Home

FirstDiscovery3.0

1. a 8 Click an atom of the ligand The ligand is now colored aquamarine FirstDiscovery 3 0 Quick Start Guide 39 Chapter 6 Creating Glide Grid Files Table Select Entry Property ePlayer 1 selected amp H01 ligand Hon H20_lig 1 ooo Q Ho2 ligand Ho H20_lig 2 ooo Q H03 ligand Hon H20_lig 3 oo Q H04 ligand Hon H20 lig Q Ho5 ligand Hon H20 _lig 5 oo gt HO6 ligand HO1_H20_lig 6 Ca a Hide Help Figure 6 2 The Project Table panel 9 In the Import panel deselect Replace workspace 10 Import the structure in the file HO1_rec mae 11 On the toolbar click the Show Hide project table button EH The Project Table panel is displayed showing the entries for the 21 structures that you have imported When you complete this exercise you will have imported the H01 receptor the cocrystal lized ligand and 19 structurally similar ligand structures into a scratch project You will also have displayed the receptor and the first ligand structure in the Workspace and colored the ligand so that it is distinguishable from the receptor Generally before you begin working on structures in a scratch project you should save the project This ensures that Maestro saves all changes to the project without prompting you if your synchronization preference is set to Automatically All data associated with a scratch project is discarded when the Maestro session is ended or when you close the project
2. 16 FirstDiscovery 3 0 Quick Start Guide Chapter 3 Introduction to Maestro Table 3 3 Mouse operations in the Project Table Task Mouse Operation Change a Boolean property value Display the Entry menu for an entry Display a version of the Property menu for a property Edit the text or the value in a table cell Include an entry exclude all others Move selected entries Paste text into a table cell Resize rows or columns Select an entry deselect all others Select or include multiple entries Toggle the entry selection or inclusion state Click repeatedly in a cell to cycle through the possi ble values On Off Clear Right click anywhere in the entry If the entry is not selected it becomes the selected entry If the entry is selected the action is applied to all selected entries Right click in the column header Click in the cell and edit the text or value Click the In column of the entry Drag the entries Middle click Drag the boundary with the middle mouse button For an unselected entry click anywhere in the row except the In column for a selected entry click the row number Click the first entry then shift click the last entry Control click the entry or the In column 3 4 6 Project Table Shortcut Keys Some frequently used project operations have been assigned shortcut key combinations The shortcuts their functions and their menu equivalents are listed in Table 3 4 Table
3. The ensemble average lt U gt values were calculated during the simulation that you ran on the HO6_altered ligand In the prediction job AG is calculated using those values and the values you supplied for the a P and y coefficients 11 5 Exercise Summary If the calculated binding energy for the modified HO6_altered ligand is more negative than those of the training set ligands then the modified molecule might be a good drug candidate If you want to stop working on the tutorial now choose Close from the Project menu in the main menu bar If a dialog box appears and asks if you would like to save the scratch project click Discard For more information about Quit panel options and log files see Section 3 12 on page 26 11 6 Running the Job With a Command Script A command script predict_lia cmd has been provided in the SCHRODINGER impact vversion tutorial maestro_cmd directory The script uses the Maestro command language in combination with Atom Specification Language ASL to accom plish the tasks described in Section 11 4 1 on page 88 Note that the script does not however start the Predict Simulation job or prepare and start the Predict Analysis it only writes out the input files To start the Predict Simulation job you must click Start on the Liaison panel after the predict_lia cmd script has finished running For more infor mation on running a command script see Section 3 7 on page 22 The script will run successfully
4. eceseseeeecseeeeeeeeeeeeeees 3 QSite pasis Setsuna aR 100 GAME isei as Ias iaa 3 job files writing 100 job type selecting wo eee 97 output files 100 QM region selection eee 96 starting jobs ss 100 quitting Maestro eee eeeeeseeeeseeeeeeeees 26 R reference ligand eect eeeeeees 53 107 Reference Ligand panel cece 33 TIgid docking oe eee eeteeeeeteeeees 32 107 S sample output Glid docking ssion 58 Liaison predict task files 0 89 Liaison simulation 0 ccccc0 82 89 OSite TES aise ecsets cata aidaceeseciecsetee tee 100 Schr dinger contact information 104 scoring preferences defining ee 54 SCTALCHVEMUIES bei cesscssssacasicssssscdsebieiacthe cess 12 SCratch Projects sesceseeseseseeeeeeeeeeeees 12 40 shortcut keys main window Project Table panel Similarity in Glide eects structures building sern era displaying in sequence DAAT OLOI a AI AAEE 111 Index T technical support oo eee etree 26 103 RO OMB AR ee naa E NEE 107 Build panelinin ia 20 main WINdOW s sssseeeereereeereee 8 11 Project Table panel cceeeeeeeeeees 14 Top View Window ceceeeeeeseeeeeeeeees 107 transformations POD A i dsssscssedsesivesesasdetusiaetisasesetab sias 106 VOCAL cscscsesceseseoisstdecsssdecdencsestassavtnsontees 106 tutorial directory creating ian OT TYPO SHYVICS 5 vissesi sssac
