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1. Figure 34 Preparing molecules Within all preparation types the following four different possibilities are available see Figure 34 Always Unconditionally performs the preparation by MMV Never Skips the preparation If Missing The preparation will only be performed if no knowledge is already present e g if bond orders exist in the Mol2 file bond orders are not assigned by MMV However if bond order information is not included MMV will assign it Remove Tries to remove preparation e g if Assign bond orders is set to remove all bond orders will be set to single bonds If Create explicit hydrogens is set to remove all hydrogen atom are removed molegro molecular viewer user manual 3 Preparation page 48 101 Notice The preparation options Always Never If Missing Remove applies to each individual molecule not each individual bond or atom For instance setting Assign bonds to If Missing results in covalent bonds being created for molecules not containing any bonds at all while molecules with bond information will preserve their bond assignments Likewise setting Create explicit hydrogens to If Missing will not add additional hydrogens to molecules containing e g polar hydrogens only In this case Always should be used if all hydrogens should be created This option allows to determine which atoms are connected covalently bound Two atoms are connected if the
2. molegro molecular viewer user manual 2 User Interface page 27 101 The Create Backbone Visualization dialog allows you to select which proteins or protein chains the backbone should be visualized for Two main graphics styles can be used The Cartoon style visualizes the secondary structure of the protein s using arrows to represent beta sheets and helical lines for alpha helices see Figure 19 Figure 19 Cartoon graphics style If the Tube graphics style is used the backbone is visualized as a spline a piecewise parametric polynomial curve interpolating the positions of the alpha carbons in the backbone see Figure 20 molegro molecular viewer user manual 2 User Interface page 28 101 Figure 20 An example of a protein backbone using the Tube graphics style It is also possible to set the color scheme for the backbone Color by structure colors the backbone based on the secondary structure information alpha helices are colored yellow beta sheets are colored blue and coil is colored gray Color by residue position colors the backbone based on the residues order of occurrence creating a rainbow color effect Color by chain colors each individual protein chain in a different color Color by atom colors the backbone by using the currently shown color of the protein backbone atoms the color used is taken from the C alpha atom On the advanced panel the Color interpolation check box allows you to determine
3. GUI Commands SLAB near far Creates a slab slicing of the 3D world Notice The Clipping Planes dialog is easier to use QUALITY value Sets OpenGL rendering quality from O to 10 LIGHT number on off ambient diffuse specular x Ly z Sets OpenGL light sources FOG LINEAR near far FOG EXP EXP2 exponent FOG OFF Sets OpenGL fog COLOR protein pose ligand water cofactor fixed cpk hbond hbond2 interaction interaction2 lt r g b Sets the color style of specified object For more information about color styles see the Visualization Settings dialog section STYLE protein pose ligand water cofactor vdw fixed stick wireframe none atomScale bondScale lineWidth Sets the visualization style of specified object The last parameter lineWidth is only used in wireframe mode and is the line width in pixels For more information about graphical styles see the Visualization Settings dialog section molegro molecular viewer user manual 12 Appendix VI Console Commands page 98 101 Determines perspective projection mode Angle is the PROJECTION perspective field of view angle for perspective projection orthogonal angle For more information see the Visualization Settings dialog section BACKGROUNDCOLOR rgb Sets the background color LABELCOLOR rg b Sets the labelling color CAVITYCOLOR r g b Sets the cavity c
4. 12 47 47 275 Process spawned 13 21 35 933 Automatic optimization of protein and ligand hydrogen postions This can be toggled in the preferences dialog 13 21 36 201 Evaluating molecule XK2_263 A Figure 45 The Ligand Map window At the top of the Ligand Map window it is possible to choose between the currently shown molecule and whether to hide other ligands and poses It is possible to select atoms synchronously in the 2D and 3D window by clicking on them It is also possible to invoke the standard context menu by right clicking on an atom This makes it possible to e g change atom properties By clicking on the Show Interactions map the interactions between the current ligand pose and the receptor is shown These interactions are the ones reported by the Ligand Energy Inspector It is possible to press the Show L E Inspector button which will open the Ligand Energy Inspector and make it possible to adjust the scoring function settings or change the scoring function By default only hydrogen bond interactions are shown It is possible to show electrostatic interactions and steric interactions as well by checking the respective checkboxes It is also possible to set a minimum interaction threshold for each type of interaction Raising the threshold slider limits the number of interactions shown The specific value of the minimum interaction threshold will be displayed in the statusbar of the main window when molegro mol
5. Enis D D E prp r t D All cos m 9 T 6 t E ic ligand je ligand flexible bonds The double summation is between all atom pairs in the ligand excluding atom pairs which are connected by two bonds or less The second term is a torsional energy term parameterized according to the hybridization types of the bonded atoms see Table 5 O is the torsional angle of the bond Notice that this angle is not necessarily uniquely determined The average of the torsional energy bond contribution was used if several torsions could be determined The last molegro molecular viewer user manual 9 Appendix III MolDock Scoring Function page 87 101 term Eciash assigns a penalty of 1000 if the distance between two heavy atoms more than two bonds apart is less than 2 0 A Thus Eciasn term punishes infeasible ligand conformations Oo m A sp sp 0 0 6 1 5 sp sp M 3 3 0 sp sp 0 0 2 3 0 Table 5 Torsional parameters the sp sp term is not enabled by default After MVD has predicted one or more promising poses using the MolDock score it calculates several additional energy terms All of these terms are stored in the DockingResults mvdresults file at the end of the docking run The rerank score is a linear combination of these terms weighted by the coefficients given in the RerankingCoefficients txt A mvdresults file is not meant to be interpreted or inspected manually Instead it should be
6. concatenated using a semi colon Notice The IDs of molecules are based on the order of occurrence in the corresponding Workspace Explorer category For instance ligand molecules listed in the Ligands category begins with index 0 with increments of 1 i e 0 1 2 3 If molecules are removed from the workspace the IDs of the molecules are changed to follow the new order of occurrence in the list molegro molecular viewer user manual 12 Appendix VI Console Commands page 95 101 Command Description Set active or reference ligand A lot of operations e g SET active reference some surfaces are only performed on the active ligand targetligand The reference ligand is used to calculate RMSDs while docking Export as Mol2 or PDB A File export dialog is opened for EARGAT ae SCE ES selection of a filename SURFACEDIALOG Shows the Surface dialog PREPAREDIALOG Shows the Preparation wizard LABELDIALOG Shows the Label dialog Downloads PDB with key 4 letter code from the GETPDB lt key gt Protein Data Bank ALIGN ae id fid2 Aligns atom id1 id2 id3 in MoleculeTarget1 with atom id1 id2 id3 in MoleculeTarget2 MoleculeTarget2 id1 id2 id3 SHOW CATEGORY f lt category gt Shows or hides Workspace Explorer category with given name HIDEIGATEGORY lt area ONM CATECOR alee REMOVE OBJECT id Removes a 3D object from the world REMOVE moleculetarget Removes an ob
7. ligands and poses are not automatically shown in the Visualization Window if the number of molecules imported exceeds 50 for each category molegro molecular viewer user manual 3 Preparation page 46 101 Import Molecules Import Preparation Wamings 1 Select which molecules to import E 479 33 atoms 1004 25 atoms 1011 46 atoms 1012 46 atoms 1013 45 atoms 1042 22 atoms 1199 43 atoms 1424 16 atoms 1460 26 atoms 1482 43 atoms 1614 74 atoms 1684 30 atoms M1894 192 stamel Specify ligand range from E to 2088 Import small molecules as Ligands Replace or add to workspace Add to current workspace C Import cofactors as ligands Figure 33 Import Molecules dialog When all relevant molecules have been imported the molecules can be automatically prepared see next section MMV automatically tries to identify cofactors a molecule is considered a cofactor if it has less than 5 heavy atoms or its name is included in a list of common cofactor names like HEM SO4 PO4 If this is not desired it is possible to override cofactor recognition by checking the Import cofactors as ligands option 3 2 Automatic Preparation Some molecular file formats support information about bond type and charge e g Mol2 while others do not e g PDB In order to maker proper predictions it is important that the structures have been properly prepare
8. non relevant parts of the complex in order to make the visualization faster Cropping is described in Section 2 10 The visualization engine is highly configurable Molecules can be drawn as lines wireframe ball and sticks capped sticks and space fill CPK molegro molecular viewer user manual 2 User Interface page 13 101 1STP mvdml Molegro Molecular Viewer PB File Edit view Rendering Preparation Tools Window Help i a Q re X X Hydrogens Fog Hide Residues Workspace Explorer x Items Options Workspace New 4 Ligands 1 H O Proteins 1 Surfaces 1 Properties Property Figure 5 Visualization of Biotin 1STP in capped stick style and electrostatic protein surface Notice Ball and stick is the preferred style for handling preparation of ligands since the visualized bond shows bond order and is color coded to display whether the bond is set rigid brown or red or flexible green molegro molecular viewer user manual 2 User Interface page 14 101 41S1P mydml Molegro Molecular Viewer File Edit View Rendering Preparation Tools Window Help G p w S E X e Hydrogens Fog Hide Residues Workspace Explorer x Items Options Workspace New Backbones 1 Interactions 7 Ligands 1 Active BTN_300 Proteins 1 O Surfaces 1 Properties x Property Value Figure 6 Main window showing different visualization styles
9. using Preparation Search Space Setup by using the context menu on the the search space item in the Workspace Explorer s Constraints category or by using the context menu on any atom or selection in the 3D view and selecting Set as center of search space The Hide Residues dialog see Figure 9 allows you to hide residues outside of a user defined sphere this can for example be used to show only the relevant residues near the binding site of the protein It is possible to set the center to of the sphere to the following objects if they are part of the workspace The center of the protein s the center of the Active Ligand the center of the Reference Ligand the center of any cavity in the workspace the center of the currently defined search space or the center of a selection of atoms if any The residues are dynamically shown hidden when the Sphere radius slider is moved The lower pane of the Hide Residues dialog allows you to restrict the types of residues shown by toggling the appropriate button If a given residue type is not contained in the sphere defined in the panel above the button corresponding to the type will be grayed and can not be toggled molegro molecular viewer user manual 2 User Interface page 18 101 Select Which Residues to Hide Hide residues outside of a sphere with Sphere center Stic Sphere radius A J 11 Only show the following residue types Asp Leu Lys Met Tp Va _
10. Atoms Total Elntra All atoms 46 235 957 0 47611 le Copy tables to clipboard Figure 39 The Ligand Energy Inspector Using the Ligand pose combo box it is possible to browse through the ligands and poses available in the Workspace To avoid visualization of other ligands and poses when inspecting a molecule you can toggle on the Hide other ligands poses check box Besides inspecting the various energy contributions it is possible to perform various actions using the Action drop down menu a Style Ligand Atoms by Energy This will scale the radius of the ligand atoms proportionally to their energy contribution Doing this makes it possible to get a visual overview of the important parts of the ligand a Style Protein Atoms by Energy As above this scales the protein atoms according to their energy contributions Notice that protein atoms not interacting with the ligand are completely hidden To make all protein atoms visible again toggle the Hide Residues toolbar button molegro molecular viewer user manual 5 Analyzing Docking Results page 63 101 a Style Water Atoms by Energy This style makes it possible to get a visual overview of important interactions between water molecules and the ligand The radius of the water atoms is scaled proportionally to their energy contributions Water molecules with favorable interactions with the ligand are colored green and unfavorable interactions are colored red Water molecul
11. BTN_300 lt Name Ligand MolDockScore Rerank Score AMSD HBond 136 795 115 526 108 464 89 7999 110 819 110 551 0 429866 47688 1 24659 73 0978 2 26061 66 3633 6 73971 46 7168 2 52896 Sorting criteria C Dynamic update notice disables multiple poses selection C Only show top 1 poses for each ligand 1st Rerank Score v 2nd MolDockScore I 3rd None Pressing OK will keep 1 and ignore 5 poses Figure 36 Pose Organizer dialog The Settings Tab Pane of the Pose Organizer can be used to customize the Pose Organizer see Figure 37 molegro molecular viewer user manual 5 Analyzing Docking Results page 57 101 Pose Organizer 20 poses Show hydrogen bonds _ Orient hydrogens to optimal position C Show electrostatic interactions _ Display only residues close to ligand slow Show matching receptor configuration Re evaluation of poses Ranking Score coefficients VN MVD Trunk Src Misc Data RerankingCoefficients bt Binding Affinty coefficients MVD Trunk Sre Misc Data BindingEnerayCoeffcients bt Recalculate Energies Pose Name The name of the ligand the pose was created from The file the pose was loaded from if any v a Add descriptor from regression model rein OC w kooo anne Tse Figure 37 Pose Organizer settings The Dynamic Update Panel The top panel Dynamic update chooses how
12. Backbone only Figure 9 Hide residues dialog The Backbone only check box can be used to toggle whether side chains are visible or not The Hide Residues dialog can be invoked by pressing the Hide Residues button in the MMV Toolbar In order to show all protein residues again select the Hide Residues button on the MMV Toolbar Cropping It is possible to delete molecules from the workspace in order to remove non relevant regions To crop molecules invoke the Hide Residues dialog and adjust the visible sphere to the desired size before clicking the Crop Molecules button A dialog will show which structures will be kept the checked molecules and which will be discarded Notice that proteins are cropped on a per residue basis residues outside the cropping sphere will be discarded All other molecule types are kept or discarded in their entirety The Workspace Finder located in the MMV Toolbar see Figure 11 allows you to quickly search for molecule names and residue atom IDs in the workspace When a name or ID number or part of it is typed in the search box the Workspace Finder will present a list of matches a maximum of 30 matches is returned It is also possible to search in atom coordinates by prepending the search with a e g searching for 1 23 will return atoms where one of the coordinates starts with 1 23 molegro molecular viewer user manual 2 User Interface page 19 101 1STP mvdml Molegro Mole
13. For the PLANTS Score the following options are available Include hydrogens in torsion term toggles whether or not hydrogens should be included when calculating the Tripos torsion potential see Appendix IV PLANTS Scoring Function for details about the PLANTS scoring function The Use original Plants setup option toggles between original Plants setup using PLANTS specific binding penalty terms and ignoring entries with dummy Tripos atom types in Tripos torsion potential and MMV MVD implementation of PLANTS score using another binding penalty term and molegro molecular viewer user manual 5 Analyzing Docking Results page 69 101 including dummy Tripos atom types in Tripos torsion potential See Appendix IV PLANTS Scoring Function for details about the different binding penalty terms available for the PLANTS scoring function It is also possible to toggle on Displaceable water evaluation and set the corresponding entropy reward if that option was used during docking Ligand Energy Inspector Ligand pose XK2_263 v C Hide other ligands poses Action v Ligand Targets Total Energy Settings Scoring function PLANTS Score v Include hydrogens in torsion term C Use original Plants setup Displaceable water evaluation C Displaceable water Entropy reward for each water displaced Re evaluate Copy tables to clipboard Figure 43 Settings tab page for PLANTS Score mol
