coupling button menu on the main toolbar P If you don t remember how to do this or are starting with this chapter see the explana tion of how to use button menus on page 7 4 Click on any atom in the Workspace A purple cube appears over the atom to indicate that you have selected it as the starting point for your measurement 5 Click on an atom that is bonded to the atom you ve just selected A dashed marker appears between the atoms and the interatomic distance measured in angstroms is displayed over the marker If you rotate the molecule in the Workspace by holding down the middle mouse button and moving the mouse you ll see that the mea surement marker moves with the structure Next we ll measure a distance between two non bonded atoms Because the measurements tool is still active the Measure distances angles dihedrals or coupling button is indented to show this with Distance selected you don t need to repeat the process of selecting Distance from the toolbar button menu 6 Click on the same atom that you clicked on in Step 4 Figure 5 2 Distance measurements Maestro 9 0 Tutorial 61 Chapter 5 Measuring Analyzing and Superimposing Structures 62 Note that the purple box appears again indicating that you ve selected this atom as the starting point for your measurement 7 Now click on a
42. estro s support for Python scripting gives users even more power than command scripting Using Python it s possible to connect discrete steps in the research pipeline and to create new interfaces that are suited to your exact needs For Maestro 9 0 Tutorial 71 Chapter 6 Beyond the Basics 72 more information on Python scripting with Maestro see Section 13 2 of the Maestro User Manual 6 2 Programs Accessible from Maestro As described in the introduction to the first chapter Maestro is more than a molecular visual ization environment it s also the interface to all of Schr dinger s chemical simulation soft ware The interfaces to these products available from the Applications menu on the main Maestro toolbar include CombiGlide CombiGlide is a structure based virtual screening program for the design of optimal focused combinatorial libraries CombiGlide significantly accelerates lead discovery and streamlines lead optimization efforts Desmond Desmond s unsurpassed speed and accuracy make possible longer time scale simulations of events of great biological and pharmaceutical importance Seamlessly integrated with Maestro Desmond provides a comprehensive set of analysis tools Epik Combining the proven reliability of Hammett and Taft methods with powerful tau tomerization tools Epik is a capable tool for adjusting ligand protonation states Glide Designed to offer the full of range of performance fro
43. ewing Molecules In this tutorial you ll be using the main toolbar a lot so it s useful to know a bit about it beforehand Notice that in Figure 2 1 most of the buttons are dimmed which means they can t be used That s because there s nothing in the Workspace The toolbar is shown to the left with all the buttons active Many of the toolbar buttons have a little triangle in the lower right corner we ll discuss those shortly The ones that don t are buttons that perform a simple action like opening a panel or changing the view of what s in the Workspace All you need to do 1s click the button to perform the action The buttons that have little triangles in the lower right corner are menu buttons If you click and hold on any of these buttons a menu appears to the lower right This menu is called a button menu You can choose an item on the menu by continuing to hold the mouse button down moving the mouse until the item you want is high lighted then releasing the mouse button The menu disappears and the item you highlighted is selected We ll call this action choosing an item from a button menu It s just like choosing an item from any other menu If you accidentally click on the wrong button just move the pointer out of the menu and release the mouse button If you chose an item that represents a group of atoms or a structural feature Atoms Bonds Molecules Residues and so on the toolbar button is
44. g Maestro 30 Figure 3 13 Selecting a dihedral angle 3 Hold down the left mouse button and move the mouse horizontally until the angle is about 0 You should see the acetyl group rotate around the C N bond as you move the mouse 4 Choose Delete Adjustments from the Adjust button menu on the main toolbar The lines and the arrow that marked the angles disappear from the Workspace 5 Finally click the button again to leave adjustment mode Congratulations You have just turned aspirin into tylenol You ve also learned how to use Grow mode replace functional groups in both Grow and Place modes and detach and reattach fragments In the remaining exercises you ll convert tylenol into ibuprofen 3 12 Duplicating a Project Entry Before we go ahead with the structural changes we need to duplicate the tylenol entry and rename it This time we ll use the keyboard shortcut for duplication 1 Make sure the tylenol entry is selected in the Project Table by clicking on its row number The entry should be highlighted in yellow Maestro 9 0 Tutorial Chapter 3 Building Molecules Using Maestro Figure 3 14 The completed tylenol structure 2 Type CTRL D Another row appears in the Project Table with the same Title 3 Now change the title to ibuprofen If you aren t sure how to do this see Section 3 6 on page 23 4 Finally click the In column of the new entry to place it in the Workspace
45. have a formal charge of 1 for a carboxylate anion Maestro 9 0 Tutorial 21 Chapter 3 Building Molecules Using Maestro 22 Figure 3 5 The ionized aspirin structure showing the formal charge 4 Click the Decrement formal charge button on the Build toolbar The button is indented When you move the pointer into the Workspace it turns into a square with an A beside it to show that you are picking atoms which will have their formal charge decremented 5 Click on the oxygen atom that the hydrogen atom was attached to You ll see that the atom is then labeled with formal charge information see Figure 3 5 6 To undisplay the atom labels choose Delete Labels from the Label atoms button menu Congratulations you ve just adjusted the geometry and formal charge of a structure In the next exercise you ll place the structure in the Maestro Project Table 3 5 Saving Your Structure to the Project Table Once you ve created your structure it s time to place it in the Project Table Placing your struc ture in the Project Table allows you to include and exclude the structure from the Workspace save it to disk copy it and add properties to it First we ll open the Project Table if it s not already open from the last chapter then add the structure to it 1 If the Project Table panel isn t open click the Open Close project table button on the main toolbar iii Maestro 9 0 Tutorial Chapter 3 Buildi
46. ibutions include easy to operate graphical user interfaces but they can be installed on a computer without removing the Windows operating system 2 1 Copying the Files You Need To Run this Tutorial To perform the exercises in this tutorial you ll need to make sure that you have the structures easily accessible These structures can be copied from the Maestro tutorial subdirectory in the installation to your own directory To copy the files under Windows 1 Click Start then click My Computer An explorer window opens 2 Move to the Schr dinger software installation This installation is not in Programs and Settings because the path to the software cannot have spaces in it It s likely to be on your C drive so start looking there if you don t know exactly where it is 3 When you get to the installation open the maestro vversion folder Here version is the 5 digit Maestro version number for example 75111 This folder should contain a folder labeled tutorial Maestro 9 0 Tutorial Chapter 2 Starting Maestro and Viewing Molecules Open another explorer window and move to the place you want to keep the tutorial files For example click Start then click My Documents You can create a folder to keep the files in if you want to Drag the tutorial folder from the first window to the second To copy the files under UNIX L Open a terminal window so that you have a command line prompt The steps to open a te