5. for example a receptor and a set of ligands You can fix entries in the Workspace by selecting the entries and choosing Fix from the Entry menu or by pressing ALT F A padlock icon replaces the diamond in the In column to denote a fixed entry To remove a fixed entry from the Workspace you must exclude it explicitly ALT X It is not affected by the inclusion or exclusion of other entries Fixing affects only the inclusion of the entry you can still rotate translate or modify the structure 3 4 5 Mouse Functions in the Project Table The Project Table supports the standard use of shift click and control click to select objects This behavior applies to the selection of entries and the inclusion of entries in the Workspace Dragging to resize rows and columns and to move rows is also supported You can drag a set of non contiguous entries to reposition them in the Project Table When you release the mouse button the entries are placed after the first unselected entry that precedes the entry on which the cursor is resting For example if you select entries 2 4 and 6 and release the mouse button on entry 3 these three entries are placed after entry 1 because entry 1 is the first unselected entry that precedes entry 3 To move entries to the top of the table drag them above the top of the table to move entries to the end of the table drag them below the end of the table A summary of project based mouse functions is provided in Table 3 3
6. In the Job text box enter HO6_dft In the QM Settings folder choose DFT B3LYP from the Method menu In the Optimization folder select Single Point from the Method menu When you open an existing command script file it is loaded into the Script area Because minimizations can be time consuming this example will calculate the QM MM energy at only one geometry To include minimization in your own QSite jobs select Mini mization instead of Single Point FirstDiscovery 3 0 Quick Start Guide 97 Chapter 13 Running a QSite DFT Job 13 5 Defining a QM Region You can select atoms for the QM region by selecting the ligand making backbone or sidechain cuts or specifying ions Typically however ion selection is used only for isolated atoms and metallic cofactors The following exercise demonstrates QM region definition by ligand selection and backbone cutting To define the QM region by ligand 1 In the QM Settings folder click the Residues Ligands button The QM Residue Ligand panel is displayed 2 Select Free ligands 3 In the Workspace pick an atom in the ligand which is the molecule depicted in the tube representation A red trace is superimposed on the ligand molecule that you select and success fully selected residues appear in the list at the top of the QM Residue Ligand selection panel QSite qsite lei Job gsitetmp Login dyal Host localhost 1 Source of job input Workspace Q Sele
7. generates an enclosing box that is large enough for most systems However if you think that actives exist that are significantly larger than the cocrystallized ligand you should consider enlarging the enclosing box using the Fit ligands with length lt option On the toolbar click the Fit to screen button The ligand the receptor the bounding box and the enclosing box are now visible in the Workspace FirstDiscovery 3 0 Quick Start Guide Chapter 6 Creating Glide Grid Files Glide glide Job grids_H01 Login saunders Host localhost 1 settings site ugana Searing output constraints simitarity Specify center of enclosing box by Ligand centroid Specify Ligand Q Active site residues Q Supplied X Y Z coordinates X 2 1893 Y 2 1411 2 2 6517 Size of bounding box for placing ligand center 10 j Y Size of enclosing box A Fit displayed ligand Fit ligands with length lt 20 00 A Scaling of vdW radii for nonpolar receptor atoms Scale radius if partial atomic charge lt 0 25 Scale by 1 00 W Display bounding box for ligand center green W Display enclosing box purple Start write Job Files Hide Help Figure 6 6 The Site folder of the Glide panel 6 8 Starting and Monitoring the Grid Calculation The instructions below describe how to start a Glide job how to interrupt a job and how to determine a job s sta
8. 6 7 Defining the Enclosing Box Center In this exercise you will use the displayed ligand to create and size the bounding box and enclosing box for a grid file calculation 1 2 3 44 In the Glide panel click the Site tab Under Specify center of enclosing box by select Ligand centroid Click Specify Ligand The Ligand To Define Grid panel is displayed Select Use displayed ligand and click Hide Make sure that the Size of bounding box for placing ligand center option is set to 10 A the default range for the ligand center in FirstDiscovery 3 0 The green bounding box defines the space through which the center of the defined ligand is allowed to move during a subsequent docking calculation You may change the size of the box to allow the ligand to sample conformations over a larger space However enlarging the box will increase the calculation time and may allow the ligands being docked to explore a region of the protein site that is larger than the region of interest In the Site folder select Fit displayed ligand in the Size of enclosing box section The purple enclosing box that appears at the same time as the bounding box repre sents the volume of the protein for which grids will be calculated Generally you should make the enclosing box as small as is consistent with the shape and charac ter of the protein s active site If you have a representative ligand in the active site choosing Fit displayed ligand
9. 7 Docking Glide glide Job dock_confgen Login saunders Host localhost 1 Settings l Bie Ligand Scoring output Constraints Similarity 4 Q Dock selected entries from project table Dock ligand s from files Ligand structure file format Maestro Specify one file in Maestro format Add File Dock all structures from ligand file Q Dock range of structures from file 1 Te 1000 Docking scoring mode Generate conformations for each input structure flexible docking Q Dock each input structure rigidly Score each input structure in place scoring output file dock_confgen scor W Allow amide bond rotations W Allow ring flips Scaling of vd radii for nonpolar ligand atoms Scale radius if partial atomic charge lt 0 15 Scale by 0 80 _ Define a reference ligand Start write Job Files Figure 7 1 The Ligand folder of the Glide panel If you already have a set of conformers perhaps from a conformational search docking the ligands using the rigid docking mode is an alternate approach Rigid docking uses the ligand structures as they are and does not generate conformations or allow the ligand s torsional angles to vary as flexible docking does 52 FirstDiscovery 3 0 Quick Start Guide Chapter 7 Docking 7 4 Specifying a Reference Ligand You can specify a reference ligand while docking Provided that the docked molecule or molecules and the re