14. The Create Label dialog makes it possible to label different object levels atoms bonds molecules or residues The labels can be chosen from a list of standard templates or constructed from a list of available variables using the Advanced tab molegro molecular viewer user manual 2 User Interface page 24 101 Create Label Label Type Atom Template PDB Atom Name and PDB Index Tana C Only selected atoms Label Expression a O Water 0 84 PDBNAME PDBID Proteins 1 1 Enter label expression in the combobox above Variable names will be substituted when evaluated Variables can be inserted from the list below Variables ELE Element number Etot Total energy FC Formal Charge a LO OUR Uhand Annnnkarldannre gt Insert in Label Expression Figure 15 Advanced label expression dialog Labels will occur in the Labels category in the Workspace Explorer assigned in groups one group for each molecule Labels can be removed or hidden using the context menu or by pressing the labels tool bar button 2 18 Creating Molecular Surfa Surfaces can be created for all molecular objects and subsequently customized In MMV surfaces are created by probing points on a uniformly spaced grid It is possible to adjust the grid resolution Resolution and probe size Probe Radius under Advanced settings Two types of surfaces are available Expanded Van der Waals this i
15. The easiest way to get acquainted with the different drawing modes is to try the preset modes listed in the Rendering menu or to use the Visualization Settings dialog to inspect and modify visualization settings described in Section 2 21 molegro molecular viewer user manual 2 User Interface page 15 101 Navigating the 3D World Mouse actions available in the 3D world Function Action Zoom By pressing both mouse buttons and moving up and down By using scroll wheel By using shift and left mouse button Free Rotation Dragging mouse cursor while holding left mouse button down Drag Atom Rotation While holding mouse over an atom Dragging mouse left mouse button down will force the atom to follow the mouse cursor Free Translation Dragging mouse cursor while holding right mouse button down Show Context Menu Click and release right mouse button All rotations are centered about the rotational center This center can be chosen by invoking the context menu on an atom right mouse button click and selecting Set as Rotational Center Another option is to choose Fit to Screen from the Workspace Explorer context menu Fit to Screen will set the rotational center to the center of the bounding box enclosing the chosen molecule If Fit to Screen is invoked from the MMV Toolbar or from the Visualization Window context menu the new rotational center will be the center of the bounding box enclosing all visible mol
16. Torsions RMSD MW LE1 LE3 Hbond Similarity Score Electro Hbond and Heavy Atoms but a few terms are renamed in order to better fit the column layout and for clarity molegro molecular viewer user manual 5 Analyzing Docking Results Column Name Description Name The internal name of the pose a concatenation of the pose id and ligand name Ligand The name of the ligand the pose was created from Workspace The workspace mvdml file containing the protein Filename The file the pose is stored as only available when inspecting docking results from a mvdresults file MolDockScore Evaluated after post processing This is the Energy term in a mvdresults file Rerank Score The reranking score arbitrary units Plants Score Evaluated before post processing only when using Plants This is the PlantsScore term in a mvdresults file RMSD The RMS deviation from a reference ligand if available Interaction The total interaction energy between the pose and the target molecule s This is the E Inter total term in a mvdresults file Cofactor The interaction energy between the pose and the cofactors This is the E Inter cofactor ligand term in a mvdresults file Protein The interaction energy between the pose and the protein This is the E Inter protein ligand term in a mvdresults file Water The interaction energy between the pose
17. and selecting the Set Tripos Atom Type menu option By default MMV automatically assigns Plants atom types Donor Acceptor molegro molecular viewer user manual 3 Preparation page 50 101 Both Nonpolar Metal before docking with PLANTS Score using the rules described in KORB 2009 However it is also possible to manually assign the Plants atom type by right clicking on the atom in question and selecting the Set Plants Atom Type menu option Notice Plants atom types are not defined for hydrogen atoms The Set Hydrogen Count menu option can be used to set the number of explicit hydrogens attached to the highlighted atom Currently the MVD scoring function MolDock Score see Appendix III for more details uses partial charges assigned when running the Preparation dialog However the assignment of charges is based on standard templates and charge assignments can be missing in some cases It is possible to manually assign partial charges to atoms by right clicking on the atom in question and selecting the Set Partial Charge menu option Bond orders can be manually assigned by right clicking on the bond in question and selecting the Set Bond Order menu option Notice that bonds are not visible in some visualization styles The most suitable view is the ball and stick style which can be set from the Rendering menu in the menu bar Flexible torsions in the ligand can manually be set rigid or flexible by right clicking on a bon
18. at a time In return it offers the possibility to visualize different interactions for molegro molecular viewer user manual 5 Analyzing Docking Results page 55 101 the current selected pose e g hydrogen bonds Even though Dynamic Update is a single selection mode it is possible to ock poses which keeps them visible even when not selected A pose can be locked by using the context menu on its entry in the table and selecting Lock or Unlock Locking is purely a visualization aid and has no other consequences for the pose When inspecting poses obtained from different ligands the Only show top option can be used to focus on the most promising poses for each ligand The selection of the top poses are based on the currently chosen Sorting criteria Pressing the Open checked poses in Data Analyzer button makes it possible to further inspect poses using the Data Analyzer Notice A detailed energy analysis is available by right clicking poses in the table and selecting Energy Inspector Additional options are available in the context menu allowing the user to select remove and export poses These options are also available from the File and Edit menus located in the Pose Organizer dialog molegro molecular viewer user manual 5 Analyzing Docking Results Pose Organizer 6 poses File Edit Table Settings page 56 101 Poses maf 00 BTN_300 BTN_300 IO C 05 BTN_300 BTN_300 C 03 BTN_300
19. by pressing the right mouse button on a given atom Entire molecules can be set to a custom color using the Workspace Explorer context menu by selecting either Set Custom Color or Set Custom Color Carbons Only molegro molecular viewer user manual 2 User Interface page 23 101 Custom Coloring is persistent it will persist after changing rendering coloring styles and takes precedence over any coloring style The Custom Coloring can be cleared using the Clear Custom Coloring option from the Workspace Explorer context menu or from the Visualization Window context menu when focusing on a given atom Notice that aromatic ring indicators pseudo bonds and single colored bonds will only have custom coloring applied if the entire molecule is selected or if the Set Custom Color command is invoked from the Workspace Explorer context menu The Custom Coloring information is stored together with the atoms in MVDML files and will be used every time the MVDML workspace file is opened in MMV LAATING nnac To create labels use the Create Label dialog which can be invoked via Create Labels in the Workspace Explorer context menu on molecular categories Proteins Ligands and Poses or via the Tools Labels menus Create Label Label Type Atom Template PDB Atom Name and PDB Index Tana C Only selected atoms a O Water 0 84 H Proteins 1 1 Figure 14 Creating a new label
20. it must be enabled by specifying the ligandes true option to the EVALUATOR initializer list in a MVDScript file or by enabling the Internal ES option in the Docking Wizard E Intra tors Torsional energy for the pose E Intra sp2 sp2 Additional sp2 sp2 torsional term for the pose Notice This is a non standard term and is zero by default it must be enabled by specifying the sp2sp2bond true option to the EVALUATOR initializer list in a MVDScript file or by enabling the Sp2 Sp2 Torsions option in the Docking Wizard Also notice that only bonds that are chosen rotatable are taken into account when calculating the torsional terms for the ligand and sp2 sp2 bonds are most often double bonds which per default are held fixed in the docking simulation E Intra vdw Steric self interaction energy for the pose calculated by a LJ12 6 VdW approximation Notice This term is not used by the MolDock score E Solvation The energy calculated from the implicit solvation model Notice This energy term is considered to be an experimental feature only Per default it is NOT calculated In order to try this feature the protein must be prepared by calling the prep solvation command from the console As of now we recommend not to use it E Soft Constraint Penalty The energy contributions from soft constraints Static terms Torsions The number of chosen rotat
21. line widths The following coloring styles can be applied to all molecules Fixed Color A user defined color Color By Element CPK Atoms are colored according to element type Color By Id or Chain Molecules are colored according to their internal molecule ID i e a single ligand will be uniformly colored but all ligands will have different colors Color By Id carbons only Same as above except only carbons are colored using this scheme Other atoms are colored according to element type Color By Hydrogen Bond Type Colors atoms according to hydrogen bonding properties donors are red acceptors green and atoms capable of both donating and accepting hydrogens are yellow Color By Partial Charge Colors according to electrostatic partial charge blue corresponds to positive charge red to negative charge molegro molecular viewer user manual 2 User Interface page 31 101 The following can only be applied to proteins a Color By Temperature B Factor The temperature factor is a measure of how much a given atom vibrates around its position in the crystal structure Notice that this information is not always present in PDB files and that it is sometimes used for other purposes The colors will be interpolated between blue for the minimum temperature and red for the maximum temperature a Color By Amino Acid Type Colors proteins according to their residue type a Color By Shapely Residue Scheme
22. manual 10 Appendix IV PLANTS Scoring Function The PLANTS scoring function PLANTS Score used by MVD is derived from the PLANTS scoring function originally proposed by Korb et al KORB 2009 The MolDock scoring function further improves these scoring functions with a new hydrogen bonding term and new charge schemes The docking scoring function Epiantsscore is defined by the following energy terms Th ste ssceee J pup F cias T ors F C site z 20 where frp is a piecewise linear potential taking into account protein ligand interactions The PLP potential is similar to the one used by MolDock Score but here more interaction types repulsive buried nonpolar hydrogen bonding and metal are taken into account whereas MolDock Score only has two one for steric interactions and one for hydrogen bonding interactions The PLP interaction parameters used by MVD are Wpp nb 2 Wpip met 4 Wolp bur 0 05 Woip nonp 0 4 Woip rep 0 5 Wtors 1 See KORB 2009 for details The ligand clash and torsional potentials faasa and fiors take into account internal ligand clashes and torsional contributions for the flexible bonds in the ligand see KORB 2009 for specific implementation details The Csite term specifies a penalty that is calculated if a ligand conformation pose is located outside the binding site defined by the search space sphere For each heavy atom located outside the binding site a constant value of
23. not molecule fragments should be combined during import Molecule fragments can be combined if any atom in one fragment can form a covalent bond to any other atom in another molegro molecular viewer user manual 6 Customizing Molegro Molecular Viewer page 79 101 fragment Molecule fragments can only be combined if they share either Mol2 substructure IDs or chain IDs in the case of PDB files The preference settings are stored when exiting the MMV application The location of the saved settings depends on the operating system used e Windows the settings are stored in the system registry e Mac OS X the settings are stored in a com molegro MMV plist file located in the lt user folder gt Library Preferences folder e Linux the settings are stored in a mmvrc file located in a hidden folder named lt user folder gt molegro Currently the following command line parameters are available lt filename gt currentPath The lt filename gt parameter can be used to import molecular files during MMV startup If more than one file is listed separated by spaces each file will be imported Example Molegro MMV bin mmv 1stp pdb The currentPath parameter can be used to override the working directory specified in the general preference settings with the current path This is particularly useful when running MMV from different working directories using a terminal window or when using a script to start u
24. not taken into account for internal hydrogen bonds in ligands and Sp2 Sp2 Torsions determines whether an additional dihedral term should be added for taking Sp2 Sp2 bonds into account molegro molecular viewer user manual 5 Analyzing Docking Results page 68 101 Ligand Energy Inspector Ligand pose XK2_263 w _ Hide other ligands poses Action v Ligand Targets Total Energy Settings Scoring function MolDock Score v Ligand evaluation C Internal ES C Internal HBond no directionality C Sp2 Sp2 torsions Displaceable water evaluation C Displaceable water Entropy reward for each water displaced 0 00 Hydrogen bond evaluation C Hydrogen positions are optimized Optimize ligand and protein hydrogen positions using the Action menu before enabling this option Copy tables to clipboard Figure 42 Settings tab page for MolDock Score It is also possible to toggle on Displaceable water evaluation and set the corresponding entropy reward if that option was used during docking The last option relates to hydrogen bond evaluation When estimating hydrogen bonds MMV does not automatically assume that rotatable hydrogen bond donors have their hydrogen atoms positioned correctly However if the hydrogen positions have been optimized using Action Optimize Ligand and Protein Hydrogen Positions enable this option to take the full geometry of the hydrogen bond into account
25. opened in MMV or MVD either by dragging it onto the workspace or by selecting File Import Docking Results mvdresults The following table explains the different terms in a mvdresults file Textual Information Ligand The name of the ligand the pose was created from Name The internal name of the pose a concatenation of the pose id and ligand name Filename The file containing the pose Workspace The workspace mvdml file containing the protein Notice This entry appears in the header of the mvdresults file Run When running multiple docking runs for each ligand this field contains the docking run number Energy terms total Energy The MolDock score arbitrary units Notice that this value is always calculated using the non optimized MolDock score and hence may differ from the PoseEnergy below which may use interpolation on precalculated grids RerankScore The reranking score arbitrary units molegro molecular viewer user manual 9 Appendix III MolDock Scoring Function page 88 101 PoseEnergy The score actually assigned to the pose during the docking Notice that since the score is calculated by the scoring function chosen in the Docking Wizard there may be small differences to the MolDock score reported in the Energy entry for instance when using the grid based version of the MolDock score the grid interpolation may result in slighty different ene