47. included Groups 2 total 1 selected Figure 5 7 The Project Table panel with the RMSD property added In addition to the abovementioned tools for superimposing using atom pairs you may have noticed that the Superposition panel contained a button labeled Select This button opens the Atom Selection dialog box an interface that allows you to select groups of atoms that can be used as input for most Maestro operations For more information on the Atom Selection dialog box see Section 5 3 of the Maestro User Manual For a more thorough description of the Superposition panel see Section 9 3 of the Maestro User Manual 5 6 Displaying Hydrogen Bonds In this exercise we ll use the results of a Glide docking job to demonstrate one of Maestro s useful analysis tools the ability to display hydrogen bonding interactions By displaying hydrogen bonding interactions it s possible to visualize the interactions that make ligand binding energetically favorable We ll begin this exercise by including the protein ligand complex in the Maestro Workspace and then use the toolbar to display and undisplay hydrogen bonding interactions 1 Clear the Workspace Click the Clear Workspace button on the toolbar 2 In the Project Table click on the square next to the entry named Protein with Glide docked ligand The protein complex appears in the Workspace The protein is colored blue and the ligand is colored orange You might want to zoom in o
48. indented after you release the mouse button This indicates that the button s action will be applied to the group of atoms you pick When you move the pointer into the Workspace it turns into a small square with a letter beside it The letter tells you what you chose on the menu The button indentation and the appearance of the pointer tells you that Maestro expects you to click on an atom pick an atom or bond in the Workspace to select some atoms The action represented by the button is then performed on these atoms To get out of this picking mode just click on the button again The button is no longer indented and the pointer has its normal appearance in the Workspace When you display the button menu again you ll see that the item you chose has a black circle beside it Other items on the button menus can be groups of atoms to which the action is applied imme diately options that are set or properties that can be applied to structures Some items open dialog boxes in which you can perform an action or select atoms to apply the button s action to Some examples of button menus are shown in Figure 2 2 Maestro 9 0 Tutorial 7 Chapter 2 Starting Maestro and Viewing Molecules 8 afa O Atoms i All Residues Protein gt Chains Protein Backbone Molecules i Protein Side Chains Entries L Waters I R HE lons All Hydrogens Nonpolar Hydrogens
49. indented appearance of the Measure distances angles dihedrals or coupling button in the toolbar with Dihedral selected you don t need to click the button again to measure another dihedral angle To measure the dihedral you click on four atoms just as for the anti conformation 10 Click the carbon atom in the terminal methyl group of the entry that you just added to in the Workspace then on the carbon atom that s bonded to it then on the remaining carbon atom and finally on the oxygen atom Maestro 9 0 Tutorial Chapter 5 Measuring Analyzing and Superimposing Structures A purple cube appears for each of the first three atoms When you click on the fourth atom the purple cubes vanish and a dihedral marker appears The dihedral measurement 63 9 s visible near the marker 11 After you ve examined both dihedral measurements delete the dihedral markers from the Workspace by choosing Delete Measurements from the Measure distances angles dihe drals or coupling button menu As you saw it s possible to view measurements on multiple Project Table entries at the same time You can display as many different measurements at the same time as you like and include angle and distance measurements along with dihedral measurements For more measurement options within Maestro choose Tools gt Measurements from the main window 5 5 Superimposing Multiple Structures Since we ve already placed multiple conformatio
50. isible again The Maestro toolbar includes several buttons for displaying and undisplaying atoms shown below This section of the tutorial will demonstrate how to use these tools You will use them again in a later part of this chapter Display only selected atoms button lt j h lt i Display only button lt i lt i Undisplay button Also display button se n Er Display atoms within N A of cur ffi rently displayed atoms button ae e 4 2 1 Using the Display Only Buttons There are two buttons in the toolbar that allow you to display only a subset of the atoms in the Workspace These buttons are the Display only selected atoms button which allows you to select individual groups of atoms for display and the Display only button which allows you to choose predefined structural feature types for display This exercise demonstrates how to use these toolbar buttons When you imported the file in the previous exercise it should have been automatically included in the Workspace If it wasn t open the Project Table panel and include the entry Protein ligand complex See Section 2 6 on page 12 for more information on including and excluding entries 1 Choose Atoms from the Display only selected atoms menu button see Figure 4 1 lt ik If you don t remember how to do this see the explanation on page 7 When you move the pointer into the Workspace you should see a yellow square wi
51. l the tools you need to perform the structure building exercises in this chapter You can also use the menu on the Show Hide the Build toolbar button to open the panel 7 The Build panel has three tabs Fragments Atom Properties and Residue Properties The Frag ments tab allows you to simply build common predefined substructures in the Workspace with one click anything from simple organic fragments to more complicated heterocycles The Atom Properties tab allows you to set element types formal charges and so on although much of this behavior can be performed using the toolbar The Residue Properties tab can be useful when building polypeptides or refining protein structures but is generally not needed when building small molecules Maestro 9 0 Tutorial Chapter 3 Building Molecules Using Maestro CM Build Atom Residue Fragments 9 Properties Properties Define grow bond Place XK Grow lan ass LI amp Pick Atoms hal Fragments Organic EEE ESE ESE Phenyl Mz ua ES fragment H7 E H je Le o H ur i y i fragments I Il Il pb HH Hy sn Tor Grow Direction forward M joining Geometry anti M Acid Figure 3 2 The Build panel 3 2 Clearing the Workspace and Building with Fragments Now that you ve opened the Build panel you can begin building the structure using Maestro s fragment libraries These pre defined groups of substructures and functional groups can be