10. Atom Selection dialog box Show hide or color ribbons Menu button with items to control the display of ribbons and atoms for pro teins and to color ribbons by various schemes Draw atoms in CPK Pick atoms for representation Menu button with a pick menu and an item to open the Atom Selection dialog box Draw bonds in tube Pick atoms for representation Menu button with a pick menu and an item to open the Atom Selection dialog box Color residue by constant color Pick residues to apply the selected color Double click to color all atoms Menu button with a list of colors Label picked atoms Menu button with a pick menu and items to open the Atom Selection dialog box to open the Atom Labels panel at the Composition folder and to delete labels FirstDiscovery 3 0 Quick Start Guide Chapter 3 Introduction to Maestro Display H bonds a Measure distances angles or dihe Pick molecules to display H bonds H drals Menu button with items to choose to 4 Pick atoms to define measurements display H bonds within the selected Menu button with items to choose molecule intra or between the selected between distance default angle or molecule and all other atoms in the dihedral measurement and to delete Workspace inter or to delete H bonds measurements 3 3 3 Mouse Functions in the Workspace The middle and right mouse buttons have special uses in the Workspace These can be used on their own and in combination
11. Command Script A command script called grids_HO1 cmd is included in the SCHRODINGER impact vversion tutorial maestro_cmd directory This script uses the Maestro command language in combination with Atom Specification Language ASL to accom plish the tasks described in this chapter Note that the script does not start the job it only writes out the input files To run the job go to the Glide panel and click Start after the script is finished For more information about running a command script see Section 3 7 on page 22 Note that the command script will execute successfully only if you have set up your working directory as specified in Section 6 1 on page 37 and run the command script from your workdir grids directory Once you run the command script save the project as described in Section 6 4 on page 40 The script written input file HO1_grids inp is compatible with both the Linux x86 and the SGI IRIX platforms FirstDiscovery 3 0 Quick Start Guide 47 Chapter 6 Creating Glide Grid Files 48 FirstDiscovery 3 0 Quick Start Guide Chapter 7 Docking The exercises in this chapter demonstrate how to use the grid files you calculated in the previous chapter to dock ligands from a multi ligand file 7 1 Preparation Before you start the exercises in this chapter follow the appropriate instructions in this section If you are continuing from the previous chapter and Maestro is running With the ligand and receptor
12. Generate Glide grid files e Dock ligands from a multi ligand file e Select the top Glide poses from a pose viewer file For the best performance in actual use Protein Preparation should be run on both the receptor and the candidate ligand structures before they are submitted to Glide This procedure is described in Chapter 4 The structure files used in Chapter 6 Chapter 7 and Chapter 8 have already been prepared For information on protein and ligand structure preparation see the FirstDiscovery User Manual and the chapter on optimizing perfor mance in the FirstDiscovery Technical Notes FirstDiscovery 3 0 Quick Start Guide 35 Chapter 5 Introduction to Glide 36 FirstDiscovery 3 0 Quick Start Guide Chapter 6 Creating Glide Grid Files This chapter contains exercises that demonstrate how to set up and start a grid file calcula tion job Grid files reflect the area of the receptor specifically the active site that will be searched when attempting to dock a ligand You will use the grid files calculated in this chapter to dock ligands in later Glide exercises 6 1 Creating a Working Directory The SCHRODINGER impact vversion tutorial structures directory of your FirstDiscovery distribution contains e A Maestro formatted receptor structure file e A multi structure file containing the receptor s cocrystallized ligand and 19 structur ally similar molecules The tutorial directory also contains sample job files These sample fil
13. Ligand Scoring output Constraints Similarity Filename of knoven inar tives Percentage of inactives fo keep 10 Yo _ Use similarity score in docking 7 i A wr Formak Ma Fienane of known artives m Base penally valie 6 00 kcalandi Fully penalize Hgamis with shnilarty 0 30 Ne panaily for igaimis with similarity 0 70 Reject fuands with similarity lt 0 00 Ligantis with similarities between G 3 ani G 76 wil be partially penalized Start write Job Files Figure 7 6 The Similarity folder of the Glide panel FirstDiscovery 3 0 Quick Start Guide 57 Chapter 7 Docking 7 7 Starting the Docking Job 1 In the Glide panel click Start The job starts and the Monitor panel is displayed 2 Dismiss the Glide panel by clicking the Hide button The required computation time for all Glide docking jobs depends on the processor speed and workload the size and flexibility of the ligands to be docked and the volume specified by the enclosing box As a rough estimate docking a typical drug like ligand takes about one minute on a 1 2 to 1 5 GHz Pentium 4 Linux machine using FirstDiscovery 3 0 default settings On a similar machine the 20 ligand docking job you started will usually finish in less than 20 minutes These files should exist after the job is complete dock_confgen inp Input file for docking job dock_confgen log Log file from docking job dock_confgen out Output file f