26. the Visualization Window The Show pivot point rotational center option toggles the visibility of the pivot point small grayish ball The Show root atom option toggles the visibility of the currently chosen root atom for each of the ligands in the workspace The root atom is used as root in the torsion tree which is used to construct the ligand conformation during the MVD docking simulation The Fade 3D labels when in background option toggles fading of labels in the Visualization Window The overall rendering quality can be specified using the Quality option Modern computers with dedicated 3D hardware should be able to run at highest quality even when rendering relatively large molecules It is easy to test new quality settings by selecting the level of quality and pressing the Apply button molegro molecular viewer user manual 6 Customizing Molegro Molecular Viewer page 76 101 Preferences Graphics General Mouse Parsing C Show pivot point rotational center _ Show root atom C Fade 3D labels when in background j Quality 10 Reset All to Defaults Figure 48 The graphics tab of the Preferences dialog S Preferences General Graphics Mouse Parsing Mouse wheel model Generic Mouse C Invert zoom direction Wheel rotation speed 1 Wheel zoom speed o5 Reset All to Defaults Figure 49 Mouse Preferences The Mouse tab
27. the Pose Organizer behaves when single pose selection Dynamic update is enabled It allows you to visualize hydrogen bonds electrostatic interactions orient hydrogens in the protein and ligand to their optimal position and dynamically show residues close to the chosen pose The Orient hydrogens to optimal position option is useful when inspecting poses as this makes it easier to see if the hydrogen bond is optimal Working with Receptor Conformations When docking with sidechain flexibility in MVD a receptor conformation is saved together with each pose When a new docking results file is imported molegro molecular viewer user manual 5 Analyzing Docking Results page 58 101 MMV automatically checks whether any receptorConfiguration files exist together with the poses If this is the case the option show matching receptor configuration under dynamic update is enabled When in dynamic update mode the pose organizer will now automatically change to the receptor conformation corresponding to the selected pose If poses are imported into the workspace their corresponding receptor conformations will automatically be added to the workspace The middle panel allows for recalculation of the MolDock Score and re ranking score terms These scoring function values are already calculated if the poses are imported from a mvdresults file Pressing the Recalculate Energies button will recalculate the energy terms using the coefficients s
28. the structures in a file using the Index specifier Molecules must be separated either by for SDF files or lt TRIPOS gt MOLECULE for multi molecule Mol2 files Only one molecule will be extracted from each section separated by these separators For PDB files only the first HETATM molecule will be imported Notices that all input structures are expected to be ligands Molecules recognized as proteins or water molecules will be ignored The optional Index specifier must be a comma separated list of either single values or intervals Notice that open intervals are allowed e g 5 or 19 Indices should be ordered strictly increasing Invalid or non existent indices will be ignored The Index specifier is 1 based the number of of the first molecule is 1 and not 0 Filenames containing spaces must be enclosed in quotation marks It is possible to specify files on shared network drives and folders Multifile data sources are identified by a Dir identifier Examples Dir C Test Molecules Pattern sdf mol2 Index 10 100 Dir C Test Pattern Stereo sdf Index 10 100 The Multifile data source takes a directory and scans it for the given pattern Patterns are specified using as a wildcard Notice that on Linux and Mac operating systems file patterns are case sensitive It is possible to specify more than one pattern by separating sub patterns with semi colons Patterns with semi colo
29. whether the backbone color should be interpolated between the atoms it passes through or should be held constant between atoms Diameter A sets the width of the backbone in angstrom Subdivision sets the resolution of the backbone the number of subdivisions between each residue in the protein Backbones appear in the Backbones category in the Workspace Explorer and can be removed via the context menu or hidden using the check box Screenshots can be made by choosing Window Capture Screen It is possible to specify whether to capture the Visualization Window only the 3D view or the entire Desktop see Figure 21 The captured region can be saved in JPG BMP or PNG file formats molegro molecular viewer user manual 2 User Interface page 29 101 Capture Screen Visualization Window PNG Figure 21 Screen Capture dialog 2 21 Visualization Settings Dialog The graphical settings for the 3D visualization can be adjusted by selecting Rendering Visualization Settings Dialog Visualization Settings Style and Color Rendering Interactions Views Choose target Proteins Graphical style Ligands Ball and stick Poses Water Atom Scale Cofactors 0 20 Bond Scale _ 0 05 Shows atoms as spheres and bonds as cylinders Coloring Fixed Color v Restore to Default Settings Figure 22 The Visualiza
30. 50 is added to the C ie term In addition a quadratic penalty is added if the ligands reference point i e the origin of the ligand s coordinate system is located outside the search space sphere KORB 2009 The 20 energy offset was originally needed for the PLANTS search algorithm and is included here in order for PLANTS scores to be comparable with the molegro molecular viewer user manual 10 Appendix IV PLANTS Scoring Function page 92 101 original PLANTS implementation The implementation of the PLANTS scoring function in MVD differs from the original PLANTS implementation in the following two cases 1 The original PLANTS implementation ignores default parameters for the Tripos torsional potential when handling dummy or S o2 typed atoms This means that contributions for these atom types are not taken into account in the torsional potential By default the MMV MVD implementation takes all atom types into account non matching types will use default settings as described by Clark et al CLARK 1989 2 The penalty term Csite used by PLANTS is not well suited for the MolDock Optimizer or the MolDock SE search algorithms By default this penalty term is replaced by penalty scheme where a constant penalty of 10000 is assigned to the total energy if a ligand heavy atom is located outside the binding site region defined by the search space sphere The settings for original PLANTS implementation can be used in MMV when re
31. 6 It allows you to browse the list of current poses to see detailed information about specific energy contributions to visualize hydrogen bonds electrostatic interactions and to calculate ranking scores The Pose Organizer can be invoked in several ways It is automatically displayed after a docking result file with mvdresults file extension has been imported to MMV by dragging and dropping the file into MMV or using File Import Docking Results mvdresults Otherwise it can be invoked by using the context menu on the Poses category in the Workspace Explorer or by pressing the table icon in the MMV Toolbar When the Pose Organizer is invoked it displays a list of poses parsed from the mvdresults file or poses currently in the workspace The table in the middle of the dialog window shows various columns with information about different energy contributions and other data for each pose The columns can be changed under the Settings tab pane A panel in the bottom of the dialog Sorting Criteria allows the user to sort the table by up to three different criteria By default the table in the middle supports multiple selection i e more than one pose can be highlighted Only highlighted poses will be visible in the 3D window This setting is useful for quick comparison of different poses This default behavior can be changed by selecting Dynamic update notice disables multiple poses selection In this mode only one pose is shown
32. Finder located at the far right side of the toolbar can be used to quickly search for molecule names and residue atom IDs see Section 2 11 for more details The Workspace Explorer window see Figure 3 contains information about the 3D objects both molecules such as proteins ligands and water molecules but also objects such as labels surfaces backbones and cavities Workspace Explorer tems Options Workspace New v Fit to screen GL Constraints 1 Ligands 1 Hide others g Poses 10 00 BTN_300 01 BTN_300 02 BTN_300 03 BTN_30 04 BTN_300 05 BTN_30 06 BTN_30 07 BTN_30 08 BTN_300 09 BTN_300 Proteins 1 K EKEK K KK K K Figure 3 Workspace Explorer window The context menu right mouse button click allows the user to a Export molecules to PDB Mol2 or SDF format a Edit workspace properties workspace title and workspace notes a Rename molecules a Remove items from the current workspace m Set the currently active ligand or reference ligand optional a Copy ligands to poses used to inspect ligands with the Pose Organizer Clone ligand or protein makes a copy of the molecule molegro molecular viewer user manual 2 User Interface page 11 101 Convert ligand to pose or cofactor a Convert protein to ligand a Convert pose to ligand used when docking poses a Inspect poses using the Pose Organizer a Prepare molecules Create labels surfaces and back
33. Same as above with alternative colors a Color By Residue ID Colors according to residue ID rainbow effect a Color By Secondary Structure Colors according to secondary structure red for helices blue for strands and yellow for turns a Color By Hydrophobicity Residue atoms are colored according to the hydropathy index proposed by Kyle and Doolittle in 1982 see http en wikipedia org wiki Hydropathy_ index for details Hydrophilic residues are colored red hydrophobic residues are colored blue The Rendering tab Figure 23 on the Visualization Settings dialog allows you to customize the rendering behavior molegro molecular viewer user manual 2 User Interface page 32 101 Visualization Settings Style and Color Rendering Interactions Views Fog Lights 3D Projection Perspective Angle Light 1 Ambient Diffuse Specular g oe Light 2 Global Coloring Background Color Ambient J Label Color Diffuse Specular J Restore to Default Settings Apply Figure 23 The Visualization Settings Rendering options Cavity Color The Fog settings enables or disables fog It is possible to adjust when the fog should begin the Near value and when the fog should reach its maximum density the Far value The 3D Projection settings manage the perspective projection In Perspective projection objects farther away from the viewer appear smaller the magnitude of this effect can be contro
34. able bonds in the ligand HeavyAtoms Number of heavy atoms MW Molecular weight in dalton co Obsolete constant term This value is always 1 Older versions of the Data Analyser required an explicit constant column in order to include a constant term in the fit it is only included for backward compatibility CO2minus Number of Carboxyl groups in ligand Csp2 Number of Sp2 hybridized carbon atoms in ligand Csp3 Number of Sp3 hybridized carbon atoms in ligand DOF Degrees of internal rotational freedom As of now this is the number of chosen rotatable bonds in the ligand and is thus equal to the Torsions term It is supposed to reflect how many rotational degrees of freedom are lost upon binding Future work may include a more advanced model where the actual conformation is inspected in order to determine whether rotational degrees of freedom are lost N Number of nitrogen atoms in ligand Nplus Number of positively charged nitrogen atoms in ligand OH Number of hydroxyl groups in ligand molegro molecular viewer user manual 9 Appendix III MolDock Scoring Function page 90 101 OPO32minus Number of PO groups in ligand OSs Number of ethers and thioethers in ligand carbonyl Number of Carbonyl groups in ligand halogen Number of Halogen groups in ligand Other terms RMSD The RMS deviation from a reference ligand if available molegro molecular viewer user
35. ace page 38 101 6 Biomolecule Generator Select molecules to apply transformation s on Transformations BY Proteins 3 3 nnd REMARK 350 GENERATING THE BIOMOLECULE REMARK 350 COORDINATES FOR A COMPLETE MULTIMER REPRESENT REMARK 350 BIOLOGICALLY SIGNIFICANT OLIGOMERIZATION STATE OF REMARK 350 MOLECULE CAN BE GENERATED BY APPLYING BIOMT TRAI REMARK 350 GIVEN BELOW BOTH NON CRYSTALLOGRAPHIC AND REMARK 350 CRYSTALLOGRAPHIC OPERATIONS ARE GIVEN REMARK 350 REMARK 350 BIOMOLECULE 1 REMARK 350 APPLY THE FOLLOWING TO CHAINS A B C REMARK 350 BIOMT1 1 1 000000 0 000000 0 000000 REMARK 350 BIOMT2 1 0 000000 1 000000 0 000000 REMARK 350 BIOMT3 1 0 000000 0 000000 1 000000 REMARK 350 BIOMT1 2 0 298065 0 901822 0 312848 REMARK 350 BIOMT2 2 0 511568 0 125786 0 849986 REMARK 350 BIOMT3 2 0 805888 0 413394 0 423851 0 v samir nen minses n nanan n rearnn n AnEAnn ai i before pressing OK Figure 28 The Biomolecule Generator The left panel on the dialog controls which molecules the transformation should be applied to This is normally the proteins or protein chains but ligands water and cofactors can also be transformed The right panel contains a text box where a transformation description can be pasted Notice that if a transformation remark was present in the last loaded PDB file it will automatically appear here It can be necessary to manually edit the transformation remarks For i
36. alization A higher threshold value results in less points being shown The Dot Size determines how large the transparent blobs that make up the volumetric fields are The Transparency slider controls how opaque the fields appear Higher values make the fields more opaque molegro molecular viewer user manual 3 Preparation Molecules can be imported into MMV using the Import Molecule menu option located in the File menu A shortcut is provided from the tool bar by clicking on the File folder icon or using the Ctrl O keyboard shortcut Molecules can also be imported by dragging and dropping the molecular file into the main application window Currently MMV supports the following file formats a Protein Data Bank pdb ent a Sybyl Mol2 mol2 a MDL sdf sd mol mdl Notice that only PDB and Mol2 files can contain proteins and water molecules In general it is recommended to use Mol2 or SDF files for ligands since they can contain bonding information From the Import Molecules dialog shown in Figure 33 it is possible to select which molecules to import prepare molecules and inspect warnings found during parsing of the imported file Notice If more than 10 ligands are present in the file typically SDF or Mol2 files a subset of the ligands can be selected for import using the Specify ligand range option see Figure 33 Since it is computationally slow to display a large number of molecules e g thousands of compounds
37. and the water molecules This is the E Inter water ligand term in a mvdresults file Internal The internal energy of the pose This is the E Intra tors ligand atoms term in a mvdresults file Torsions The number of chosen rotatable bonds in the pose Soft Constraints The energy contributions from soft constraints This is the E Soft Constraint Penalty term in a mvdresults file Electro Short range electrostatic protein ligand interations r lt 4 5A ElectroLong Long range electrostatic protein ligand interations r gt 4 5A HBond Hydrogen bonding energy Heavy Atoms Number of heavy atoms in ligand MW Molecular weight in dalton LE1 Ligand Efficiency 1 MolDock Score divided by Heavy Atoms count LE3 Ligand Efficiency 3 Rerank Score divided by Heavy Atoms count molegro molecular viewer user manual page 59 101 5 Analyzing Docking Results page 60 101 Column Name Description Docking Score Evaluated before post processing either Plants or MolDock This is the PoseEnergy term in a mvdresults file Similarity Score The similarity score if docking with templates DisplacedWater The energy contributions from non displaced and displaced water interactions if enabled SMILES Contains connectivity information useful for 2D depictions Table 1 Column names available in the Pose Organizer dialog After import
38. aromatic ring contains an atom which has out of plane bonds it is degraded to be non aromatic Notice that this is only a geometrical check for aromacity It does not include more advanced checks such as Hutckel s rule and may fail on overlapping ring systems a All atoms with average bond angles gt 155 are marked as SP1 a All atoms with average bond angles gt 115 are marked as SP2 a All remaining atoms are marked SP3 a All atoms part of aromatic rings are marked as SP2 a Ensure that if an atom is SP2 or SP it must be connected to another SP or SP2 or a terminal atom Otherwise the atom is degraded i e SP2 gt SP3 molegro molecular viewer user manual 8 Appendix II Automatic Preparation page 83 101 a Lastly the geometry surrounding a SP2 atom should be planar otherwise it is degraded to SP3 a All atom bonds are set to unknown All implicit hydrogens are set to 1 a All bonds to SP3 atoms are set to single order a Next a template file containing standard chemical motifs POO C NH2 NH2 is processed The templates are located in the file misc data preparationTemplates xml m All unset SP2 SP2 bonds involved in a planar geometry less than 10 degrees are set to double a Next all SP2 atoms are checked to see if a double bond to a neighbour atom is possible If several atom bonds are possible the atom with highest electro negativity is chosen If this still results in several pos