52. lbar click on the amine fragment Maestro 9 0 Tutorial 27 Chapter 3 Building Molecules Using Maestro 28 Figure 3 11 The structure after conversion of acetate to acetamide 2 Click on the oxygen atom that connects the acetate group to the ring The oxygen atom is replaced with an NH group the acetate group is now an acetamide group 3 10 Replacing Functional Groups in Grow Mode Maestro has two modes for adding or replacing fragments in a molecule Place mode and Grow mode So far you have been using Place mode in which you click to place a fragment in the desired location In Grow mode the location of the fragment is determined by the grow bond which is displayed in the Workspace as a green arrow This mode is very useful for rapidly adding fragments to a molecule All you need to do is to click on the fragment you want to add next and it s added to the structure You can also use Grow mode to replace frag ments which is what you ll do in this exercise 1 In the Build panel select Grow A green arrow appears on the C H bond next to the carboxylate group see Figure 3 12 This isn t the place we want to add a fragment so we ll move the grow bond It s possi ble that the green arrow might be somewhere else but it doesn t matter if it is 2 Make sure that Pick is selected in the Define grow bond section and that Atoms is selected on the Pick menu 3 Click on the ring carbon tha
53. le from the installation subdi rectory maestro vversion tutorial copy it now from this directory to your working direc tory To import the file into Maestro 1 Click the Import structures toolbar button to open the Import panel i 2 Ensure that the file format is set to Maestro 3 Select the file visualization exercises mae from the Files list 4 Click Open to import the multi structure Maestro file You re now ready to begin the exercises in this chapter 1 PDB structures are experimental protein structures The data in these structures can be incomplete missing hydrogen atoms formal charges and so on The protein preparation process ensures that all atoms are present and have the correct charges and bonding patterns and can also do other tasks to clean up the structures Maestro 9 0 Tutorial 43 Chapter 4 Changing the Appearance of Structures 44 4 2 Displaying and Undisplaying Atoms One of the most common changes you might want to make to the molecular representation is to display or undisplay structural features In order to draw attention to certain parts of a molec ular structure it 1s often helpful to display only a portion of the entire structure Rather than doing so by deleting other parts of the structure th s can be done using Maestro s undisplay and display tools These tools allow you to make visible parts of the structure invisible and to make invisible parts of the structure v
54. lences are correct Now we ll set the bond orders the way they need to be 6 On the Build toolbar click the Decrement bond order toolbar button tal 7 In the Workspace click twice on the carbon nitrogen bond The triple bond turns back into a single bond The hydrogen atoms aren t added back again so the nitrogen is missing a hydrogen atom We ll add hydrogens later when we have finished changing the rest of the structure Maestro 9 0 Tutorial Chapter 3 Building Molecules Using Maestro Figure 3 16 The structure after conversion of N and O to C 3 14 Changing Elements Once you ve built a molecule it s possible to change the atoms in the molecule to atoms of a different element without deleting and then rebuilding a substructure In this exercise you ll see how to change elements using the Build toolbar This is the next step in converting tylenol to ibuprofen 1 Choose C from the Set element button menu on the Build toolbar 2 Click on the nitrogen atom then on the two oxygen atoms The blue nitrogen atom and the red oxygen atoms are replaced with gray carbon atoms changing the side chains into hydrocarbon chains No hydrogen atoms were added to the carbons we ll add these in a later exercise For less commonly modeled elements that aren t available from the toolbar you can open the Atom Properties tab in the Build panel choose Element from the Property option menu and then select an
55. m 1 s 1 total 0 0 selected Figure 3 8 The Project Table panel with the title highlighted in the duplicated entry 2 In the Project Table menu bar choose Entry gt Duplicate gt In Place Another row appears in the Project Table with the same title This isn t a problem for Maestro because the entry also has an entry ID which is unique and is used to identify the entry It also has an entry name that is normally hidden To see it choose Show Entry Name from the Property menu You can also duplicate an entry in place with CTRL D Now we ll change the title so we can tell which entry is which There s no need to change the entry name 3 Click in the Title column of the third row of the Project Table The cell background turns white and the text is highlighted in blue A cursor appears where you clicked in the text to indicate that you can edit the contents of the table cell 4 Change the title to tylenol and press ENTER The cursor disappears and the background goes back to yellow The title is now changed 3 Deleting Bonds and Reattaching Fragments Now that you have duplicated and renamed the aspirin entry you can modify the new entry to create another molecule This process can be useful when you want to make a series of mole cules that have a similar core structure but with different groups attached In this exercise you ll move the acetate group from the ortho position to the para positio
56. m extremely high through put to extremely high accuracy Glide is Schr dinger s ligand docking program Through the Maestro interface it s possible to screen millions of compounds against a target receptor and retrieve and evaluate likely hits Jaguar Emphasizing speed and accuracy Jaguar is Schr dinger s widely used software for ab initio quantum mechanical QM calculations The Maestro interface to Jaguar allows users to easily set up calculations based on the desired task and level of theory Liaison The Maestro interface for Liaison facilitates the setup and applications of linear interaction LIA calculations to predict the binding energies of lead candidates MacroModel A general purpose molecular modeling MM program MacroModel is equipped with a full range of proven computational methodologies Using the Maestro interface it s possible to set up and run anything from simple molecular minimizations to active site conformational searches MCPRO MCPRO is a highly configurable general purpose Monte Carlo simulation package for biomolecules with an easy to use interface to accommodate both novice and advanced users Relative binding affinities for protein ligand complexes can be predicted via multiple approaches Maestro 9 0 Tutorial Chapter 6 Beyond the Basics Phase Phase is Schr dinger s full featured tool for ligand based drug design and includes a step by step wizard like interface that intuitively
57. mmarized in the table below Font Example Use Sans serif Project Table Names of GUI features such as panels menus menu items buttons and labels Monospace SSCHRODINGER maestro File names directory names commands envi ronment variables and screen output Italic filename Text that the user must replace with a value Sans serif CTRL H Keyboard keys uppercase Links to other locations in the current document or to other PDF documents are colored like this Document Conventions In descriptions of command syntax the following UNIX conventions are used braces enclose a choice of required items square brackets enclose optional items and the bar symbol separates items in a list from which one item must be chosen Lines of command syntax that wrap should be interpreted as a single command File name path and environment variable syntax is generally given with the UNIX conven tions To obtain the Windows conventions replace the forward slash with the backslash in path or directory names and replace the at the beginning of an environment variable with a at each end For example SCHRODINGER maestro becomes SCHRODINGER maestro In this document to type text means to type the required text in the specified location and to enter text means to type the required text then press the ENTER key References to literature sources are given in square brackets like this 10 Maestro 9 0 Tutorial vV vi Maest