14. Settings tab For help see Section 6 5 on page 41 Choose Dock one or more ligands from the Choose Glide function option menu Changing the Glide function changes the options and tabs that are available In the Job text box delete gl idetmp and type dock_confgen Make sure that Choose docking mode is set to Standard speed and precision For information about the Extra precision option see the FirstDiscovery User Manual or click the Help button and navigate to the Glide Settings folder topic Click the Select button next to the Base name for grid files text box and choose grids_H01 grd in the file selector The name grids_H01 is displayed in the text box The Directory for grid files text box displays the directory workdir grids The grid files are now specified In the next exercise you will start selecting ligands for docking 7 3 Selecting Ligands for Docking You can select the ligand for docking in flexible docking mode by specifying a multi ligand file or by selecting entries in the Project Table Choose one of these methods To specify ligands from a multi ligand file 1 2 50 In the Glide panel click the Ligand tab Make sure that Dock ligand s from files is selected FirstDiscovery 3 0 Quick Start Guide Chapter 7 Docking 3 Make sure that Ligand structure file format is set to Maestro If a file already appears in the Specify one file in Maestro format list select it and then c
15. are analyzed After docking jobs are complete the conformers or poses are ranked according to their overall interaction with the receptor The results can be posted to a pose view file which can be examined using the Glide Pose Viewer panel Glide Pose Viewer Panel An analysis tool that displays the results of Glide docking jobs These results which are recorded in a pose view file include the ligand name pose number overall score number of contacts and other data The poses within the file are arranged in the list according to score ligands with the most energetically favorable inter actions with the receptor appear at the beginning and ligands with less favorable interac tions appear near the end The Glide Pose Viewer panel can also be used to visualize contacts and hydrogen bonds between ligand and receptor molecules or to write structure files containing one or more ligand poses GlideScore Glide s scoring function based on ChemScore GlideScore is used in ranking ligand poses found in docking In Liaison GlideScore is used in an alternative binding energy model Global Transformation Simultaneous translation or rotation of all Workspace atoms Grid Files Files written by Glide during grid setup These files contain data about the properties of the associated receptor and are used during docking Ligand Centroid Used to define the enclosing box center a ligand centroid is the point whose x y and z coordi
16. folder view the default settings When Keep at most n poses is set to the default value of 1000 up to 1000 ligand poses with the highest scores i e the most favorable interactions with the receptor are saved in a pose viewer file However leaving the Keep at most n poses per ligand value set to 1 for this exercise ensures that no more than 20 poses one for each ligand will be collected and written to the pose viewer file 2 Optional Click Help to open the Glide Panel help topic In the Contents click Glide Panel Features then choose Output from the list of folders Glide glide Job dock_confgen Login saunders Host localhost 1 Settings site Ligand Scoring output Constraints simitarity Elimination of duplicate poses clustering Discard pose as duplicate if RMS distance lt 0 5 A and maximum atomic displacement lt 1 3 A Structure output Write pose viewer file dack_confgen_py mae include receptor Q Write ligand pose file dock_confgen_lib mae exclude receptor Keep at most 1000 poses Keep at most 1 poses per ligand Start write Job Files Hide Help Figure 7 4 The Output folder of the Glide panel FirstDiscovery 3 0 Quick Start Guide 55 Chapter 7 Docking 7 6 Glide Constraints and Similarity Glide constraints are required interactions either receptor ligand H bonds or metal ligand interactions that you can specify as docking criteria T
17. in the main menu bar 7 9 Running the Job With a Command Script A command script called dock_H01 cmd is provided in the SCHRODINGER impact vversion tutorial maestro_cmd directory The script uses the Maestro command language in combination with Atom Specification Language ASL to accom plish the tasks described in this chapter Note that the script does not start the job it only writes out the input files To start the job you must click Start on the Glide panel after the script has finished running For more information on how to run a command script see Section 3 7 on page 22 Note that the command script will execute successfully only if you have set up the working directory as specified in Section 6 1 on page 37 and if you run the script from the workdir glide directory FirstDiscovery 3 0 Quick Start Guide 59 Chapter 7 Docking 60 FirstDiscovery 3 0 Quick Start Guide Chapter 8 Examining Glide Data The exercises in this chapter describe how to use the Glide Pose Viewer panel to display the results of a Glide docking job and how to write pose files some of which will be used in the Liaison section The emphasis in this chapter is on visual rather than numerical data For a more complete discussion of Glide output data ligand poses and scoring see the online help and the FirstDiscovery User Manual 8 1 Preparation Before you start the exercises in this chapter follow the appropriate instructions in this