39. atom types are assigned according to the scheme shown in Table 4 molegro molecular viewer user manual 9 Appendix III MolDock Scoring Function page 86 101 type atoms acceptor N and O with no Hs attached donor N and S with one or more Hs attached both O with one H attached or O in water molecule nonpolar all other atoms Table 4 Hydrogen bond types The PLP hydrogen bond term mentioned above only depends on the distance between atoms In order to take into account the directionality of the hydrogen bonding the geometry of the hydrogen bond is examined and the following factor Hractor is Multiplied to the PLP hydrogen bond strength Hyactor O Zp 4 2 90 150 D 24 4003 90 100 D Zp 4 44 90 100 Here AA Acceptor Antecedent denotes a heavy atom connected to the acceptor A D denotes the donor and H is the donated hydrogen atom The ramp function is defined as D A Amin Amax O for ASAmin and A Amin Amax 1 for A Amax and is linearly interpolated between these values for Amn lt A lt Amax If it is not possible to calculate one of these factors it is omitted This is for example the case for hydroxyl rotors where the exact location of the hydrogen is not investigated during docking and the two first factors cannot be calculated The angle checks above were motivated by the approach taken by McDonald and Thornton MCDONALD 1994 Entra is the internal energy of the ligand
40. avorable interactions The bottom panel Summary atom energjies displays the sum of all atom interactions Notice that this is not the full energy of the ligand Some interactions like covalent bonding energies and constraint energies are not included For a complete list of energy contributions see the Total Energy tab The Target tab displays a list of all targets atoms residues and molecules involved in an interaction with the inspected ligand or pose It is possible to switch between two views a Show Residue Molecule Contributions which shows protein residues and water cofactor molecules interacting with the inspected molecule a Show Atom Contributions which shows individual atoms in proteins molegro molecular viewer user manual 5 Analyzing Docking Results page 65 101 cofactors and water molecules in the workspace interacting with the inspected molecule The atoms residues and molecules are only displayed in the list if the interaction energy is greater then 0 3 in MolDock Score units As with the Ligand Atom Energy table selecting atoms residues or molecules in the table will select them in the 3D view and vice versa In addition it is possible to hide non selected residues by toggling on the Hide Non Selected Residues check box The energy contributions are also divided into the same categories as in the Ligand Atom Table for instance EElec and Epair Ligand Energy Inspector Ligand pos
41. bones a Fit the molecule to the visualization window The Workspace Explorer can also be used to inspect molecules in the Visualization Window using the left mouse button to select the molecules or by using keyboard shortcuts see below The Options button see Figure 3 contains settings used to customize the behavior when inspecting molecules The Fit to screen option will automatically zoom selected molecules so that they fit into the Visualization Window The Show hydrogen bonds option can be used to display hydrogen bonds only applicable for ligands and poses The Hide others option toggles whether other checked molecules in the current workspace category are allowed or not Keyboard shortcuts are also available for inspecting molecules Pressing the Shift button while clicking the left mouse button on a molecule in the chosen category e g Ligands or Poses will fit the selected molecule in the Visualization Window and all other molecules located in the same category are hidden Alternatively using Ctri Shift when clicking on a molecule hydrogen bonds are shown for the selected molecule Instead of using the mouse to select molecules to inspect Up or Down keys can be used to browse the molecules present in the currently selected Workspace Explorer category If the Ctrl and Shift shortcuts are omitted the settings enabled in the Options panel will be used The Properties Window contains information about the currently selected
42. cesscee cesses eeseeeeeeensesaeeeees 91 11 Appendix V Keyboard ShNortcuts cccccesscceeseeeeeeenesseeeeeeeeeennanssaeeees 93 12 Appendix VI Console COMMANGG c cscccceeesceeeeneessseeeeeneeeennneseeeeeees 94 13 Appendix VII Third Party Copyrights ccccseceeesseeeeesseeeeeneeeeneeeees 100 14 Appendix VIII ReferenceS sssssssssrssssnsssssnnnnrosansannsnnrrsnrrnnnrnenennnes 101 molegro molecular viewer user manual 1 Introduction Molegro Molecular Viewer MMV is an application for studying and analyzing how ligands interact with macromolecules MMV can be used to a Inspect docking results consisting of high scoring poses found by Molegro Virtual Docker MVD the molecular docking software product offered by Molegro Inspect and visualize molecular structures obtained from other sources such as the Protein Data Bank This manual describes various aspects of MMV from how to use the GUI importing preparing and visualizing molecules to inspecting and analyzing docking results from Molegro Virtual Docker Notice The main focus of MVD and MMV is on studying protein ligand interactions MMV is currently not supporting DNA and RNA molecules It is possible to import DNA and RNA molecules in MMV but they will appear as ligand molecules Molegro Molecular Viewer is developed by Molegro a CLC bio company Finlandsgade 10 12 8200 Aarhus N Denmark http www clicbio com molegr
43. ches Protein to be aligned 1AH3 A v Reference Bn Using the alignment above align additional molecules 3 Arg 3 fC Proteins 0 2 a M Ligands 3 5 5 O CAC_317 13 atoms CO NAP_316 75 atoms AYA_1 A 9 atoms NAP_318 55 atoms TOL_320 38 atoms a Match by residue type and PDB index Match by residue type and position Target offset Figure 29 The Structural Protein Alignment dialog box The first step is to choose a reference protein and a protein to be aligned the target protein The target protein is the protein which will be translated and re oriented When two proteins have been chosen the list on the right side of the dialog will suggest a matching between residues in the proteins Green entries indicate which residues that will be aligned By default the matching will be done using Match by residue type and PDB index where two residues will molegro molecular viewer user manual 2 User Interface page 40 101 be matched if they are of the same kind and have identical PDB residue identifiers Two PDB crystal structures may have similar sequences but different PDB residue identifiers In this case it is possible to Match by residue type and position This will match two residues if their positions in the sequences are identical It is also possible to add a index offset to the target protein index Sometimes a number of other molecules are associat
44. cular Viewer File Edit View Rendering Preparation Tools Window Help s A Q am ii S x Hydrogens Fog Hide Residues as a ISTP 1STP Asp 67 1STP Asn 81 1STP Asn 82 1STP Asn 85 1STP Asn 105 1STP v Figure 10 Workspace Finder dialog By default the Fit to screen option is enabled so that items molecules residues or atoms are fitted to the Visualization Window while browsing the list of results found The Fit to screen option can be disabled in the options panel invoked by pressing the small button on the right hand side of the Workspace Finder search box The Workspace Finder is invoked by typing characters in the search box text field located in the far right side of the MMV Toolbar A result is selected by pressing the Return key Pressing the Escape Esc key or mouse clicking outside the Workspace Finder window will cancel the current search query The Sequence Viewer dialog see Figure 11 allows you to inspect protein residues in an easy manner Using the context menu on the Sequence Viewer window it is possible to select residue atoms in the Visualization Window hide non selected residues change between one and three letter residue names and toggle details about secondary structure Residues near cavities are indicated with a green ribbon the distance threshold may be set using the sequence viewer s context menu and broken protein chains are indicated with vertical line
45. customizes how the mouse interacts with the 3D world MMV supports the 360 degrees scroll ball on the Apple Mighty Mouse Currently the 360 degrees scroll bar feature is only supported on Mac OS X since no mouse drivers are available for other platforms but the mouse still works as a generic mouse on Windows and Linux To enable Apple Mighty Mouse support select it under Mouse wheel model When Apple Mighty Mouse mode is selected the scroll ball can be used to rotate the 3D world Additionally the scroll ball button can be used to zoom in molegro molecular viewer user manual 6 Customizing Molegro Molecular Viewer page 77 101 the 3D world by pressing the button while using the scroll ball as a standard mouse wheel However to enable the zoom option the scroll ball button should be set to Button 3 in the Mac OS X Mouse preferences dialog see Figure 50 Invert zoom direction toggles how the the 3D worlds zooms rotating the scroll wheel towards the user will normally make the 3D objects appear larger but this behavior can be inverted by toggling this option on The setting also applies to zooming using both mouse buttons It is also possible to adjust the mouse wheel sensitivity by using the Wheel rotation speed and Wheel zoom speed sliders Keyboard amp Mouse lt ShowAll Q Keyboard Trackpad Mouse Bluetooth Keyboard Shortcuts Button 3 4 z J Primary Button Hag Secondary But
46. d That is that the atom connectivity is known and that the correct bond order and charges have been assigned The Prepare Molecules dialog allows the user to perform the necessary preparation It is invoked automatically when importing Mol2 SDF or PDB files and can be invoked manually by selecting Preparation Prepare molegro molecular viewer user manual 3 Preparation page 47 101 Molecules or by using the context menu e g Prepare Ligand on molecules in the Workspace Explorer Import Molecules Import ioni Wamings 0 Assign All Below Assign bonds Assign bond orders and hybridization Create explicit hydrogens Assign charges calculated by MVD Detect flexible torsions in ligands Assign Tripos atom types Notice Custom v v If Missing Y Always Always v v v v v If Missing T he preparation options If Missing Always Never Remove applies to each individual molecule not each individual bond or atom For instance setting Assign bonds to If Missing results in covalent bonds being created for molecules not containing any bonds at all while molecules with bond information will preserve their bond assignments Likewise setting Create explicit hydrogens to If Missing will not add additional hydrogens to molecules containing e g polar hydrogens only In this case Always should be used if all hydrogens should be created
47. d and selecting the Set Flexibility menu option molegro molecular viewer user manual 4 Data Sources There are several ways to import ligands and prepare them in Molegro Molecular Viewer Ligands can be imported in the GUI using Import Molecules from the File menu and included in the workspace This is the easiest way to import data but it can be slow if working with thousands of ligands Ligands can be read from a Data Source Ligands are streamed from a source such as a large file and the selected molecules are imported This can be particularly useful when importing a subset from e g an SDF file containing a large number of compounds since only the selected molecules are loaded into main memory Currently two types of data sources are available File data sources These are single files containing multiple structures such as SDF multi molecule Mol2 or MVDML It is possible to read a subset of the molecules contained in the file Multifile data sources These can be used when the input structures are split over several different files A multifile data source may contain files with a mixture of different data formats File data sources are identified by a File identifier Examples File fileserver molecules mol23 mol2 File C Test Molecules steroids sdf Index 2 4 8 12 34 molegro molecular viewer user manual 4 Data Sources page 52 101 It is possible to import a subset of
48. drop down menu The following types of energy contributions may be listed for a ligand atom a EPair This is the pairwise PLP steric and hydrogen bonding energy between a ligand atom and a receptor atom Pairwise interactions between a ligand and either cofactors or water molecules will show up as EPair cofactor and EPair water a EIntra This is the internal ligand energy between a ligand atom and the other atoms in the ligand a EElec This is the pairwise electrostatic interactions For the protein they are divided into long range and short range interactions EElec R lt 4 5 A and EElec R gt 4 5 A The second table Hydrogen Bonds and Strong Electrostatic Interactions shows a list of all hydrogen bond and strong electrostatic interactions between the ligand and the target atoms From the Options drop down menu it is possible to show or hide the table but it is also possible to toggle the table to display covalent bonds instead Show Covalent Bond Energies Finally the Options menu also makes it possible to toggle whether hydrogen bonds and strong electrostatic interactions should be visualized in the GUI Hydrogen bonds are visualized as dashed lines where strong hydrogen bonds appear more solid and strong electrostatic interactions are visualized as partial spheres oriented in the direction of the interaction Green partial spheres correspond to favorable interactions while yellow spheres correspond to non f
49. e ZAE v C Hide other ligands poses Action v Ligand Targets TotalEnergy Settings Show Residue Molecule Contributions v C Hide Non Selected Residues Molecule Residue ID Total EPair A THVR A Ala 28 11 6603 11 6603 THVR A Arg 8 281096 2 81096 1HVR A Asp 12379 1279 1H R A Asp 293 B2772 83272 1H R A Asp 30 9 41378 9 41378 1HVR A Gly 27 4 936 4 936 1HVR A Gly 48 7 3479 7 3479 1HVR A Gly 49 10 5076 10 5076 1HVR A lle 47 8 8103 8 8103 1HVR A lle 50 17 5595 17 5595 1H R A lle 84 7 12269 7 12269 THVR A Leu 23 1 50949 1 50949 THVA A Leu 76 0 779384 0 779384 1H R A 81 2 99427 2 99427 AYR TAL 31 0541081 054091 0 Clear Selection Copy tables to clipboard Figure 41 Targets tab page The Total Energy Tab The Total Energy tab displays a hierarchical breakdown of the various energy contributions molegro molecular viewer user manual 5 Analyzing Docking Results page 66 101 When using the PLANTS scoring function the following columns are shown The Value column displays the various terms which the PLANTS Score is based on The PLANTS Score column shows how the PLANTS score energy is composed The PLANTS score is a sum of a subset of the Value terms all terms are given the same weight For the MolDock scoring function the following columns are available The Value column displays the various terms whic
50. ecular viewer user manual 5 Analyzing Docking Results page 72 101 adjusting the sliders Notice that for steric interactions only non favorable interactions clashes are shown showing the numerous positive interactions would clutter the interaction diagram However by placing the mouse cursor over an atom or residue the favorable steric interactions will also be shown It is also possible to visualize how much each ligand atom contributes to the overall binding interaction By clicking Interaction Overlay a sphere centered at each atom visualizes the strength of the interactions for this specific atom By enabling the Hide Residues option it is possible to hide residues in the 3D visualization window that are not shown in the 2D Ligand Map The Redo Layout button makes it possible to calculate a new layout for the molecule and its interactions for instance if the layout contains clashing bonds It is possible to zoom in and out using either the mouse wheel or the zoom buttons in the lower right corner of the window The RMSD Matrix dialog can be used to quickly inspect deviations between molecules in the workspace In addition to the standard measure Pairwise Atom Atom RMSD by ID two variants Pairwise Atom Atom RMSD checking all automorphisms and Pairwise Atom Atom RMSD by nearest unmatched neighbour of the RMSD measure tries to take intrinsic symmetries of the molecule into account when calculating RMSD The recommended ch
51. ecules in the Visualization Window Manipulating Visualization Objects All objects in the 3D world have context menu actions These can be used for changing their properties e g setting hybridization partial charge implicit hydrogens or hydrogen bond types for atoms and bond order or bond flexibility for bonds See Section 3 3 for more details N 2 Console Window The Console Window at the bottom of the screen displays information warnings and errors The input field at the bottom of the console window molegro molecular viewer user manual 2 User Interface page 16 101 allows the user to enter console commands The amount of information in the console can be controlled with the associated context menu right mouse button click e g info warnings and debug messages can be turned off Clipping Planes allows you to change the clipping planes of the visualization window i e how close and how far away objects are drawn This can for example be useful if you want to visualize the interior of a protein or a ligand deeply buried inside a macromolecule Far lo J Near 60 I Figure 7 Clipping Planes dockable window Clipping Planes can be enabled by choosing Window Clipping Planes from the menu bar Clipping Planes are enabled when the Clipping Planes window is shown and disabled when it is closed Adjust the near and far slider until the desired region is shown A Search Space is defined by a position