58. n The new entry should already be in the Workspace because when you duplicate a single entry it is automatically included If the square beside the tylenol entry is not filled click in the square Now you re ready to continue Maestro 9 0 Tutorial Chapter 3 Building Molecules Using Maestro 4 u A f Figure 3 9 Detaching moving and reattaching the acetate fragment 1 Choose Bonds from the Delete button menu on the main toolbar x If you don t remember how to do this see the explanation on page 7 When you move the pointer into the Workspace it turns into a square with an B beside it to show that you are picking bonds which will be deleted 2 Click on the bond between the ring and the acetate oxygen see Figure 3 9 The bond disappears and there are two fragments in the Workspace 3 Click the Delete toolbar button again to exit Delete mode Next we want to move the acetate fragment Normally when you move something in the Workspace everything moves To move this fragment and leave everything else where it is we must perform a local transformation A Choose Molecules from the Local transformation button menu on the main toolbar S Note that the button is indented to show that we are doing a local transformation 5 Click an atom in the acetate fragment This selects the acetate molecule for a local transformation You can now move the frag ment without moving the rest of
59. n the ligand and center the ligand in the Workspace To do this drag horizontally with the middle and right mouse buttons or use the mouse wheel then right click on a ligand atom Maestro 9 0 Tutorial 67 Chapter 5 Measuring Analyzing and Superimposing Structures Figure 5 8 Protein ligand complex showing hydrogen bonds between the ligand and the protein left and internal protein hydrogen bonds right 3 To display hydrogen bonding interactions between the ligand and the receptor choose Inter H bonds from the Display H bonds button menu 4 Click on any atom in the ligand colored orange to display intermolecular hydrogen bonds between that molecule and all other molecules in the Workspace You ll see that hydrogen bonding interactions are marked with dashed yellow lines 5 To display intramolecular hydrogen bonding interactions choose Intra H bonds from the Display H bonds button menu 6 Click on any atom in the protein structure colored blue to visualize intramolecular hydrogen bonds You ll see many dashed yellow markers appear among these are the hydrogen bonding interactions that form helices and sheets resulting in the overall structure of the protein 68 Maestro 9 0 Tutorial Chapter 5 Measuring Analyzing and Superimposing Structures 7 Undisplay the hydrogen bonds by choosing Delete H bonds from the Display H bonds button menu 8 Finally close the Project Table by clicking on the Op
60. ng Molecules Using Maestro Create Entry from Workspace RIE Title ionized aspirin Figure 3 6 The Create Entry from Workspace dialog box 2 Click the Create entry from Workspace button on the main toolbar gs The Create entry from Workspace dialog box opens 3 Set the Title to ionized aspirin 4 Click Create to add the structure to the Project Table The structure is added to the Project Table as an entry in the second row 3 6 Copying and Renaming a Project Entry For the next few exercises you ll need a copy of the aspirin structure that you just created We ll create a copy by duplicating the aspirin entry and renaming it 1 Make sure the aspirin entry is selected by clicking on its row number The entry should be highlighted in yellow as in Figure 3 7 to show that it is selected Project Table tutorial Table Select ae Property Group ePlayer MA kc HA 20 E _ small molecule ionized aspirin multi structure file Figure 3 7 The Project Table panel with the aspirin entry Maestro 9 0 Tutorial 23 Chapter 3 Building Molecules Using Maestro 24 Project Table tutorial Table Select Entry Property Group ePlayer HAKEN 20 Ee ie IL dI ODI 1 Ti T small molecule m ionized aspirin tylenol multi structure file 40 sd molecule 61 zum ies ESS da Mi 2D structure height za en __Clse Help Entries 6 total 6 shown 1 selected 1 included
61. ns of a molecule in the Workspace we re ready to superimpose the two structures Maestro s Superposition panel allows you to easily align two or more structures and calculate the root mean square deviation RMSD between atom pairs This can be useful when examining the results of MacroModel conformation searches comparing computational results to experimentally determined structures or any other time you might want to gauge geometric differences between multiple structures In this exercise we ll open the Superposition panel and then go on to align the conformations used in the previous exercise 1 If the two Project Table entries used in the previous exercise are not present in the Work space locate the entries in the project table click on the square for n propanol staggered and then control click on the square for n propanol anti 2 Open the Superposition panel by choosing Tools gt Superposition from the main window When the Superposition panel appears docked in the Workspace you ll see that it has a number of tabs that have controls for defining molecules and substructures that you can align We ll use the ASL tab in this example 3 Select the Create property option 4 Click on the ASL tab 5 Click All to perform the RMSD calculation for all atoms You ll notice that one of the conformations is aligned on top of the other and the RMSD value is again printed in the table at the bottom of the panel If you scroll
62. ns to increment the bond but this time we ll draw in the second bond 9 Click back on the carbon atom that s bonded to the oxygen see Figure 3 18 The bond changes from a single bond to a double bond and the carbon atom becomes the active atom Notice that even though we are drawing with oxygen the carbon atom didn t turn into an oxygen atom If you click on an atom that s already there it doesn t change to a different element That s very useful for drawing in bonds you don t have to worry about which element you have selected 10 Click again near the active carbon atom away from the other atoms see Figure 3 18 Another oxygen atom is placed New atoms are always atoms of the selected element old atoms keep their elemental identity You can also join one atom to another in Draw mode We ll do this and then undo the opera tion 11 Click on the carbon atom you placed first A bond is created to form a 4 membered ring 12 Click the Undo button on the main toolbar The bond disappears and the purple cube is now on the oxygen atom 13 Click the active oxygen atom to finish drawing Finally we need to add hydrogen atoms We could draw in the hydrogen atoms on this struc ture and feel free to do so if you like but as we saw in Section 3 8 Maestro provides a conve nient way of automatically adding hydrogen atoms wherever they re needed 14 Double click the Add hydrogens button to add the necessa
63. ny atom in the Workspace that s not bonded to the atom that you clicked on in the previous step You ll see that a new distance marker appears between the two atoms that you just clicked on You may also have noticed that the width of the original measurement marker decreased when you made the new measurement This is because the wide dashed lines simply indicate that this is the most recently measured distance Finally after measuring the distances we can remove the markers from the Workspace 8 Choose Delete Measurements from the Measure distances angles dihedrals or coupling button menu The structure remains in the Workspace unchanged and the distance markers disappear 5 3 Measuring Angles Another easily performed analysis task is angle measurement In this example we ll use the structure from the previous exercise to see that angles can be measured in much the same way that distances can be measured 1 Choose Angle from the Measure distances angles dihedrals or coupling button menu A 2 Click the oxygen of the carbonyl near the middle of the molecule Yov ll notice that a purple cube appears to indicate that you ve selected an atom to begin an angle measurement 3 Click the carbonyl carbon atom You ll see a second purple cube appear indicating that you ve selected the clicked atom to be part of your angle measurement This second atom clicked will always be the vertex of the angle that is measured