18. instead see the FirstDiscovery User Manual The Liaison simula tion you completed in the previous chapter calculated the terms inside the angle brackets in the LRM equation The Fit job will determine the amp B and y coefficients based on the terms from the previous chapter and the free energy values in the training set These coef ficients will then be used in a Predict job 11 1 Preparation Before you start the exercises follow the appropriate instructions in this section If you are continuing from the previous chapter and Maestro is open To continue with the exercises in this chapter make sure that you have set up a working directory and performed a multiple ligand Liaison simulation Then proceed to Section 11 2 on page 86 If you are continuing but with a new Maestro session If Maestro is not currently running open a terminal window move to the workdir f it subdirectory and start Maestro according to the instructions in Section 3 2 on page 5 Then open the Liaison panel delete the name impact tmp from the Job text box and type fit_sim in its place Import the file HO1_rec mae from the workdir structures directory If you are starting the tutorial with this chapter 1 If you have not yet done so create a working directory using the instructions in Section 6 1 on page 37 2 Copy the items you will need to complete the exercises in this chapter or run the Liaison Simulation job now using a provided command scr
19. same manner as the cocrystallized ligand you should keep those waters After 28 FirstDiscovery 3 0 Quick Start Guide Chapter 4 Protein Preparation adding hydrogens to such waters you should orient them appropriately to facilitate receptor ligand contacts See the FirstDiscovery User Manual for more information However if you intend to search for ligands that might displace one or more waters you should delete some or all of the water molecules For lett it is reasonable to delete all water molecules To delete all water molecules choose one of the following e Choose Waters from the Delete button menu in the toolbar x ail The water molecules are deleted e Enter this command in the Maestro command input area delete res HOH 4 4 Adjusting the Ligand The ligand has been represented without bond order or formal charge information This information must be added It is convenient to display only the ligand while doing this For most ligands and cofactors you can do this by undisplaying the protein backbone and side chains To undisplay protein components 1 Choose Protein Backbone from the Undisplay button menu in the toolbar lt a al The protein backbone disappears 2 Repeat Step 1 for Protein Side Chains The rest of the protein disappears 3 Click the Fit to screen toolbar button to get a closer look at the ligand The ligand appears to consist of three disconnected fragments FirstDiscovery 3 0
20. simpler Click OK again to exit the ASD Only the ligand appears in the Workspace FirstDiscovery 3 0 Quick Start Guide Chapter 4 Protein Preparation To adjust bond orders 1 Choose Element from the Color all atoms by scheme button menu in the toolbar D 2 Click the Show Hide Build panel button on the toolbar to open the Build panel 3 In the Build panel toolbar click Increment bond order Gl 4 In the Workspace pick three bonds in each phenyl ring to increment them from sin gle to double 5 Pick the two S O single bonds to make them double as well If dialog boxes appear with warnings about atom valences click OK to close them 6 Double the C O single bond To adjust formal charge One of the amidopheny nitrogens in the 4 TAPAP ligand should be protonated 1 Double one of the two equivalent C N bonds The double bond is displayed but Maestro removes a hydrogen from the double bonded nitrogen to maintain neutrality 2 In the Build panel toolbar click Increment formal charge y 3 Click the C N nitrogen 4 Choose Formal Charge from the Label atoms button menu in the toolbar al The C N nitrogen has formal charge 1 The missing hydrogen will be added automatically in the preparation job 5 Click Hide to close the Build panel FirstDiscovery 3 0 Quick Start Guide 31 Chapter 4 Protein Preparation 4 5 Running Protein Preparation on the Structure 32 1 Open the ProteinPrep p
21. such as those that contain metals or represent transition states QSite is uniquely equipped to perform QM MM calculations because it combines the superior speed and power of Jaguar with the recognized accuracy of the OPLS AA force field For information about Jaguar see the Jaguar User Manual Maestro is Schr dinger s powerful unified multi platform graphical user interface GUD It is designed to simplify modeling tasks such as molecule building and data anal ysis and also to facilitate the set up and submission of jobs to Schr dinger s integrated computational programs Glide Liaison QSite Impact MacroModel Jaguar Prime and QikProp The main Maestro features include a project based data management facility a scripting language for automating large or repetitive tasks a wide range of useful display options a comprehensive molecular builder and surfacing and entry plot ting facilities For more detailed information about the Maestro interface see Chapter 3 of this manual the Maestro online help or the Maestro User Manual FirstDiscovery 3 0 Quick Start Guide 3 Chapter 2 The FirstDiscovery Suite The Impact computational engine can perform molecular mechanics calculations either through the Maestro interface or from the command line For information on running basic Impact jobs see the Maestro online help the FirstDiscovery User Manual or the FirstDis covery Command Reference Manual 4 FirstDiscovery 3 0 Qu