52. ed with a protein a bound ligand or cofactor or another protein chain It is possible to select a number of additional molecules and apply the same transformation that aligns the target protein to the reference protein to the additional molecules This is done by checking the desired molecules in the workspace view on the left side of the dialog Notice that if the reference or target protein is selected as part of an additional alignment they will be ignored since they are already considered It is possible to perform a simple alignment of small molecules in MMV By selecting three atoms in one ligand and selecting three atoms in another ligand a new context menu appears when clicking on an atom in one of the molecules Align This will align the molecules The atoms are aligned in the same order as they are selected that is the first selected atom in ligand 1 is aligned to the first selected atom in ligand 2 etc Therefore it is important to ensure that the selection order is correct and that no other atoms are selected Alignments can be undone click the undo button in the tool bar Notice Only alignments with three selected atoms in each molecule are possible When importing molecules from PDB or SDF files header and annotation information is stored as part of the current workspace For PDB files the header is stored For SDF files the first 4 lines and any annotations are stored Imported notes can be shown using the context
53. egro molecular viewer user manual 5 Analyzing Docking Results page 70 101 Ligand Energ nspector Ligand pose XK2_263 Hide other ligands poses Ligand Targets Total Energy Settings Scoring function O J Include hydrogens in torsion term Use original Plants setup Displaceable water evaluation F Displaceable water Entropy reward for each water displaced 0 00 Re evaluate Copy tables to clipboard 5 4 Ligand Map 2D Depictions The Ligand Map makes it possible to depict molecules ligands and poses in the workspace in 2D This makes it easier to inspect the molecules make selections and to analyze receptor interactions The Ligand Map can be toggled on and off using the Ligand Map button on the tool bar in the main window molegro molecular viewer user manual 5 Analyzing Docking Results page 71 101 Q 1hvr mvdml Molegro Virtual Docker File Edit View Rendering Preparation Docking Tools Window Help SRN S fos Hie Ress ugana Man Thpos atom t C 2 Plants atom Nonpolar Hydro 0 Clear Selection Time Description 2i0 40 9 9 BANY VAA UREAUIY QUBVERSIUN LEUNUU 17 YES HUIA MV U MV U Vise LUM UVUA YVL H 1 12 47 47 266 Saved copy of curent workspace as f SUBVERSION CHECKOUT Projects Trunk MVD MVD VisualStudio DockingOutput 121 Unnamed_complex mvdmi 12 47 47 271 Docking in separate process 12 47 47 272 Spawning process
54. es with no interactions to the ligand are hidden If the Displaceable water evaluation option is selected the following coloring scheme applies displaced waters are colored yellow non displaced waters are colored green if they are favorable and red if they are not favorable Optimize Ligand and Protein Hydrogen Positions When docking with Molegro Virtual Docker the exact positions of the rotatable hydrogen atoms are not calculated Instead it is assumed that the hydrogens are pointing in the optimal direction In order to view the optimal direction of the rotatable hydrogens apply this option Any rotatable hydrogens on the protein and ligand which are involved in hydrogen bonds will be oriented to the optimal direction a Minimize Ligand This performs an energy minimization of the current molecule with regard to its MolDock score energy Figure 40 An example of the Style Ligand Atoms by Energy visualization where atoms are scaled according to their energy contributions The Ligand tab page consists of three tables molegro molecular viewer user manual 5 Analyzing Docking Results page 64 101 The Atom Energies table shows information about individual atoms in the ligand When hovering the mouse over an atom in the 3D view it will automatically be highlighted in the table Similarly when selecting entries in the table atoms will be selected in the 3D GUI It is possible to show or hide this table using the Options
55. estacke eee 46 3 3 ManWal Pr paration sisn2sciessiscevewds ei vaods viveiaviusis A ENA eden 49 4 Data S OUNCES erne uea a EE E A NEO ENEN NEE Ei 51 4 1 Data SOURCES SyntaX eseis naaa a a E ERRER ERa 51 molegro molecular viewer user manual page 4 101 4 2 Loading Data Sources Directly into the WorkSpace cccceeeeeneeeee eens 52 5 Analyzing DOCKING RESUNS ccscoccacscccansteadanesnnsusasdseapaceseegastisinetoaseninedzabses 54 5 1 POSS Organiz r asane sens e E EE E ERE 54 5 2 Saving Molecules and Solutions Found ssssssssresrrssssrenrsnnrrrrrern 60 5 3 Ligand Energy INSPGClOM sicievedsesveniewsweriigasaiersieeee in edewnde eeeeeiewendends 61 5 4 Ligand Map 2D DEPICHONS 6 sicicss ce cscsecesasdesexstacsegatecsenstsidengederescaese 70 5 5 RMSD Matix vcscoressacaresesecsesesecrenecoueersonimenecnesey TEREA RATARA ARR ENEA 72 6 Customizing Molegro Molecular Viewer ccccseeceensseeeeeeeeeeennnsnseeeeees 74 6 1 General PreferenceS sssssssrsssssurrrrosannrrsnnrsenonsanesnrrsnrrnnnrnenenanennn 74 6 2 Command Line Parameters vs sessevscedevvevetaasentecsieeeddasetiedeesedindeiaaunds 79 7 Appendix I Supported File Formats cccccceceesceeeeneeeenenssseeeeeseeeennes 80 8 Appendix II Automatic Preparation ccccceceseeeeenenesseeeeeeeeeennnsssaeeenes 82 9 Appendix III MolDock Scoring FUNCtION ccccceeeeeeeeeeeeeneneeeeeeenseeees 84 10 Appendix IV PLANTS Scoring FUNCtION ccc
56. ettings Apply Figure 25 The Visualization Settings Views tab The lower panel allows you to create new views based on the current visualization settings By pressing New View a dialog allows you to specify the name for the new view after which it is added to the list of views on the main window menu bar Views are stored as parts of the viewermacros xml file and appear under the View menu item It is also possible to modify the macro in the text area before committing it as a macro Modified macros can be tested by pressing Test Macro before they molegro molecular viewer user manual 2 User Interface page 35 101 are stored permanently The default visualization settings used by MMV can be changed by pressing the Use as Default Settings button If needed the default visualization settings can also be restored to the factory settings by pressing the Restore Default Settings to Factory Settings button The factory settings are the initial settings used by MMV when started for the first time At that point the factory settings are also used as the default visualization settings The current visualization settings shown in the Visualization Settings dialog will be stored in the MVDML workspace file when saving the workspace When importing workspaces containing visualization settings these stored settings will be used instead of the default settings Notice When making a new workspace or clearing the current work
57. evaluating ligands and poses by enabling Use original Plants setup option in the Ligand Energy Inspector dialog molegro molecular viewer user manual 11 Appendix V Keyboard Shortcuts The following list contains the keyboard shortcuts available in MMV On Mac OS X the CTRL key is replaced by the command key CTRL O CTRL SHIFT O CTRL SHIFT C CTRL S CTRL F CTRL H CTRL C CTRL L CTRL P CTRL W CTRL Z CTRL Y CTRL Q CTRL 1 to 8 Fi to F9 Import Molecules Open Workspace Clear Workspace Save Workspace Toggle full screen Toggle dockable windows Toggle Cofactors category on off Toggle Ligands category on off Toggle Proteins category on off Toggle Water category on off Undo Redo Quit MMV Invoke misc visualization views Invoke misc dialogs molegro molecular viewer user manual 12 Appendix VI Console Commands When entering commands in the console the following commands can be used Notice Some commands require a molecule target these can be described using the following syntax Ligand O the ligand with ID 0 Ligand 4 5 6 the Ligands with IDs 4 5 and 6 Multiple IDs are separated by comma Ligands All ligands By using the plural form of a category all molecules in it are selected The categories are Pose Cofactor Protein Water Ligand Poses Cofactors Proteins Ligands Water 0 All Poses Cofactors Proteins Ligands and the first Water molecule Multiple targets can be
58. h the MolDock Score and the Rerank Score are based on The MolDock Score column shows how the MolDock score energy is composed The MolDock score is a sum of a subset of the Value terms all terms are given the same weight The Rerank Score uses a weighted combination of the terms used by the MolDock score mixed with a few addition terms the Rerank Score includes the Steric by LJ12 6 terms which are Lennard Jones approximations to the steric energy the MolDock score uses a piecewise linear potential to approximate the steric energy The coefficients for the weighted Rerank Score are given in the Rerank Weight column and the weighted terms and their summations are given in the Rerank Score column The relation between the terms showed in the Ligand Energy Inspector and the terms found in a mvdresults file is shown in the table below Ligand Energy Inspector Term MVDResults Term Total Energy External Ligand interaction Protein Ligand interactions Steric by PLP Steric Steric by LJ12 6 VdW LJ12 6 Hydrogen bonds HBond Hydrogen bonds no directionality NoHBond90 Electrostatic short range Electro Electrostatic long range ElectroLong Cofactor Ligand E Inter cofactor ligand Steric by PLP Not present in the mvdresults file but can be calculated as E Inter cofactor ligand Cofactor hbond Cofactor elec Steric by LJ12 6 Cofactor VdW molegro
59. haar D K Bouzida D Rejto P A Fully Automated And Rapid Flexible Docking of Inhibitors Covalently Bound to Serine Proteases Proceedings of the Seventh International Conference on Evolutionary Programming 1998 449 461 YANG 2004 Yang J M Chen C C GEMDOCK A Generic Evolutionary Method for Molecular Docking Proteins 2004 55 288 304 MCDONALD 1994 McDonald I K Thornton J M Satisfying Hydrogen Bonding Potential in Proteins J Mol Biol 1994 238 777 793 KORB 2009 Korb O Stutzle T Exner T E Empirical Scoring Functions for Advanced Protein Ligand Docking with PLANTS J Chem Inf Model 2009 49 1 84 96 CLARK 1989 Clark M Cramer III R D Opdenbosch N Van Validation of the General Purpose Tripos 5 2 Force Field J Comp Chem 1989 10 8 982 1012 molegro molecular viewer user manual
60. ialog controls the size and rendering options It is possible to specify an image size in either pixels or physical units In order to use physical units it is necessary to specify the printing resolution of the physical media the default resolution is 300 DPI dots per inch It is possible to choose between inches and cm as units but the DPI is always specified in inches Shadows can be toggled on and off and it is possible to specify a font scale since text is drawn differently by the raytracing engine text may appear either too large or too small This can be adjusted using the font scale settings Adaptive antialias is a technique for reducing jarred boundaries between objects Higher settings produce higher quality but takes longer time to render molegro molecular viewer user manual 2 User Interface page 37 101 Figure 27 The output preview window After the output has been rendered a preview window appears with the result and the output can be saved as a bitmap The PNG format produces the highest quality images since it uses loss less compression while the JPG format produces the smallest file sizes 2 23 Biomolecule Generator Some PDB files contain transformation information for generating biomolecules To apply these transformations invoke the Biomolecule Generator by choosing Tools Biomolecule Generator molegro molecular viewer user manual 2 User Interf
61. ibution has the theoretically predicted molegro molecular viewer user manual 9 Appendix III MolDock Scoring Function page 85 101 magnitude the other energy terms are empirically motivated and the total energy does not necessarily correlate with the true binding affinity The charges are set according to the scheme listed in Table 2 Metal ions are assigned a charge of 1 e g Na or 2 e g Zn Ca Fe charge ligand atoms protein atoms 0 5 N atoms in C NH2 2 His ND1 NE2 Arg NH1 NH2 1 0 N atoms in N CH3 2 Lys N NH3 0 5 O atoms in COO S0 Asp OD1 0D2 PO2 PO2 Glu OE1 0E2 0 66 O atoms in PO3 0 33 O atoms in SO3 1 0 N atoms in SO2NH Table 2 Charge templates Epp is a piecewise linear potential using two different sets of parameters One set for approximating the steric Van der Waals term between atoms and another stronger potential for hydrogen bonds The linear potential is defined by the following functional form Ep p O Ao Eprp R1 0 Epip R2 Epip R3 A Ep p r 0 forr R and is linearly interpolated between these values The parameters used here see Table 3 were adopted from GEMDOCK YANG 2004 Ao Ai Ri R2 R3 R4 hydrogen bond 20 0 2 5 2 3 2 6 3 1 3 6 steric 20 0 0 4 3 3 3 6 4 5 6 0 Table 3 PLP parameters A bond is considered a hydrogen bond if one of the atoms can donate a hydrogen atom and the other atom can accept it The
62. ing and preparing molecules all information can be saved in a MVD Workspace MVDML file which contains all relevant information position of atoms charges hybridization bond orders ligand flexibility To save a workspace select File Save Workspace As Alternatively use the keyboard shortcut Ctrl S Notice Visualization objects surfaces labels interactions are not saved in MVDML files The Export Molecules dialog can be used to export all or a selection of the molecules available in the workspace see Figure 38 molegro molecular viewer user manual 5 Analyzing Docking Results page 61 101 Export Molecules Molecules Water 84 Proteins 1 1STP 1741 atoms a Ligands 1 BTN_300 30 atoms Notice Proteins and waters cannot be exported to MDL Mol files sdf sd mol mdl Output scheme One single file v Figure 38 Export Molecules dialog Select which molecules to export To export molecules select File Export Molecules or Export Molecules from the Workspace context menu in the Workspace Explorer also available for proteins ligands cofactors and poses Notice Proteins and water molecules cannot be exported to SDF files Exporting P S To save the poses obtained from the docking runs either use the Export Molecules dialog described above or save the poses from the Pose Organizer dialog Li igand En A The Ligand Energy Inspector al
63. ings Style and Color Rendering Interactions Views Hydrogen Bonds Minimum Maximum Energy J Thickness 0 0 0 5 1 0 1 5 2 0 25 Electrostatic Interactions Minimum Maximum Energy Negative Positive 5 0 3 0 1 0 1 0 30 Restore to Default Settings Apply Figure 24 Settings for hydrogen bonds and electrostatic interactions molegro molecular viewer user manual 2 User Interface page 34 101 Preset Views The Views tab Figure 25 in the Visualization Settings dialog controls the preset views the macros residing under the View menu item on the main window menu bar The upper panel on the tab allows you to activate a preset view by pressing the Select button or delete a view the Delete button Notice that when deleting a view you are not able to recover it Visualization Settings Style and Color Rendering Interactions Views Preset views Hydrogen Bond Interactions Docking View Preparation View Hydrophobicity Electrostatic Interactions Pose Organizer View Secondary Structure View Macro based on current settings Visualization Settings A New View style ligand vdw 0 2 0 05 Test Macro style pose vdw 0 2 0 05 style protein wireframe 0 15 0 15 2 style water wireframe 0 15 0 15 2 style cofactor vdw 0 2 0 05 Color settings color ligand fixed 1 1 0 v Use as Default Settings Restore Default Settings to Factory Settings Restore to Default S
64. ir distance is more than 0 44 and less than the sum of their covalent radii plus a threshold of 0 45A the threshold is set to 0 4852 if one of the atoms is Phosphorus This options allows recognition of bond orders whether bonds are single double or triple the number of hydrogens attached to the atoms and their hybridization SP SP2 SP3 Also aromatic rings will be detected It should be noted that this assignment is not always perfect different protonation states can be difficult to assign properly A detailed description can be found in Appendix II Automatic Preparation Notice The algorithm only assigns the number of implicit hydrogens to each atom No actual atoms will be added The next option Create explicit hydrogens allows you to add explicit hydrogens based on the implicit ones Creates hydrogens matching the predicted number of hydrogens in the step above The hydrogens are placed according to geometric criteria i e SP3 hybridized atoms are kept at a 109 degrees geometry The hydrogens are placed at standard distances according to the atom they are connected to No energy minimization is performed This option allows to assign partial charges to each atom based on the scheme described in Appendix III Table 2 This option determines which bonds that should be considered flexible during docking It is advisable always to set this option to either If Missing or molegro molecular viewer user manual 3 Prepa