64. om SCHRODINGER maestro vversion tutorial copy it now from this directory to your working directory To import the file into Maestro 1 Click the Import structures toolbar button to open the Import panel Ensure that the file format is set to Maestro Select the file analysis_exercises mae from the list Click Open to import the multi structure Maestro file N A WwW N If the Project Table panel isn t open open it by clicking the Open Close Project Table toolbar button EE Maestro 9 0 Tutorial 59 Chapter 5 Measuring Analyzing and Superimposing Structures 60 Project Table tutorial Table Select Entry Property Group ePlayer RK MA 20 BY ied td lm OM I 9 Small Molecule 61 10 T n propanol anti 11 n propanol staggered 12 I Protein with Glide docked Ligand 2D structure height gt e Close Help Entries 12 total 12 shown 4 selected 1 included Groups 2 total 1 selectei Figure 5 1 The Project Table panel with the new entries In the Project Table panel you ll notice that several new rows have been added These rows represent new entries in the Project Table Some of these entries contain only one molecule while other entries contain multiple molecules The Project Table has an easy to use set of controls that allow you to record structure related properties present the results of calculations and include and exclude entries in the Work space You ve alread
65. ool allows you to select combinations of atoms that are a bit more complicated than those in the tutorial examples To learn more about the Atom Selection dialog box see Section 5 3 of the Maestro User Manual 4 3 Changing the Atom Coloring Scheme When working in a three dimensional modeling environment you can use color to show infor mation about a structure In most cases Maestro uses an element based coloring scheme by default In this exercise we ll use atom coloring schemes to visualize information about our protein structure Take a moment to look over the protein structure in the Workspace Right now the color scheme represents various elements in the Workspace but it can also tell you about calculated and experimental structural properties 1 Choose Atom Partial Charge from the Color Scheme button menu Fai 5 The atoms are colored by their partial charge The correspondence of the colors to the partial charges is shown in the table below The partial charge is an estimate of the real charge on an atom as opposed to the formal charge which is always an integer and is derived from valency rules These partial charges came from a MacroModel calculation Color Charge Range blue gt 0 25 aquamarine 0 15 to 0 25 green 0 05 to 0 15 white 0 05 to 0 05 yellow 0 15 to 0 05 orange 0 25 to 0 15 red lt 0 25 Maestro 9 0 Tutorial 49 Chapter 4 Changing the Appearance of Structures
66. ou want to save the file in place other than your tutorial directory navigate to the place you want to save the structure 4 Enter the name analgesics sdf in the File name text box The sdf extension tells Maestro that you want to save the file in MDL SD format 5 Click Save The Export panel closes and the file should now be saved to disk To learn more about to exporting your structures see Section 3 2 of the Maestro User Manual 42 Maestro 9 0 Tutorial Chapter 4 Changing the Appearance of Structures Now that you know how to import and build structures using Maestro you re ready to change the way structures appear in the Workspace Using Maestro s visualization tools you can color atoms change the three dimensional representation of atoms and bonds and view molecular surfaces This section of the tutorial will demonstrate how to make such changes allowing you to draw attention to important structural features and create presentation quality graphics 4 1 Getting Ready for the Exercises in this Chapter To perform the exercises in this chapter you ll need to import the structure file visualization_exercises mae This file includes a protein ligand complex originally taken from the PDB Protein Data Bank and prepared using Schr dinger s Protein Prepara tion Guide This protein ligand complex contains a protein structure a ligand and several active site water molecules If you haven t already copied this fi
67. rUCtUres 43 4 1 Getting Ready for the Exercises in this Chapter 43 4 2 Displaying and Undisplaying Atoms nennen nennen 44 4 3 Changing the Atom Coloring Scheme 49 4 4 Changing the Appearance of Atoms and Bonds 51 4 5 Displaying the Protein Backbone as a Ribbon 53 4 6 Creating and Displaying a Molecular Surface n 55 Chapter 5 Measuring Analyzing and Superimposing Structures 59 5 1 Getting Ready for the Exercises in this Chapter 59 5 2 Measuring Distances i 60 5 3 Measuring Angles u 40u404040 een 62 5 4 Measuring DIR Erra 63 5 5 Superimposing Multiple Structures 4 su44442222nnnnnnnnnnnnnnnnnnnenennn 65 5 6 Displaying Hydrogen BondSs Rn nn nn nn nn nennen rr rr rr rn nn rn rna 67 Chapter 6 Beyond the BaSICS csscsssssssssssecsssseessssesssssesssssecssseesssseesssneesssneesssneesee 71 6 1 Advanced Maestro Features rr rrrrr rr rr r rr nr rr rr RR RR Rn nn annan 71 6 2 Programs Accessible from Maestro 72 Ul 75 IV Maestro 9 0 Tutorial Document Conventions In addition to the use of italics for names of documents the font conventions that are used in this document are su
68. ragments with optimized geometries and the structures you create usually have reasonable geometries When you have been using Draw mode the structures usually need cleaning up The Build panel allows you to clean up the structure using the UFF universal force field minimizer e Click the Clean up geometry button on the Build toolbar Ce As the structure is refined a dialog box appears that says Cleanup in progress and you can see the structure changing in the Workspace When cleanup is finished notice how the func tional groups have moved see Figure 3 21 The UFF minimizer is suitable for refining manually built structures but it offers less accuracy and flexibility than the minimizers and force fields present in software such as MacroModel and it sometimes doesn t give good geometries for groups that should be planar Always check your structures after using the UFF minimizer Figure 3 21 The ibuprofen structure before left and after right cleanup Maestro 9 0 Tutorial 39 Chapter 3 Building Molecules Using Maestro 3 18 Changing the Chirality Ibuprofen is a chiral molecule The configuration at the chiral atom of the actual molecule the CH carbon atom in the CH CH COOH group is S We need to check the chirality of this atom and change it if it isn t correct First we ll label the atoms with their chirality labels 1 Choose Chirality from the Label atoms button menu on the main toolbar
69. rminal window vary slightly between operating systems but it is generally possible to right click in your desktop and select an option like New Terminal from the menu that appears Next set the SCHRODINGER environment variable This environment variable contains the path to your installation of Maestro How you set the SCHRODINGER environment variable depends on the shell used in the terminal win dow If you are using either the bash or ksh shell enter the following command export SCHRODINGER installation directory If you are using either the csh or the tcsh shell enter the following command setenv SCHRODINGER installation directory In the commands above installation directory should be replaced with the path to the directory where Maestro is installed If you re not sure which shell you re using you can type the command which SHELL which will return the location and name of the shell that you re using Change to a directory for which you have write permission cd my directory If you like create a subdirectory for the tutorial and change to that subdirectory mkdir p my subdirectory cd my subdirectory Copy the tutorial files to your current working directory with the following command cp SSCHRODINGER maestro vversion tutorial Here version is the 5 digit Maestro version number for example 75111 Many UNIX systems have a graphical file manager that operates much like a Windows system You can us