22. the atoms in the Work space For each item on the Property menu Element MacroModel Type Partial Charge PDB Atom Name Grow Name and Atom Name there is a set of tools you can use to change the atom properties For example the Element tools consist of a periodic table from which you can choose an element and pick an atom to change it to an atom of the selected element Similarly the Residue Properties folder provides tools for changing the properties of resi dues the residue number the residue name and the chain name To adjust bond lengths bond angles dihedral angles and chiralities during or after building a structure use the Adjust panel which you open from the Edit menu on the main menu bar or with the Display Adjust panel button on the Build panel toolbar 4 FirstDiscovery 3 0 Quick Start Guide 19 Chapter 3 Introduction to Maestro The toolbar of the Build panel provides quick access to tools for drawing and modifying structures and labeling atoms See Section 3 3 2 on page 8 for a description of the types of toolbar buttons The toolbar buttons and their use are described below HEA k g H 20 Draw Draw structures freehand in the Workspace Menu button with a list of elements to draw with default C Each click in the Workspace places an atom and connects it to the previ ous atom Delete Choose an object to delete Menu button with a pick menu and other items Same as the Delete button on the main tool
23. with the SHIFT and CTRL keys to perform common operations such as rotation translation centering and zooming Apart from centering a molecule on an atom all these operations involve dragging Table 3 1 Mapping of Workspace operations to mouse actions Operation Action Rotate about the x and y axes Drag with middle mouse button Rotate about the x axis only Drag vertically with SHIFT and middle mouse button Rotate about the y axis only Drag horizontally with SHIFT and middle mouse button Rotate about the z axis Drag horizontally with CTRL and middle mouse button Spot center on an atom Right click Translate in the x y plane Drag with right mouse button Translate along the y axis Drag vertically with SHIFT and right mouse button Translate along the x axis Drag horizontally with SHIFT and right mouse button Translate about the z axis Drag horizontally with CTRL and right mouse button Zoom Drag horizontally with middle and right mouse buttons or with SHIFT CTRL and middle mouse button 3 3 4 Shortcut Key Combinations Some frequently used operations that can be performed in the main window have been assigned shortcut key combinations The shortcuts their functions and their menu equiva lents are listed in Table 3 2 FirstDiscovery 3 0 Quick Start Guide 11 Chapter 3 Introduction to Maestro Table 3 2 Shortcut keys in the Maestro main window Keys Action Equivalent Menu Choices ALT B Show Build panel Edit gt
24. 0 Quick Start Guide Selecting First Imported Structure from this menu causes only the first struc ture in the imported file to be displayed Pi ge oe Navigate to your Import import Chapter 6 Creating Glide Grid Files ees jon FirstDiscovery_Tutorial tutorial structures Format Maestro Filter mdo au et Directories my Files HO1_H20_lig mae HO1_rec mae HO6_al tered mae HO6alt_qsite mae LLL Launch Directory S working Directory Selection ry_Tutorial tutorial structures HO1_H20_1ig mae All Files W Replace workspace W Use graphical info W import all structures Stark 1 gO i Fefah Include in workspace First Imported Structure Import Filter Figure 6 1 The mport panel HO1_H20_lig mae 6 Click Import workdir structures Ensure that Maestro is selected from the Format menu Ensure that Import all structures is selected directory To import only some of the struc tures in a file deselect mport all structures and type the desired struc ture numbers in the Start and Total boxes Ensure that First Imported Structure is selected from the Include in workspace menu select the file Each ligand in the file HO1_H20_lig mae is placed in its own entry in the Project Table and the entry containing the first ligand is automatically included 7 Choose aquamarine from the Color residue by constant color button menu
25. 3 4 Shortcut keys in the Project Table Keys Action Equivalent Menu Choices ALT A Select all entries Select gt All ALT F Fix entry in Workspace Entry gt Fix ALT I Show Import panel Table gt Import Structures ALT N Include only selected entries Entry gt Include Only ALT U Deselect all entries Select gt None ALT X Exclude selected entries Entry gt Exclude ALT Z Undo Redo last command Edit gt Undo Redo in main window FirstDiscovery 3 0 Quick Start Guide 17 Chapter 3 Introduction to Maestro 3 5 Building a Structure After you start Maestro the first task is usually to create or import a structure You can open existing Maestro projects or import structures from other sources to obtain a struc ture To build a structure you use the Build panel which you can open by choosing Frag ments from the Edit menu or by clicking the Show Hide Build panel button in the toolbar The Build panel allows you to create structures by drawing or placing atoms or fragments in the Workspace and connecting them into a larger structure to adjust atom positions and bond orders and to change atom properties This panel contains a toolbar and three folders The Fragments folder offers a variety of molecular fragments from which to build a struc ture To place a fragment in the Workspace 1 Select Place 2 Choose a fragment library from the Fragments menu 3 Click a fragment 4 Click in the Workspace where you want the fragme