65. irtual Docker uses their own MVDML file format MVDML is a shorthand notation for Molegro Virtual Docker Markup Language and is an XML based file format In general MVDML molegro molecular viewer user manual 7 Appendix I Supported File Formats page 81 101 can be used to store the following information Molecular structures atom coordinates atom types partial charges bond orders hybridization states Constraints location type and constraint parameters Search space center and radius State information workspace properties Cavities location cavity grid points Camera settings position and angle Visualization settings e g style and color of molecules rendering options hydrogen bonds and electrostatic interactions See description of Visualization Settings dialog for an overview of all settings Notice Purely graphical objects e g labels interactions annotations backbones and surfaces are not saved molegro molecular viewer user manual 8 Appendix Il Automatic Preparation The principles behind automatic preparation in MMV are described below omaticity a All rings closed loops are identified a These rings are weeded out until a smallest subset capable of covering all ring bonds remains a These rings are considered aromatic if 1 For 5 cycles the mean torsion angle is less then 9 5 2 For 6 cycles the mean torsion angle is less then 12 a If the
66. ject from the workspace CD Print current directory DIR Shows dir of MVDML files in current directory PREV Loads previous MVDML file in current directory NEXT Loads next MVDML file in current directory RMSD Invokes RMSD dialog Selection of objects molegro molecular viewer user manual 12 Appendix VI Console Commands page 96 101 SELECT ID lt id gt SELECT ATOM lt x y z gt SELECT RESIDUE lt id gt SELECT RESIDUEID lt id gt SELECT ID selects all atoms with id id SELECT ATOM selects closest atom to specified x y Z position SELECT RESIDUE selects residue with residue index id SELECT RESIDUEID selects residue with internal residue index id STATUS Shows info about the objects in the workspace and Visualization Window Loaded modules are also listed SAVE filename Saves a MVDML file Do not include extension in filename LOAD filename Loads a MVDML file Do not include extension in filename ADD P SURF radius resolution probesize ADD P SURF LIGAND resolution probesize Adds a molecular surface Notice It is much easier to use the Surface dialog in the GUI If prepended by p the surface will be colored by electrostatic potential If followed by the surface will carved a Connolly surface We recommend the carved surfaces for best visualization If not followed by existing surfaces
67. l be shown in the Properties Window If three connected atoms are selected the angle that they span will be shown in the Properties Window If no atoms are selected and a bond is highlighted the field Torsion Angles in the Properties Window will show the torsion angle s defined through this bond molegro molecular viewer user manual 2 User Interface page 22 101 g Annotation Distance 2 47 A Torsion 4 19 Angle 26 89 Selection Deselect All Set Selection as Center of Search Space Set Selection as Center of Distance Constraint Create Distance Annotation Nitrogen Atom Set as Center of Search Space Create Distance Constraint Set as Rotational Center Figure 13 Annotations and measurements Measurements can also be made permanent as annotations There are different kinds of annotations To create annotations select 1 4 atoms and use the context menu right click mouse button and choose Create Annotation The text can be edited before the annotation label is created Annotations are added to the Workspace Explorer category Annotations Atoms can be manually selected in the Visualization Window using the mouse Using the context menu when focusing on a specific atom it is also possible to select deselect atoms molecules molecules carbon only rings for ligands cofactors poses and amino acids for proteins The atoms in a selection can be set to a custom color using the context menu invoked
68. ll PDB molecules with same chain ID Reset All to Defaults Figure 51 Parsing preferences The Default File Encoding drop down box allows you to choose which encoding should be used It is recommended to use the default setting UTF 8 Unicode Using the UTF 8 encoding all Unicode characters can be encoded and since molecular data files rarely contain special characters it is more space efficient than UTF 16 where each character always uses at least 2 bytes Files stored as 8 bit ANSI ASCII files will also be imported correctly as Unicode if they do not contain any special national characters and UTF 16 will also be automatically recognized in this mode It is also possible to store data as Locale 8 bit In this encoding all characters are stored as a single byte meaning only 256 characters can be represented The actual characters included in this set depends on the current national codepage settings on the machine This option should only be used when exporting data to older software products not capable of parsing Unicode text Break unrealistic bonds during import Mol2 SDF determines whether or not unrealistic bonds parsed from Mol2 or SDF files should be ignored during import A bond is considered unrealistic if the distance between two bonded atoms is more than the sum of their covalent radii plus a threshold of 0 7 The Combine Mol2 substructures and small PDB molecules with same chain ID option is used to decide whether or
69. lled by adjusting the field of view Angle parameter In Orthographic projection object sizes are independent of their distance from the viewer The Global Coloring settings allow you to adjust the background color the color labels are drawn with and the color cavities predicted binding pockets are drawn with The Lights section controls the global lightning of the 3D world It is possible to enable one or two light sources Their positions can be adjusted directly in the 3D sphere view The light source color can be changed by clicking the color selector next to the light checkbox molegro molecular viewer user manual 2 User Interface page 33 101 OpenGL Lights contain three different parts Ambient light always reaches an object independent of its position relative to the light source Diffuse lightning is dependent on whether the object faces the light source or faces away from it The reflected light is emitted equally in all directions Specular lightning is also dependent on the objects orientation towards the light source but the reflected light is emitted mainly in the direction of the reflected light ray creating highlights The Interactions tab Figure 24 on the Visualization Settings dialog allows you to customize the appearance of hydrogen bonds energy thresholds thickness of bond and color and electrostatic interactions energy thresholds and color shown in the Visualization Window Visualization Sett
70. lows you to get detailed information about the energy interactions for a given ligand or pose The Ligand Energy Inspector can be invoked in different ways It can be started using the context menu in the Workspace Explorer by choosing Open Energy Inspector on any Ligand or Pose item It can also be started from the Pose Organizer using the context menu on any pose entry or by selecting Tools Ligand Energy Inspector Notice the ligand energy inspector evaluates the energy of the ligand or pose when invoked This means that the proteins water molecules and cofactors currently in the workspace are taken into account If the workspace molegro molecular viewer user manual 5 Analyzing Docking Results page 62 101 has been changed the energy displayed here may not be the same as the one displayed in the Pose Organizer since these were assigned during the docking evaluation Ligand Energy Inspector Ligand pose i aNeA s v _ Hide other ligands poses Action v Ligand Targets Total Energy Settings Atom Energies Options ID Name Total EPair EPai cofactor Elntra io E 6 42352 4 76673 0 1 65679 i 0 9 92978 10 5101 0 0 580304 2 N 2 80002 2 27183 0 0 52819 Ved A la CECAFA AACA LAL AAL Hydrogen Bonds and Strong Electrostatic interactions Options ID Donor Energy Lenath target 2 16943 3 16611 ligand 2 5 3 0145 ligand 2 5 2 86465 barack 1 0017C 3 997190 Summary atom energies Type Heavy
71. menu on any molecule in the Workspace Explorer or by selecting a molecule in the Workspace Explorer and pressing the Show PDB Header or the Show SDF Header button for PDB and SDF files respectively molegro molecular viewer user manual 2 User Interface page 41 101 lt PDB File Header 1STP pdb PDB File Header 1STP pdb HEADER BIOTIN BINDING PROTEIN 12 MAR 92 1STP 15TP Z COMPND STREPTAVIDIN COMPLEX WITH BIOTIN 1STP 3 SOURCE STREPTOMYCES AVIDINII 15TP 4 AUTHOR P C WEBER F R SALEMME 1STPA 1 REVDAT 2 15 OCT 94 15TPA 1 AUTHOR 1STPA 2 REVDAT 1 15 OCT 92 15TP O 1STP 6 JBNL AUTH P C WEBER D H OHLENDORF J J WENDOLOSKI F R SALEMME 1STP 7 JENL TITL STRUCTURAL ORIGINS OF HIGH AFFINITY BIOTIN BINDING 1STP 8 JENL TITL Z TO STREPTAVIDIN 1STP 9 JRNL REF SCIENCE V 243 85 1989 1STP 10 JRNL REFN ASTM SCIEAS US ISSN 0036 8075 038 1S5TP 11 REMARK 1STP 12 REMARK REFERENCE 1 1STP 13 REMARK AUTH P C WEBER J J WENDOLOSKI M W PANTOLIANO F R SALEMME 1STP 14 REMARK TITL CRYSTALLOGRAPHIC AND THERMODYNAMIC COMPARISON OF 1STP 15 REMARK TITL 2 NATURAL AND SYNTHETIC LIGANDS BOUND TO STREPTAVIDIN 1STP 16 REMARK REF J AM CHEM SOC V 114 3197 1992 15TP 17 REMARK REFN ASTM JACSAT US ISSN 0002 7863 004 1STP 18 REMARK 1STP 19 Figure 30 PDB header information shown for imported PDB file A workspace may contain an arbitrary number of import notes and each molecule may have a reference to one of these notes Imported notes a
72. molecular viewer user manual 5 Analyzing Docking Results page 67 101 Hydrogen bonds Cofactor hbond Electrostatic Cofactor elec Water Ligand interactions E Inter water ligand Displacable Water interactions E DisplacedWater Internal Ligand interactions E Intra tors ligand atoms Torsional strain E Intra tors Torsional strain Sp2 sp2 E Intra sp2 sp2 Hydrogen bonds E Intra hbond Steric by PLP E Intra steric Steric by LJ12 6 E Intra vdw Electrostatic E Intra elec Search Space Penalty E Penal Soft Constraint Penalty E Soft Constraint Penalty On the settings tab the ligand evaluation can be customized This can be important when inspecting poses from a docking run Since the Ligand Energy Inspector is not aware of which scoring function settings were used during the docking it is necessary to match the settings here to those selected in the Docking Wizard The scoring function combo box allows to choose between the docking scoring functions available in MMV and MVD MolDock Score and PLANTS Score For MolDock Score the following options are available Internal ES toggles whether internal electrostatic interactions should be calculated for a pose Internal Hbond no directionality toggles whether a pose should be allowed to have internal hydrogen bonds notice that hydrogen bond directionality is
73. molegro molecular viewer Ge Git ves teremo Penwene Te pma Ge Mycogera fog Hide Pemcuee Pepeng IYN pljrn the pMa IVN MVU bunk Md MFU un pe Papero EINS Oton the p Mote SYN AD uk MA Naaa upd Pacang 204_2E Otan the MNoaga TVN MD Tunk MANT Aaaa un pd Pagano SOL_I0E7 pOton iie g Moapa EYN MVD Taak Mua MTA u pat Barg secondary tutae if ted wth 16 ego Sch srece ousted Hong rosne r notapece LC bi page 2 101 ll bio Molegro A CLC bio company Copyright 2005 2012 Molegro A CLC bio company All rights reserved Molegro Molecular Viewer MMV Molegro Virtual Docker MVD Molegro Data Modeller MDM Molegro Virtual Grid MVG and MolDock are trademarks of CLC bio All other trademarks mentioned in this user manual are the property of their respective owners All trademarks are acknowledged Information in this document is subject to change without notice and is provided as is with no warranty CLC bio makes no warranty of any kind with regard to this material including but not limited to the implied warranties of merchantability and fitness for a particular purpose CLC bio shall not be liable for errors contained herein or for any direct indirect special incidental or consequential damages in connection with the use of this material molegro molecular viewer user manual page 3 101 Table of Contents 1 PAPOOUICHION sx Seheneidereeseonitinonaie e a E E e a E E RE E 5 1 1 Contact InformatlONks
74. ng energy between protein and ligand calculated by PLP Electro The short range r lt 4 5A electrostatic protein ligand interaction energy ElectroLong The long range r gt 4 5A electrostatic protein ligand interaction energy NoHBond90 This is the hydrogen bonding energy protein ligand as calculated if the directionality of the hbond was not taken into account Notice This term is not used by the MolDock score VdW LJ12 6 Protein steric interaction energy from a LJ 12 6 VdW potential approximation Notice This term is not used by the MolDock score E Inter water ligand The MolDockScore interaction energy between the pose and the water molecules E Intra tors ligand atoms The total internal MolDockScore energy of the pose E Intra steric Steric self interaction energy for the pose calculated by PLP molegro molecular viewer user manual 9 Appendix III MolDock Scoring Function page 89 101 E Intra hbond Hydrogen bonding self interaction energy for the pose calculated by PLP Notice This is a non standard term and is zero by default it must be enabled by specifying the internalhbond true option to the EVALUATOR initializer list in a MVDScript file or by enabling the Internal HBond option in the Docking Wizard E Intra elec Electrostatic self interaction energy for the pose Notice This is a non standard term and is zero by default
75. ns must be surrounded by quotes As with file data sources it is possible to specify a subset using the molecule index specifier Index Notice that the Index specifier refers to the molecule index not the file index By using the File Import From Datasource menu item it is possible to directly load a number of molecules into the workspace This can be useful for importing a small subset of the molecules in a data source to check that the parsing and preparation is okay Notice that all molecules are loaded into memory which can make the system slow to work with The Data Source dialog for defining the data source is shown in Figure 35 molegro molecular viewer user manual 4 Data Sources page 53 101 Data source Examples File Molecules SDF Index 10 100 10000 10010 Dir G Molecules pattem SDF MOL2 Index 40 1000 Data source description C Documents and Settings Mikael Desktop zinc 2 sdf More information Figure 35 Specifying a data source Specify the data source on the Data source description line input or use either the Dir or File button to choose a directory or file from a dialog The Preparation tab determines how the data source should be prepared These settings are described in Section 3 2 molegro molecular viewer user manual 5 Analyzing Docking Results The Pose Organizer is used to inspect poses found by Molegro Virtual Docker see Figure 3
76. nstance the remarks may contain redundant identity transformations which should be removed Example of identity transformation REMARK 350 BIOMT1 1 1 000000 0 000000 0 000000 0 00000 REMARK 350 BIOMT2 1 0 000000 1 000000 0 000000 0 00000 REMARK 350 BIOMT3 1 0 000000 0 000000 1 000000 0 00000 PDB transformation remarks are triplets of remark lines named BIOMT1 3 The first three columns constitute a rotation matrix and the last column is a translation vector For some complex structures the transformation description may contain several steps where different transformations are applied to different subsets of the molecules In this case it is necessary to run the Biomolecule Generator multiple times Also notice that biomolecules can be very large Always render the protein in wireframe before attempting to generate large biomolecules molegro molecular viewer user manual 2 User Interface page 39 101 2 24 Structural Alignment of Proteins It is possible to structurally align proteins in MMV A structural alignment is done by matching a number of residues in two proteins and calculating the translation and rotation that minimizes the RMSD between the alpha carbons in the matched residues The Structural Protein Alignment dialog can be invoked by selecting Tools Structural Protein Alignment from the main menu Structural Protein Alignment Reference protein 2ACR A w Matched residues 272 mat
77. nstraints visualized as small spheres cavities visualized as a grid mesh and various graphical objects molecular surfaces backbone visualizations labels etc By default an empty workspace is shown when starting MMV A workspace can be saved cleared replaced by or appended to other workspaces The content of the current workspace is listed in the Workspace Explorer window which also allows for manipulation of the various items available see Section 2 4 for more details Notice When saving a workspace in the internal MVDML format not all 3D visualization objects are saved e g labels interactions annotations backbones and surfaces For more information about the MVDML format see Appendix I and Section 5 2 MMV can visualize constraints and cavities when importing MVDML files created by Molegro Virtual Docker MVD but MMV does not support creation of constraints and detection of cavities on its own The user interface in MMV is composed of a central 3D view referred to as the Visualization Window or 3D world together with a number of dockable windows introduced below molegro molecular viewer user manual 2 User Interface page 9 101 121p MVDML MVD2006 File Edit View Rendering Preparation Docking Window Help B2RhAa0 e Haon KX oF Tp ressee Workspace Explorer x A a a gt a x o amp D a a Visualization Window pa D7 e Position 8 649 35 121 20 a Atom ID 10 Bemet 8 Prope