70. ro 9 0 Tutorial Chapter 1 About This Tutorial This document is designed to show you how to use the basic capabilities of Maestro in easy steps In the early parts of the book we will explain everything in great detail what to do with the mouse where to click where buttons are and so on so you aren t missing any part of the procedure At the same time we ll provide a more compact notation for explaining what to do Later in the book we ll use the compact notation with references back to the explanation and still later we ll just use the compact notation By that time you ll have learnt what it means and how to perform the actions and won t need the detailed explanation But itll always be there to refer back to This tutorial is designed for you to work through from the beginning but you can start at any of the chapters if you so desire However the explanations in the later chapter are more compact so you might have to go back to the earlier chapters to find out how to perform an action If you are reading this book online you may notice that there are words that are marked in an indigo color like this Contents These are links to other parts of the book If you click on the word in your PDF reader it takes you to the other part of the book To go back to the place you came from click the Back button in your PDF reader Try it with the word Contents above It will take you to the table of contents for this book
71. ry hydrogen atoms H Hydrogen atoms are added to all the carbon atoms that are missing them and to the sin gly bonded oxygen in the carboxylate group 36 Maestro 9 0 Tutorial Chapter 3 Building Molecules Using Maestro Figure 3 19 The hydrogen and carbon atoms to move 3 16 Moving Atoms When you ve been drawing atoms it s usually the case that they aren t in the optimum loca tion the bond lengths and angles can be far from what they are in the real structure Also when you are drawing atoms they are always placed in the same plane If you want to place atoms in a different plane you can rotate the structure and start placing them again but if they are already in place you might want to move them The Build panel provides a tool for moving atoms that have already been placed In this exercise you ll move some of the atoms so that they are in a more realistic location In the next exercise you ll use another tool to get much better structures First let s move one of the CH hydrogens out of the plane 1 Choose Z from the Move button menu on the Build toolbar E 2 Click on the CH hydrogen atom in the CH CH COOH group see Figure 3 19 Although it looks like nothing happened the hydrogen moved 0 5 away from you in the z direction each click You can rotate the structure to see what happened Click the Reset Workspace button when you have finished looking at the rotated structure
72. s 3 Double click on multi structure_file sdf to import it 4 Click the Open Close Project table button on the toolbar to open the Project Table panel iz In the Project Table you ll notice that several entries represented by various rows with text in them are highlighted in yellow These highlighted entries are the structures that 66 2 you just imported You ll also notice a tan row with a in the In column This is the label row for an entry group When you imported the structures they were added as a group named after the file they came from You can open and close the group by clicking its In column You can include the structures in the Workspace or exclude them from the Workspace by clicking on the squares to the left of the title text in the In column There is no limit to the number of entries that can be included in the Workspace A filled square indicates that the structure is currently included in the Workspace By default only the first new entry in this case sd_molecule_ 01 is included in the Workspace when you import multiple Structures 5 Include sd_molecule_02 in the Workspace by clicking the square next to its title Later on we ll just say Include entry in the Workspace Maestro 9 0 Tutorial Chapter 2 Starting Maestro and Viewing Molecules When you click the molecule that was originally in the Workspace sd_molecule_01 is excluded from the Workspace and sd_molecule_
73. sidues that have any atoms within 4 A of the currently displayed ligand are now visi ble These residues are all part of the active site and include some water molecules 6 To display the remaining water molecules without undisplaying any of the currently visi ble atoms choose Waters from the Also display button menu Observe that the ligand active site residues and waters are all visible If you want to enlarge the view of the structure click the Fit to screen button 7 To display the protein backbone without undisplaying any of the currently visible atoms choose Protein Backbone from the Also display button menu Observe that the protein backbone ligand active site residues and water molecules are all visible To view the entire structure click the Fit to screen button again Maestro 9 0 Tutorial Chapter 4 Changing the Appearance of Structures Now that you know how to operate the various tools that control atom visibility you can apply the same basic steps when working with structures of your own Keep in mind that there may be more than one way to display or undisplay any given set of atoms feel free to use whatever method works best for you We ll be using many of these controls again in a later exercise You may have noticed that most of the menus for the toolbar buttons described in the above exercises all had an option called Select When you choose this option Maestro opens the Atom Selection dialog box This t
74. stro The x axis is the horizontal axis and the y axis is the vertical axis The z axis is the axis coming out of the screen towards you this is the positive z direction Now let s try some manipulations And by the way when you do these manipulations you aren t really changing the position of the molecule It s as if you were operating a video camera and you are changing the camera angle to get a different view of the molecule Rotating the molecule e To rotate the molecule left or right around the y axis place the pointer anywhere in the Workspace hold down the middle mouse button and move the mouse to the left or right The pointer changes to an arrow going around in a circle with the letters xy above it to show that you are rotating around the x horizontal or y vertical axis e To rotate the molecule up or down around the x axis repeat the above step but move the mouse up or down You can rotate in both directions simultaneously by moving the mouse diagonally If you want to make sure you rotate only in the x direction or the y direction hold down the SHIFT key along with the middle mouse button e To rotate the molecule in the plane of the screen around the z axis place the pointer any where in the Workspace hold down the CTRL key and the middle mouse button and move the mouse to the left or right The pointer changes to an arrow going around in a circle with the letter z above it to show that you