26. Build ALT C Create entry Project gt Create Entry From Workspace ALT E Show Command Script Editor panel Edit gt Command Script Editor ALT F Open Find Atoms panel Edit gt Find ALT H Show Help panel Help gt Help ALT I Show Import panel Project gt Import Structures ALT M Show Measurements panel Tools gt Measurements ALT N New project Project gt New ALT O Open project Project gt Open ALT P Print Maestro gt Print ALT Q Quit Maestro gt Quit ALT S Show Sets panel Tools gt Sets ALT T Show Project Table panel Project gt Show Table ALT W Close project Project gt Close ALT Z Undo Redo last command Edit gt Undo Redo 3 4 Maestro Projects All the work you do in Maestro is done within a project A project consists of a set of entries each of which contains one or more chemical structures and their associated data In any Maestro session there can be only one Maestro project open If you do not specify a project when you start Maestro a scratch project is created You can work in a scratch project without saving it but you must save it in order to use it in future sessions Maestro also creates a scratch project when you close a project Likewise if there is no entry displayed in the Workspace Maestro creates a scratch entry Structures that you build in the Workspace constitute a scratch entry until you save the structures as project entries The scratch entry is not saved with the project unless you explicitly in
27. FirstDiscovery 3 0 Quick Start Guide Copyright 2004 Schr dinger LLC All rights reserved Schr dinger FirstDiscovery Glide Impact Jaguar Liaison LigPrep Maestro Prime QSite and QikProp are trademarks of Schr dinger LLC MacroModel is a registered trademark of Schr dinger LLC To the maximum extent permitted by applicable law this publication is provided as is without warranty of any kind This publication may contain trademarks of other companies Revision A June 2004 Contents Chapter 1 Document OvervieW seseesessossessesoossesoossossessocsosoesoossessossossessossesse 1 Chapter 2 The FirstDiscovery Suite sssccssscssscssscssscsccssccesecssscsrseessserees 3 Chapter 3 Introduction to Maestro csscsccsssscssscsescssscsccssccssccssesssesscessoerees 5 3 1 General Interface BEHAVIOR s c c ess cscs sii Sass ba sanes ida peedsseden TE 5 3 2 Starting MASS IO enopes a EEA EEE ra E E EON SE 5 3 3 The Maestro Main Window iicscci seiisiiscisciceevscetcsssscaees hades secteat n R En 6 J31 Th Menu Baf enoni nin nanea R R i 7 BDZ The TOOL DaT eisie iani nen EEE E AAA EEEE EENE EAE 8 3 3 3 Mouse Functions in the Workspace ceseeseeceseeeseeceeeeneeteaeeeeeesnes 11 3 3 4 Shortcut Key Combinations 5 c cc icssecsiedesatetesvcsseteiescadaetontedsteteseetaces 11 34 Macs to Projete openeen eE a E E E E ia ES 12 3 4 1 The Project Table Toolbar oseeesseesesssessees
28. Follow the instructions in the next exercise to save your project 6 4 Saving a Scratch Project This section describes how to save the project that you created in the preceding exercise 1 From the Project menu in the main window choose Save As The Save Project As project selector is displayed 2 Navigate to your working directory or click the Working Directory button 40 FirstDiscovery 3 0 Quick Start Guide Double click here to move up a level in the directory structure Chapter 6 Creating Glide Grid Files Project As ation FirstDiscovery_Tutorial tutorial pri Directories Items brial tutorial e tutorial irial tutorial fit irial tutorial glide irial tutorial grids irial tutorial lia_structures rial tutorial maestro_cmd yrial tutorial predict Launch Directory Working Directory Project dmentation FirstDiscovery_Tutorial tutorial Filter Cancel Make Dir Figure 6 3 The Save Project As file selector 3 In the Project text box type docking at the end of the text Maestro appends the prj extension to the project name you assign 4 Click Save The title bar in the main window and the title text box in the Project Table panel contain the new project name 6 5 The Glide Panel Choosing and Naming a Grid Generation Job To select the grid calculation function and assign a name to the job 1 From the Applications menu in the main window choose Glide The Glid
29. Glide Pose Viewer panel to display the ranked list of scored poses generated during a Glide docking job 1 In the main window choose Glide Pose Viewer from the Tools menu The Glide Pose Viewer panel is displayed 2 In the Poses folder click Open The Read Pose Files file selector is displayed 3 Navigate to the workdir glide directory 4 Select the dock_confgen_pv mae file and click Open The ligand poses in the file are listed in the Pose Viewer panel as shown in Figure 8 1 on page 63 Each ligand pose is identified by index number title ligand number conformation number and pose number For each pose the table gives the GlideScore G Score E Model Energy and various contact counts associated with the pose receptor combination Some of these pose properties are described later in this chapter 5 Deselect the Display option The receptor structure is cleared from the Workspace This is helpful if you want to examine the structure of a selected ligand or if you want to center the display on a ligand before redisplaying the receptor 6 On the toolbar click the Fit to screen button The ligand is resized and repositioned in the Workspace so that the structure is entirely visible You have now opened the dock_confgen_pv mae pose viewer file viewed the first pose and optimized the pose s position in the Workspace 8 3 Viewing Poses When you opened the Glide Pose Viewer panel pose 1 was automatically selected and dis
30. If you want to continue with the Liaison exercises proceed to the next chapter If you want to stop working on the tutorial now choose Close Project from the Project menu in the main menu bar If a dialog box appears and asks if you would like to save the scratch project click Discard For more information about Quit panel options and log files see Section 3 12 on page 26 70 FirstDiscovery 3 0 Quick Start Guide Chapter 9 Introduction to Liaison Liaison uses the Linear Response Method LRM to calculate free energies of binding for a protein and a group of ligands that are structurally similar to one another The binding free energies are calculated in three steps using the equation AG a lr lt U yaw gt B Clare gt lt U slec gt y lt U gt lt U 25 Here lt gt represents the ensemble average b represents the bound form of the ligand f represents the free form of the ligand and amp B and y are the coefficients U gw Ueiec and elec U a are the van der Waals electrostatic and cavity energy terms respectively in the continuum solvent model Liaison also calculates the GlideScore over the course of the LRM simulation The average GlideScore can then be used to predict binding energies using the alternate model AG a lt GlideScore gt b where a is the GlideScore coefficient and b is a constant The exercises in Chapter 10 and Chapter 11 demonstrate e How to perform Liaison simulations on mul