78. o molecular viewer user manual 1 Introduction page 6 101 VAT no DK 28 30 50 87 Telephone 45 70 22 55 09 Fax 45 70 22 55 19 E mail info clcbio com If you have questions or comments regarding the program you are welcome to contact our support function E mail support clicbio com The system requirements for Molegro Molecular Viewer are a Windows 7 Vista XP 2003 or 2000 a Linux Most standard distributions We provide both 32 and 64 bit builds such as Fedora Core 3 or later versions and Red Hat Please send a mail to Ssupport clcbio com if the program does not work on a particular distribution and we will try to provide a new build a Mac OS X 10 5 Intel and later versions If you discover a program error please mail the information to support clcbio com Remember to specify how the error can be reproduced the version number of Molegro Molecular Viewer in question and the operating system that was used If possible inclusion of molecular files used e g Mol2 PDB MVDML will make it easier for us to reproduce and correct the error The following formatting styles are used in this manual a All GUI text labels and keyboard shortcuts are written in bold face with initial capital letters Examples Workspace Explorer Fixed Color Ctrl O a Menus and menu items are identified using dividing lines and bold face Example View Docking View indicates that the user should first select the Vie
79. ogen bond i e spots near a hydrogen donor in the protein They appear as blue regions Notice that the fields do not take direction into account for instance the position of the hydrogen in a hydroxyl group is not taken into account when calculating the field it is assumed to be able to point in any direction Hydrogen Donor Favorable The regions show favorable spots for heavy atoms in the ligand that are able to donate a hydrogen to a hydrogen bond They appear in yellow Electrostatic Show the electrostatic potential of the protein Red molegro molecular viewer user manual 2 User Interface page 44 101 regions correspond to a nearby negative electro static charge in the protein Blue regions correspond to a nearby positive charge in the protein The electrostatic potential is the sum of the Coulomb potentials for each atom in the protein with a distance dependent dielectric constant The electrostatic field is not used with the PLANTS Scoring function All the fields take the steric interaction into account so that only grid positions where it is possible to place an atom without steric clashes with the protein are shown For instance there may be charged regions inside the protein which are not shown because it is not possible to place a ligand atom there It is possible to adjust the appearance of the fields The Threshold slider determines at which point an interaction is strong enough to be included in the visu
80. oice is Pairwise Atom Atom RMSD checking all automorphisms which is also used by default RMSD Matrix Pairwise Atom Atom RMSD checking all automorphisms Name 0 1 2 0 XK2_263 0 579023 1 25688 1 30984 1 00 XK2_263 1 28563 1 32552 2 01 XK2_263 1 25688 1 28563 1 71806 3 02 XK2_263 1 30984 1 32552 1 71806 lt Molecule 1 00 XK2_263 Molecule 2 XK2_263 RMSD 0 579023 Copy to Clipboard Figure 46 RMSD Matrix dialog molegro molecular viewer user manual 5 Analyzing Docking Results page 73 101 The dialog can be invoked by choosing RMSD Matrix from the Tools menu The Copy to Clipboard button can be used to copy the table to the clipboard for further inspection in an external text editor or spreadsheet molegro molecular viewer user manual 6 Customizing Molegro Molecular Viewer 6 1 General Preferences Molegro Molecular Viewer can be customized using the Preferences dialog which can be invoked from the Edit menu or by pressing F4 Preference settings are categorized in General Graphics Mouse and Parsing tabs Preferences Graphics Mouse Parsing C Load most recent workspace on startup if any C Check for new updates on startup C Create system log in directory below System log directory requires restart Logs Working directory c Molegro Src Myd MYVD VisualStudio PDF viewer Reset All to Defa
81. olor Rebuilds all objects in the Visualizer Window This command is necessary to call after the visualization styles or coloring schemes have been updated Otherwise graphical changes will not be reflected in the GUI REBUILD The label command works in the following way it scans the input string for known variables like ID HYB ELE see below and replaces them with their value That is the command label bond bond_number id will add a label of type bond number x to every bond underscores are replaced with spaces To clear all labels use label without any argument Variable Description Atom labels Syntax Addlabel string ID Internal atom index Type Hydrogen bond type non polar acceptor donor both The yP HBOND variable below is probably of more use PC Partial Charge PC PC ignores atoms with no partial charge HYB Hybridization HYB HYB only displays hybridization for atoms with other hybridizations than SP3 or unknown SP2 Labels SP2 hybridized atoms SYM Element symbol H C N ELE Element number IH Number of implicit hydrogens HBOND Hydrogen bond type shown as D A D A non polar molegro molecular viewer user manual 12 Appendix VI Console Commands page 99 101 HBOND HBOND ignores non polar atoms ETOT Shows the total energy of the atom This requires that the energy has been evaluated using the eval command PDB At
82. om Name Show PDB atom name PDB Index Show PDB atom index Bond labels Syntax Addlabel bond string ID Internal bond index Type Bond order single double triple aromatic Shows the total energy of the bond ETOT This requires that the energy has been evaluated using the eval command Residue Labels Syntax Addlabel residue string ID Internal residue index LONGNAME Full residue name histidine cysteine NAME 3 letter abbreviation HIS CYS LETTER 1 letter abbreviation molegro molecular viewer user manual 13 Appendix VII Third Party Copyrights Icons The icon set used in MMV is taken from The Tango Icon Library http tango freedesktop org Tango_Desktop_ Project They are released under the Creative Commons Share Alike license http creativecommons org licenses by sa 2 5 molegro molecular viewer user manual 14 Appendix VIII References THOMSEN 2006 Thomsen R Christensen M H MolDock A New Technique for High Accuracy Molecular Docking J Med Chem 2006 49 11 3315 3321 LGEHLHAAR 1995 Gehlhaar D K Verkhivker G Rejto P A Fogel D B Fogel L J Freer S T Docking Conformationally Flexible Small Molecules Into a Protein Binding Site Through Evolutionary Programming Proceedings of the Fourth International Conference on Evolutionary Programming 1995 615 627 GEHLHAAR 1998 Gehl
83. or highlighted 3D object s in the Visualization Window and provides useful information while preparing and modifying the molecules Figure 4 shows an example of different properties for a highlighted atom molegro molecular viewer user manual 2 User Interface page 12 101 Property Selection Position Residue Intemal residue ID Atom ID Element PDB atom name Implicit hydrogens VdW radius Covalent radius Hydrogen bonding Partial charge Hybridization Temperature Average angle Value 2 164 8 951 26 069 GLY 52 51 458 C 6 CA 0 17A 0 68 A Nonpolar 0 Sp3 42 34 112 039 Clear Selection Figure 4 Example of properties for a selected atom The Visualization Window see Figure 5 visualizes all the selected molecules in the workspace and all custom graphical objects e g labels annotations charges backbones surfaces and cavities Notice Cavities can be imported and visualized from MVDML files but not created in MMV MVD is required to create cavities For large molecules it can be computationally slow to display all atoms Therefore it is recommended to adjust the view to the user s needs Often it is a good idea to add a molecular surface perhaps transparent to give some idea of the 3D structure Alternatively switching to wireframe visualization style and hiding non polar or all hydrogens atoms can also improve the visualization speed significantly Also consider cropping removing
84. p MMV Example Molegro MMV bin mmv currentPath molegro molecular viewer user manual 7 Appendix Supported File Formats MMV accepts the following molecular structure formats PDB Protein Data Bank Supported file extensions pdb ent a Mol2 Sybyl Mol2 format Supported file extensions mol2 m SDF MDL format Supported file extensions sdf sd for multiple structures and mol md for a single molecular structure Currently the following information is ignored during import of molecular structures a Lone pairs and dummy atoms all file formats a When alternative atoms are reported only the first alternative is used The remainder is ignored all file formats If one of the other alternatives should be used change the order of occurrence in the the file before import a CONNECT records PDB format a SUBSTRUCTURE records are ignored during import but created when structures are exported Mol2 format Notice Although extensive testing and validation of the import and export of these file formats have been conducted parsing errors may occur Compliance with the file format standards protocols will reduce parsing problems significantly The import export routines used have been extended to handle deviations from the file format protocols but parsing errors may still occur Found parsing errors can be reported send email to bugs molegro com Additionally Molegro Molecular Viewer and Molegro V
85. pecified in the file for the re ranking scores Notice that the default evaluator settings will be used e g internal ligand hydrogen bonds are not enabled The reranking score function is computationally more expensive than the scoring function used during the docking simulation but it is generally better than the docking score function at determining the best pose among several poses originating from the same ligand The default reranking coefficients are listed in the file Misc Data RerankingCoefficients txt The bottom panel Table columns determines which columns descriptors that are shown in the table on the first tab Table 1 describes the descriptors that are available New descriptors can be added from regression models created using the Molegro Data Modeller MDM software product see www molegro com for more details about MDM To add a new descriptor simply press the Add descriptor from regression model button and chose the regression model from a saved Molegro Data Modeling MDM file Notice that the regression model should only be using the same descriptors as the ones that are available in the DockingResults files only valid regression models will be available in the dialog The Pose Organiser shows a subset of the terms in the mvdresults file as columns in the Poses table Some of the terms use the same terminology as in the mvdresults file Specifically Name Ligand Filename Workspace RerankScore
86. ration page 49 101 Always If this option is set to Remove the ligand will be considered rigid during docking This option is used to assign Tripos atom types using a built in heuristic If the option is set to Never atom types will be imported from the molecule file instead of being assigned by MMV only available for Mol2 structural files The Remove option will set all atom types to Undefined Always will assign Tripos atom types to all atoms using built in assignment rules and If Missing default will assign atom types to Dummy Undefined and Other typed atoms using built in rules all other atom types will be imported from the Mol2 file Atom hydrogen bonding types acceptor donor both or non polar are always set during preparation Molecules can be manually prepared using the context menus of highlighted atoms or bonds see below Hybridization SP SP2 SP3 can be manually assigned to atoms by right clicking on the atom in question and selecting the Set Hybridization menu option Hydrogen bond type donor acceptor both non polar can be manually assigned to atoms by right clicking on the atom in question and selecting the Set Hydrogen Bond Type menu option Sometimes the built in assignment scheme fails in assigning correct Tripos atom types to specific atom In such cases it is possible to change the Tripos atom type for nitrogen oxygen carbon and sulphur atoms by right clicking on the atom in question
87. re stored in the MVDML workspace file and they can be viewed and deleted using the Workspace Properties dialog molegro molecular viewer user manual 2 User Interface page 42 101 S Workspace Properties Workspace title 1 STP Last saved not set C Show properties window when loading workspace User notes Here you can write comments and notes Imported notes PDB Header for 1STP pdb Select All Delete Selected Show Selected Figure 31 Imported PDB and SDF notes can be shown and deleted using the Workspace Properties dialog Notes that are no longer referenced by a molecule are automatically removed 2 27 Energy Maps It is possible to visualize the force fields in Molegro Molecular Viewer using the Energy Map Visualization dialog The Energy Map Visualization dialog can be invoked by pressing the Energy Map button on the main GUI toolbar molegro molecular viewer user manual 2 User Interface page 43 101 amp 1HVR mvdml Molegro Virtual Dockes File Edt View Rendering Preparation Docking Tools Window Help B 75 Q E E Hogens Fog Hide Residues Search Space _ Ligand Map Eneray Map items Options v Workspace New a A Backbones 2 a O Cavities 1 a O Cofactors 2 E Constraints 1 a Z Energy Map 1 E Ligands 51 Proteins 2 a a O Surfaces 2 Energy Grid MolDock Score GRID V Ste
88. rgies as compared to the non grid MolDock score version SimilarityScore Similarity Score if docking templates are enabled LE1 Ligand Efficiency 1 MolDock Score divided by Heavy Atoms count LE3 Ligand Efficiency 3 Rerank Score divided by Heavy Atoms count Energy terms contributions E Total The total MolDock Score energy is the sum of internal ligand energies protein interaction energies and soft penalties E Inter total The total MolDock Score interaction energy between the pose and the target molecule s E Inter cofactor ligand The total MolDock Score interaction energy between the pose and the cofactors The sum of the steric interaction energies calculated by PLP and the electric and hydrogen bonding terms below Cofactor VdW The steric interaction energy between the pose and the cofactors calculated using a LJ12 6 approximation Notice This term is not used by the MolDock score Cofactor elec The electrostatic interaction energy between the pose and the cofactors Cofactor hbond The hydrogen bonding interaction energy between the pose and the cofactors calculated by PLP E Inter protein ligand The MolDock Score interaction energy between the pose and the protein Equal to Sterict HBond Electro ElectroLong below Steric Steric interaction energy between the protein and the ligand calculated by PLP HBond Hydrogen bondi
89. ric Favorable J Hydrogen Acceptor Favorable Property Vee 7 Hydrogen Donor Favorable Selected Atoms 36 7 Bectrostatic Threshold Dot Size Transparency Clear Selection Time Description 14 15 34 268 Process spawned 14 35 17 326 Energy Maps work better when there is no transparent objects Tumed off Search Space 14 35 17 334 Found grid in workspace 14 35 17 335 Started creating grid Radius 15 Resolution 0 55 Points per side 55 Total points 166375 Layers 5 Mem 6 35 14 35 18 231 Created grid with 166375 points 1514 atoms 12515261 entries written 14 36 04 977 Building secondary structure 3d object with 8 regions 14 36 05 017 __ Building secondary structure 3d object with 8 regions Figure 32 Energy Grid Visualization The MolDock GRID and PLANTS Score GRID scoring functions use a precalculated energy grid during the docking simulations to accelerate the protein ligand interaction calculations Visualising these potential fields makes it possible to gain an understanding of which regions are attractive to the atoms in a ligand Four different types of energy potentials can be shown Steric Favorable These are the regions where it is favorable to place non polar atoms These volumes are visualized in green This field will be strongest near the surfaces and in cavities Hydrogen Acceptor Favorable These are the spots where it is favorable to place a ligand atom capable of accepting a hydr