75. t s attached to the carboxylate group then on the carboxylate carbon see Figure 3 12 The green arrow moves to the bond you just picked and is pointing towards the carboxy late If you had picked the atoms in the other order the bond would be pointing in the opposite direction The atom that the arrow head points to is the one that is replaced Maestro 9 0 Tutorial Chapter 3 Building Molecules Using Maestro Figure 3 12 Moving the grow bond 4 Click on the hydroxyl fragment in the Build panel T HT zu u The carboxylate is replaced with a hydroxyl group 5 Deselect Grow in the Build panel 3 11 Adjusting a Dihedral Angle Finally the acetyl group needs to be rotated around the C N bond becaus the methyl group is too close to the ring hydrogen We ll change a dihedral angle to do this 1 Choose Dihedral from the Adjust button menu on the main toolbar Lt I l 2 Click on the carbon atom in the ring that the nitrogen atom is attached to then the nitro gen atom then the carbonyl carbon atom and finallv the oxvgen atc m see Figure 3 13 At each click a purple box appears around the atom When you have clicked the fourth atom the boxes disappear and the angle is marked with a red line over the bonds and a turquoise arrow with the value of the angle next to it The angle should be about 180 it might be plus or minus Maestro 9 0 Tutorial 29 Chapter 3 Building Molecules Usin
76. ter of the interface is the Maestro Workspace which remains empty until you import structures build molecules or open a project e At the top of the Maestro interface is the Maestro menu bar which gives you access to all kinds of options features and programs e On the left hand side of the interface is the main Maestro toolbar all of the frequently used Maestro tasks can be performed using the toolbar Maestro 9 0 Tutorial Chapter 2 Starting Maestro and Viewing Molecules Title bar Menu bar Project Edit View Display Tools Applications Workflows Scripts Help Workspace Toolbar Status bar atoms 0 0 Entries 0 0 Res 0 Chn 0 Mol 0 Chg 0 Jobs 0 0 Auto Help area iddle xy rotate ctrl middle z rotate right xy translate right click on atom spot cente Figure 2 1 The Maestro main window e The status bar near the bottom of the window gives information about the number of atoms and molecules in the Workspace and also displays more specific structural infor mation when you pause the pointer over an atom in the Workspace e At the bottom of the window is the Auto Help area This area automatically displays a hint about the task you re doing There are other features that can be added to the main window that aren t displayed by default You can display these features using the Display menu For more information see Section 2 2 of the Maestro User Manual Maestro 9 0 Tutorial Chapter 2 Starting Maestro and Vi
77. th the letter A next to it indicating that you can select atoms in the Workspace Maestro 9 0 Tutorial Chapter 4 Changing the Appearance of Structures thy Na Atoms Residues T Protein Chains A Protein Backbone gt Molecules Le Protein Side Chains Entries e Waters Adm amp tons All Hydrogens 2 R 9 L Nonpolar Hydrogens HS H Polar Hydrogens Membrane Figure 4 1 Display only selected atoms and Display only button menus 2 Hold down the left mouse button drag the pointer over any set of atoms in the Workspace creating a dotted yellow box and let go of the left mouse button The atoms that were not within the yellow box are undisplayed only the atoms that you selected remain visible 3 Choose All from the Display only button menu see Figure 4 1 All atoms in the Workspace are displayed again Figure 4 2 Atoms selected for display left and the result right Maestro 9 0 Tutorial 45 Chapter 4 Changing the Appearance of Structures 46 Figure 4 3 Residue displayed left and protein backbone displayed right 4 Choose Residues from the Display only selected atoms button menu In a protein a residue typically refers to a single amino ac d subunit a ligand a water molecule or a cofactor When you move the pointer into the Workspace you should see a yellow square with the letter R next to it indicating that you c
78. the Project Table to the right you ll see that a property has been added that contains the RMSD value for the staggered conformation Maestro 9 0 Tutorial 65 Chapter 5 Measuring Analyzing and Superimposing Structures Superposition EJE I Entries to superimpose Included entries gt Selected entries Calculate in place no transformation A 40 I 3 39 2 38 Delete Delete All 1 Pick atom pairs Show markers Superimpose Atom Pairs RMSD Figure 5 5 The Superposition panel Maestro can also calculate a root mean square deviation RMSD for structures without aligning them This capability is useful when you want to compare two structures in the context of another structure such as two ligands docked to a receptor To calculate the RMSD without aligning the structures select the Calculate in place no transformation option Figure 5 6 The superimposed propanol conformers 66 Maestro 9 0 Tutorial Chapter 5 Measuring Analyzing and Superimposing Structures Project Table tutorial Table Select Entry Property Group ePlayer 20 La By bl OR 20 Hee erden Ci Small Molecule 01 E n propanol anti 0 000000e n propanol staggered 1 039645 Protein with Glide docked ligand 2D structure heig ht A Close Close Help Help Entries 12 total 12 shown 4 selected 2
79. tomatically apply molecular representations or styles to the Workspace see Section 6 5 of the Maestro User Manual 4 5 Displaying the Protein Backbone as a Ribbon In addition to representing atoms and bonds using 3D features Maestro can also represent protein backbones using three dimensional ribbons Ribbons can be turned on or off using the Show hide or color ribbons button on the Maestro toolbar In this exercise you ll represent the protein backbone using a ribbon 1 Click the Fit to screen toolbar button so you can see all of the protein 2 From the Show hide or color ribbons button menu choose Show Ribbons for All Resi dues The protein is now represented by ribbons that trace the protein backbone instead of atoms but the ligand and the water molecules remain in their previous representation 3 Choose Display Atoms from the Show hide or color ribbons button menu The protein atoms reappear with the ribbons displayed as well Observe that the ribbon follows the protein backbone 4 Choose Delete Ribbons from the Show hide or color ribbons button menu The ribbons disappear leaving the atoms on display The default coloring scheme for ribbons is to color according to residue position As you follow the ribbon along you ll see the colors progress through the spectrum as the residue number increases The menu on the ribbons button includes alternate coloring schemes that you can select Once you
80. ture into other molecules Figure 3 3 The completed aspirin structure Maestro 9 0 Tutorial 19 Chapter 3 Building Molecules Using Maestro 3 3 Adjusting Angles Some of the angles in the structure you ve just built don t look quite right In this exercise we ll adjust the C O C angle of the ester to make the structure look a bit better 1 Click and hold on the Adjust button on the main Maestro toolbar not the Build toolbar and choose Angle from the menu that appears Hj If you don t remember how to do this see the explanation on page 7 Notice that the pointer changes to a yellow square with an A beside it to indicate that you are picking atoms in this case to define the angle 2 Click on the carbon atom in the ring then the oxygen atom then the carbon atom of the carboxylate see Figure 3 4 At each click a purple box appears around the atom When you have clicked the third atom the boxes disappear and the angle is marked with a green line over the bonds and an orange arrow with the value of the angle next to it see Figure 3 4 3 Hold down the left mouse button and move the mouse left or right until the angle is about 120 this is called dragging horizontally with the left mouse button You ll see the angle and its value change as you move the mouse The atoms that move are the ones attached to the last atom you picked in Step 2 You can also use the mouse wheel to change the