90. risisiicuis sidii eadun ia anaa REA E RAAE AANER 5 1 2 Systemi ReqUiIr MEnNtSi rerin irni aa aeaa EE 6 1 3 Reporting Program ErrOrfS ss sssssssssrrssrrrnnrrrnnnrnnnrnnnnrnnnnnnnrnnnrrnnnnnnnnn 6 1 4 Text Formats Used in the Manual sires ccsvideccawesdiswisodeasateresttededcecndaneess 6 1 5 Keyboard SHORES tetcedetatwis boetcluiuboidieutportluabioteriusoiavaliemiatonue batons 7 1 6 Screenshots Used In the Manual cccccesssccceeeeeeeeeeseeeeeeeeenteeeees 7 1 7 Future UpdateS s sssssssssssrrrreesarnrrensannrrsnesnnnrnsennnssssnnnsonnnnnrenanenna 7 t8 PDF Heleri erranen naa EEEN EA AE E AAEREN 7 2 User Interfaco sn ioien Ea EEA EE EEE a EE DE 8 2 1 Basi COMCEP S seniore o EE R E EEEE Eia 8 2 2 OVErV EWisiisrertininen ninanda aa EA ed ee VANTANT 8 2 3 MDOID EN censenda ea EEA Da a a E TEE 9 2A Workspace EXplOre irren ninnunannu aE Ea EER aAa a i 10 2 5 Properties WiINdOW sre brrnoseien oniinn e a a RE opens ose 11 2 6 Vis alization WINKOW ascisuiisciowscsnciwids thewdds u 12 2 7 Console WiNdOWisriccrirusicisnnr ic A E E Ea 15 2 8 Clipping PlANGS 2s cccecicecweeseiocetseskesseikasccdolactcecsdewacsccsceseesesaneeicateaun 16 2 9 Creating a Search SP aCe sorreran vasecasnssteemanatear nana seereebeckawketdadeees 16 2 10 Hiding Distant RESiGUGSisc0 vote ereenn terete haere tite 17 2 11 Workspace FINGED is sisvscasionsdsvevnad iraran vulssieuwtssioavivesiase en KNA 18 2 12 Seg ente VIEW CP iiitide irinin E EEEE EE AE RE 19 2 13 Wo
91. rkspace POD IleS vevccecawrscexexccsescssceecssuncuresncisust eden ccnenmeraigcecat 21 2 14 Measurements and AnnotatiOns ccccecceeeee eee teense nese eeeene eee ennnaa 21 2 15 Selection of Atoms Amino Acids Rings and Molecules c sseeeees 22 2 16 Custom Coloring of Atoms Amino Acids and Molecules 0005 22 2 17 Creating eae 1S onto cg ean ewes tande cece one ersevegcte areca pause cect atoniemssece 23 2 18 Creating Molecular SUMACES icics acsear oedensuetaueivdenteddoneeadader ddessiadaws dx 24 2 19 Creating Protein Backbone ViSUaliZAtIONS cc cece eee cece eee eee ee ees 26 2 20 Making ScreenShots acis nide e E E EEEE ten 28 2 21 Visualization Settings DidlOQsissicssincs evseuss eveviiewianis views eraneaeviendvadenns 29 2 22 High Quality RENGSHING dcsscecetes chseeieeeie einai de tasieews eevee ehewenaeeees 35 2 23 Biomolecule Generator s sssssssrrssersrnsssnnnnsssnnnrnosnnnsnnrrsnnrnnnennnnna 37 2 24 Structural Alignment Of ProteinsS 1 c 060ssccccsvececesereeessteeneeeesseseeeees 39 2 25 Structural Alignment of Small MoleculeS sssssssssssssssrassrrrsrresrrnnn 40 2 26 PDB atid SDF Import NOUCS isis si cwsds ti cusdsseensd ertensd velaudsyaens bes eesdanenden 40 2 27 ENEY MSD Sismisusdascaniansesdevisue ELaNA EAA ENG E R 42 3 Preparatif siii serina a ea R E A T EEA 45 3 1 Import OF M lec lES ense nipirs minnepinne GE EEE ENEI EEE 45 3 2 Automatic Preparation isiiicaiiewere iva tertavereic
92. rties Window Hydrogen b Acceptor Partial charge 0 5 Hybridization Temperature 0 Average an 0 Clear Selection Time Description 12 37 55 725 Macros loaded Console Wincow Figure 1 Main application window The MMV Toolbar provides easy and fast access to commonly used actions such as import of molecules and pose inspection using the Pose Organizer Import Molecules Fitto Screen Screen Capture E G T C OL re nt Se in Eeo Se gt Label Dialog Toggle Hydrogens On Off Visualization Settings Docking Wizard Figure 2 MMV Toolbar The MMV Toolbar also contains different toggle buttons The Hydrogens button makes it easy to switch between different view modes Show all hydrogens Show only polar hydrogens and Hide all hydrogens The Fog button is used to toggle fog effects on and off The Hide Residues button is used to toggle whether residues should be hidden or not see Section 2 10 molegro molecular viewer user manual 2 User Interface page 10 101 for more details The Search Space button makes it possible to define and toggle Search Spaces on and off see Chapter 2 9 and the Ligand Map button is used to toggle on 2D visualization of a ligand or pose and its interactions with the protein see Section 5 4 for more details Finally the Energy Map button visualizes the force field generated by the proteins in the workspace see Chapter 2 27 The Workspace
93. s an approximation to the surface created by expanding the Van der Waals radius of each atom with the Probe Radius Molecular surface this is an approximation to the surface defined by the contact area of the probe and Van der Waals sized spheres Surfaces can be colored by Hydrophobicity Electrostatic Potential or Solid Color Surfaces can be drawn transparently as dots lines or solid polygons molegro molecular viewer user manual 2 User Interface page 25 101 Create Surface iSurface Target vt a O Cofactors 2 Proteins 2 O Poses 1 O Ligands 1 eee Surface type coloring Electrostatic Figure 16 Creating a new surface Surfaces can be created via Create Surface from the context menu in the Workspace Explorer or via Tools Surfaces molegro molecular viewer user manual 2 User Interface page 26 101 Create Surface Surface Target Appearance Drawing style Solid Transparency Figure 17 Changing surface appearance 2 19 Creating Protein Backbone Visualizations The backbone of the protein can be visualized by using the Create Backbone Visualization dialog The dialog can be invoked by using the context menu on the Proteins category or a single protein item in the Workspace Explorer 2 Create Backbone Visualization Backbone Target Target s Figure 18 Creating a new backbone
94. s between residue endpoints molegro molecular viewer user manual 2 User Interface page 20 101 4HVR mvydml Molegro Molecular Viewer File Edit view Rendering Preparation Tools Window Help 5 Q igs X Hydrogens Fog Hide Residues Search x Workspace Explorer F Items Options E Workspace New 4 O Ligands 1 Proteins 2 Sequence Viewer Figure 11 Sequence viewer with selection of four residues highlighted in the Visualization Window The Sequence Viewer dialog can be invoked by selecting Window Sequence Viewer or using the Ctrl Shift S keyboard shortcut molegro molecular viewer user manual 2 User Interface page 21 101 2 13 Workspace Properties Workspaces can contain user specified notes Further the title of the workspace can be changed using the Workspace Properties dialog The Workspace Properties dialog can be found in the Edit Properties context menu on the Workspace item in the Workspace Explorer or via Edit Workspace Properties see Figure 12 2 Workspace Properties Workspace title 1407 Last saved not set _ Show properties window when loading workspace Workspace notes Here you can write comments and notes Figure 12 Workspace Properties dialog 2 14 Measurements and Annotations Distances and angles can be measured directly in the 3D world see Figure 13 If two atoms are selected the distance between them wil
95. sibilities the atom closest to the current one will be chosen molegro molecular viewer user manual 9 Appendix Ill MolDock Scoring Function The MolDock scoring function MolDock Score used by MVD THOMSEN 2006 is derived from the PLP scoring functions originally proposed by Gehlhaar et al GEHLHAAR 1995 1998 and later extended by Yang et al YANG 2004 The MolDock scoring function further improves these scoring functions with a new hydrogen bonding term and new charge schemes The docking scoring function Escore is defined by the following energy terms Epp t E score inter intra where Enter is the ligand protein interaction energy qi Ew Vo L Breet 3320 A ie ligand je protein Fj The summation runs over all heavy atoms in the ligand and all heavy atoms in the protein including any cofactor atoms and water molecule atoms that might be present The Epp term is a piecewise linear potential described below The second term describes the electrostatic interactions between charged atoms It is a Coulomb potential with a distance dependent dielectric constant given by D r 4r The numerical value of 332 0 fixes the units of the electrostatic energy to kilocalories per mole To ensure that no energy contribution can be higher than the clash penalty the electrostatic energy is cut off at the level corresponding to a distance of 2 0 A for distances less than 2 0 A Notice that although the electrostatic energy contr
96. space the default visualization settings will be used It is possible to create high quality screenshots by selecting Rendering High Quality Render Raytrace The High Quality Render Raytrace dialog makes is possible to create images in arbitrary size and higher quality than when saving screenshots from the OpenGL view The High quality render uses a raytrace engine to create the output image This has some graphical advantages as compared to the default OpenGL rendering for instance spheres are not converted into triangle meshes before being drawn and it possible to create shadow effects Since another rendering technique is used the output may deviate from the OpenGL view The High Quality Render also makes it possible to create high resolution images suitable for publications Notice that a few graphical objects are not supported by the raytracer dot surfaces protonation guides and energy grids The raytracer also ignores clipping planes and the light source settings in the Visualization Settings Dialog molegro molecular viewer user manual 2 User Interface page 36 101 Pixel size Width pixels Height pixels Double size Half size Window size Physical size Resolution DPI 300 00 Units inches x Width finches 1 29 1 91 V Create shadows Font scale 1 00 Adaptive antialias Low 4 samples per pixel Figure 26 The High Quality Output dialog The High Quality Output d
97. tion Settings dialog molegro molecular viewer user manual 2 User Interface page 30 101 From the Style and Color tab select a category from the list on the left side of the tab one of Proteins Ligands Poses Water and Cofactors and adjust either its graphical style or color scheme The following graphical styles can be chosen Ball and Stick Atoms are drawn as spheres balls and bonds are drawn as cylinders sticks The Atom Scale parameter sets the fraction of the Van der Waals radius that is used as radius for the sphere Bond Scale is the diameter of the bonds in Angstrom This is the preferred graphical style for modifying and inspecting bond and atom properties since the bond order is visualized and the atoms are easy to select Stick Bonds are drawn as cylinders Bond Scale is the diameter of the bonds in Angstrom Spacefill CPK Atoms are drawn as spheres balls Bonds are not drawn The Atom Scale parameter sets the fraction of the Van der Waals radius that is used as radius for the sphere Wireframe This is by far the fastest way to draw molecules Bonds are drawn as lines between atoms No atoms are drawn but notice that it is still possible to do atom selections in the GUI Notice all bonds are drawn as single lines double bonds and delocalized bonds are also drawn as single lines It is possible to adjust the line width in pixels Notice that not all OpenGL implementations support non integer
98. ton ry Expos All Windows Scrolling Options 360 Degree ay Tracking Scrolling Double Click e yeee O _ s Y VY i i Y ost P Eci i 1 Slow Fast Slow Fast Slow V Zoom using scroll ball while holding Control 7 Options Figure 50 Mighty Mouse preferences on Mac OS X The final settings tab Parsing contains the Minimum protein size PDB import option This option is used for setting the minimum number of heavy atoms required for parsing a molecule as a protein during PDB import default is 69 heavy atoms If the parsed molecule contains less heavy atoms than the specified threshold value it is parsed as a ligand and residue information is ignored The Parsing tab also determines how MMV handles non standard characters such as special national characters This setting is used when importing and exporting molecular structures in text file format such as SDF Mol2 PDB files and when working with other text files such as mvdresults and mvdscript molegro molecular viewer user manual 6 Customizing Molegro Molecular Viewer page 78 101 files XML files such as MVDs internal MVDML file format are always stored as UTF 8 E lt Preferences General Graphics Mouse Parsing Minimum protein size PDE import 69 J Default File Encoding UTF 8 also reads UTF 16 and ASCII v C Break unrealistic bonds during import Mol2 SDF Default Combine Mol2 substructures and sma
99. ults Apply Cancel Figure 47 First tab of the preferences dialog In the General tab see Figure 47 the following settings are available a The Load most recent workspace on startup if any option toggles automatic import of the last used workspace molegro molecular viewer user manual 6 Customizing Molegro Molecular Viewer page 75 101 The Check for new updates on startup option enables MMV to automatically check for new updates during startup The Create system log in directory below option is used to toggle whether a system log is created for each execution of MMV The system log contains information about user actions conducted and is used to track potential bugs and performance problems By default the log files are stored in the Logs directory located in the same directory as the mmv executable file but another directory can be used if needed e g if user has no write permissions to the directory used Notice If you encounter problems with MMV please email the log file created before the crash to bugs molegro com The Working directory setting is used to set the current Working directory which is the root path for file related operators e g when loading and saving molecular structure files and log files The PDF viewer setting is used to specify the executable of an external PDF viewer which can be used instead of the default built in viewer The Graphics tab see Figure 48 contains settings related to
100. w menu and then select the Docking View menu item a Filenames are written in mono spaced font Example Molegro MMV bin mmv exe molegro molecular viewer user manual 1 Introduction page 7 101 The keyboard shortcuts used in the manual works for Windows and Linux versions of MMV On Mac OS X the CTRL key is replaced by the command key and function key shortcuts e g F1 should be invoked by pressing the function key and the fn key e g fn F1 The screenshots used in the manual are taken from the Windows XP and Vista versions of MMV Therefore dialogs and other GUI related material may Slightly differ on Linux and Mac OS X versions Molegro Molecular Viewer contains a built in version checker making it easy to check for new program updates including new features and bug fixes To check for new updates select Help Check for Updates A window showing available updates and details about changes made will appear The Molegro Molecular Viewer User Manual can be invoked using the built in PDF reader by choosing Help MMV Help from the menu bar The executable for the PDF reader can be specified in the Preferences molegro molecular viewer user manual 2 User Interface Molegro Molecular Viewer is based on the notion of workspaces The workspace is the central component and represents all the information available to the user in terms of molecules proteins ligands cofactors water molecules and poses user defined co
101. will be removed If no radius is given the surface will cover the protein If a radius is given the surface will cover the protein in the given radius but centered at the current active ligand If the variant with LIGAND argument is used the surface will cover the currently active ligand Resolution is typically 0 4 0 9 Don t choose higher resolutions i e lower than 0 4 unless you are prepared to wait for a long time The default value of the probesize 1 2 should be fine for most purposes Examples ADD PSURF 10 Electrostatic carved protein surface with radius 10A centered at the active ligand ADD SURF ligand 0 4 Carved ligand surface with resolution 0 4 DELETE Charges HBOND Deletes specified objects molegro molecular viewer user manual 12 Appendix VI Console Commands page 97 101 Labels Poses LIST POSES Shows all poses with info about parameters CLS Clears console log CLEAR workspace selection CLEAR workspace removes all items in the current workspace CLEAR selection clears current selection HIDE hydrogens labels Hides either hydrogens or labels SHOW hydrogens labels Shows either hydrogens or labels FITTOSCREEN Fit all molecules in the visualization window Used for labeling objects This command is described in detail in the paragraph below ADDLABEL Notice It is much easier to use the Label dialog in the GUI
102. x y z and a radius The search space is mainly used to define the volume for docking simulation only available in Molegro Virtual Docker but may be used for other purposes as well for instance cropping molecules in the workspace making a partial molecular surface or hiding molecules outside the search space The Search Space button on the main GUI toolbar makes it easy to toggle the search space on and off Toggling the Search Space button is identical to using the checkbox for the search space item in the Workspace s Constraints category with one exception if there is no search space in the workspace pressing the Search Space button will invoke the Search Space Setup dialog molegro molecular viewer user manual 2 User Interface page 17 101 Search Space Setup yy E a ES Center Coordinates X sY 15 95 Set center of workspace Radius A Figure 8 Search Space Setup Dialog The Search Space Dialog makes it possible to set the center and the radius of the search space It is possible to directly set the center coordinates of the search space or to place the center on either The center of the proteins in the workspace a The center of a ligand or a pose in the workspace only the first 10 molecules in each category are shown a The center of a cavity only the 10 largest cavities are shown a The center of all selected objects The Search Space Setup dialog may also be invoked from the application menu

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