81. uare with an AIB beside it The square is the target area when an atom is inside the square and you click that atom is selected for the operation you are doing Once you click the hydrogen atom is replaced with a carboxylic acid group Now you have a benzoic acid molecule in the Workspace To complete the structure of aspirin we need to add an acetate group We can do this by adding the other carboxylic acid group and a methyl group in two steps Click on the other carboxylic acid fragment whose O H bond is divided by a curved line Maestro 9 0 Tutorial Chapter 3 Building Molecules Using Maestro 9 Click on the ring hydrogen atom nearest to the OH of the acid group as indicated in the figure to the right The acid is added to form an ester but it is a formate ester not an acetate ester The last step is to add a methyl group in place of the formate hydrogen 10 Click on the methyl fragment H da H 11 Now click on the hydrogen of the formate group as indicated in the figure to the right DO 4 12 The formate group is converted into acetate You should now have a structure that looks like the one in Figure 3 3 below Congratulations You ve just successfully built aspirin acetylsalicylic acid in a few easy steps using Maestro s fragment library In the following exercises you ll see how to adjust the positions of the atoms in a molecule and transform this struc
82. uild Panel 16 3 2 Clearing the Workspace and Building with Fragments 17 3 3 Adjusting NOIGS unse nee 20 3 4 Deleting and Labeling Atoms and Adjusting Formal Charge 21 3 5 Saving Your Structure to the Project Table 22 3 6 Copying and Renaming a Project Entry 23 3 7 Deleting Bonds and Reattaching Fragments 24 3 8 Adding Hydrogen Atoms to a Structure 27 3 9 Substituting Functional Groups in Place Mode 27 3 10 Replacing Functional Groups in Grow Mode 28 3 11 Adjusting a Dihedral Angle nn nr r rr rn nr rn rn rr rn rr rn rna 29 3 12 Duplicating a Project Entry nnssosmnssssssrsrrrreserseeeeeerennrnnnennnnnnnn nn rrr nr rr nr rn rr rr rn rr rn rna 30 3 13 Changing Bond Orders 31 Maestro 9 0 Tutorial Contents 3 14 Changing Elements i 33 3 15 Adding Atoms by Freehand Drawing nr nn rna 34 3 16 TMOVING ATOMS inneren 37 3 17 Cleaning Up Structures ssessssssesesrerrrrrrssrseneeenerrrrrrrrrrnrrrrnr rr rr r rr rr rr nr nr enn RAR RR nn annen 39 3 18 Changing the Chirality nssnnssssssssssseesrrrrrrsrssnesenerrrrsrrrrenenrrrrrrrrr rr rr nr rr rr rr rr rr RR n nan 40 3 19 Exporting Structures to a File inr r rr rr nr nr nana 41 Chapter 4 Changing the Appearance of St
83. where you want it To put it back in the Workspace click the docking button again Note that the markers disappear and the Local transformation button is no longer indented the mode has been turned off by this panel 8 Make sure that Pick to define atom pairs and Show markers are both selected 9 Click on the ring carbon atom in the para or 4 position then on the singly bonded oxy gen atom of the acetate fragment see Figure 3 9 Connect and Fuse ex Connect or fuse atoms __________ 19 3 x a oc D DL T Du mt 3 a Li Show markers ie 3 Connect luotaa dl Fuse Close Help Figure 3 10 The Connect amp Fuse panel 26 Maestro 9 0 Tutorial Chapter 3 Building Molecules Using Maestro A purple box appears around the carbon atom on the first click On the second click a green dotted line appears between the two atoms see Figure 3 9 In the Connect or fuse atoms list in the Connect amp Fuse panel the atom numbers of the two atoms are displayed 10 Click Connect A bond appears between the acetate oxygen and the ring carbon and the hydrogen that was attached to the ring is deleted The methyl group of the acetate is very close to the ring We will adjust the structure later If you want to connect two molecules with more than one bond you can select more atom pairs When you click Connect a bond is created for each atom pair
84. y done some of these operations in earlier chapters of this tutorial The exercises in this chapter will walk you through any necessary Project Table manipulations but for more information on the Project Table see Chapter 8 of the Maestro User Manual We Il be using the Project Table quite a bit in these exercises so we re going to leave it open If it gets in the way you can move it or you can close it and re open it when you need to use it again To close the Project Table panel click the Open Close Project Table button in the toolbar it should be indented or click the Close button in the bottom right hand corner of the Project Table panel You re now ready to begin the exercises in this chapter 5 2 Measuring Distances One simple analysis task is to determine the distance between two atoms These can be any two atoms bonded or non bonded In this example we ll use the Measure distances angles dihedrals or coupling button on Maestro s toolbar to determine bonded and non bonded inter atomic distances on a structure that has been optimized using Jaguar To begin we ll make sure that the appropriate Project Table entry is included in the Work space Maestro 9 0 Tutorial Chapter 5 Measuring Analyzing and Superimposing Structures 1 In the Project Table find the entry named Small Molecule 01 2 Click the square in the In column for the entry to ensure that this entry is included in the Workspace and all oth
85. ydrogens attached to it We ll add those later Figure 3 17 Adding a carbon atom by drawing 34 Maestro 9 0 Tutorial Chapter 3 Building Molecules Using Maestro 4 Click again on the new carbon atom The purple box disappears to show that you ve finished drawing at th s location We need to add a carboxylic acid group to the carbon atom We could do this with the frag ments but this time we ll do it by drawing 5 Click on the same carbon atom as you clicked on in Step 2 see Figure 3 18 The purple box around the atom reappears 6 Click near this carbon atom but away from the carbon and hydrogen atoms see Figure 3 18 Another new carbon atom is placed and bonded to the first carbon atom Now we ll change the element we re drawing with to oxygen so we can draw the acid group 7 Choose O from the Draw structures button menu on the Build toolbar f La Notice that the purple box disappeared from around the carbon atom when you changed elements This indicates that drawing is no longer active and you have to pick an atom to start drawing again Figure 3 18 Completing the carboxylate group by drawing Maestro 9 0 Tutorial 35 Chapter 3 Building Molecules Using Maestro 8 Click on the carbon atom you just placed then click near the active carbon atom see Figure 3 18 A red oxygen atom appears bonded to the carbon atom but the bond is only a single bond We could use the toolbar butto
86. yl group in the molecule and click on the carbon atom in that group A purple cube appears indicating that you ve selected this atom to be used as part of the dihedral measurement Maestro 9 0 Tutorial 63 Chapter 5 Measuring Analyzing and Superimposing Structures 64 Figure 5 4 Measuring a dihedral angle 5 Next click on the carbon atom that is bonded to the one you clicked on in the previous step After doing so another purple cube appears 6 Click on the one remaining carbon atom in the structure A third purple cube appears 7 Finally click on the red oxygen atom A marker is superimposed over the structure and the measurement 180 is displayed over the marker It might be 180 instead of 180 After measuring the dihedral angle of the anti conformation we ll include the staggered conformation in the Workspace and measure the corresponding dihedral angle 8 Locate the entry n propanol staggered in the Project Table 9 Control click click while holding down the CTRL key the square next to the entry name to include this entry in the Workspace You ll notice that control clicking makes the staggered entry appear in the Workspace next to the anti entry rather than replacing it This is because control clicking has no effect on the inclusion of other entries it only affects the entry you are working with Because the measurement tool is still active indicated by the

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