31. In the Workspace click on an atom in the ligand The ligand molecule is marked in purple In the ASD click Add in the upper right portion of the panel The markers on the ligand molecule turn blue In the ASD click Proximity in the lower right portion of the panel The Proximity dialog box is displayed Make sure that Within is selected Type 5 into the text box make sure that Angstroms is selected and under Fill select Residues Click Update Markers The blue trace markers now include several nearby residues as well as the ligand Click OK to close the Proximity dialog box 10 Examine the atom specification language ASL expression in the ASL box When you click OK in the ASD all atoms that are more than 5 A from the ligand are undisplayed Hiding the residues that do not come into contact with the ligand allows you to better examine the ligand receptor interactions The ASL expression uses the fillres option This option causes all residues con taining one or more atoms within 5 A of the ligand to be displayed in full If illres had not been used only the atoms that met the proximity condition would be displayed and the other portions of these residues would be omitted Click OK In the Workspace only the ligand and the nearby residues are displayed FirstDiscovery 3 0 Quick Start Guide 65 Chapter 8 Examining Glide Data 8 6 Coloring Carbons by Molecule Number Assigning a distin
32. Molecuie cnain entry smsna ser Sequence Residue Type Residue Number Add Classification Subtract Backbone Side Chain __ Subtract Secondary Structure Intersect Atoms Matching 96 ASL E Show markers res num gt 200 j Proximity 7 Create Set All Undo Sec Clear Invert Matching 800 atoms OK Cancel Help Figure 3 4 The Atom Selection dialog box FirstDiscovery 3 0 Quick Start Guide 21 Chapter 3 Introduction to Maestro combine this group with the existing atom group using the buttons on the right the Add button Boolean OR includes all atoms in the new group or the existing group the Subtract button Boolean AND NOT excludes atoms in the new group from the existing group and the Intersect button Boolean AND includes only those atoms that are in both the new group and the existing group The existing group is expressed in Atom Specifica tion Language ASL in the ASL text box and is shown with light blue markers in the Workspace The current selection is shown with purple markers When you are satisfied with the selection click OK to apply the operation you have chosen with the selection you have made The operation is described in a bar at the top of the Atom Selection dialog box Some operations take effect immediately such as deleting atoms Others merely define a set of atoms to be used in a subsequent task such as selecting atoms for creation of a surface When the Atom
33. Quick Start Guide 29 Chapter 4 Protein Preparation This structure has no cofactors or metals and waters have already been deleted so what remains should be the ligand In this case however part of the ligand is miss ing too Maestro recognizes amidophenylalanine PAP as an amino acid residue although a nonstandard one and includes its backbone and side chain when it undisplays the Protein Backbone and Protein Side Chains To display the entire ligand without the protein you must use a different technique Choose All from the Also display button menu sly The entire structure is redisplayed To display only selected residues 30 1 Choose Select from the Display only button menu in the toolbar lt j al The Atom Selection dialog box ASD appears titled Select To Display Only Click the Residue tab and select Residue Type Scroll down the Residue Type list PAP PIP and TOS are at the end of the list because they are not standard residues In the list click on PAP In the Workspace the PAP residue is marked in magenta Click on TOS and drag over PIP and PAP to select all three The entire ligand is now marked in magenta Click the Add button The Atom Specification Language ASL expression for your selection appears in the ASL text box and the ligand is marked in cyan Click Create Set and type the set name 4 TAPAP then click OK This makes future references to the ligand
34. Selection dialog box is open you cannot perform other actions except for rotation and translation of structures and picking You can also open the help viewer 3 7 Maestro Command Scripts Although you can perform nearly all Maestro supported operations through menus and panels you can also perform operations using Maestro commands or compilations of these commands called scripts Command scripts can be used to automate lengthy procedures or repetitive tasks Because all Maestro commands are logged and displayed in the Command Script Editor panel you can create a command script by performing the operations with the GUI controls copying the logged commands from the Command History list into the Script area of the panel then saving the list of copied commands as a script Short scripts can also be saved as macros which are run from the keys F1 through F12 See the Maestro User Manual for details To run an existing command script 1 Open the Command Script Editor panel from the Edit menu in the main window 2 Click Open Local and navigate to the directory containing the desired script 3 Select a script in the Files list and click Open The command script is loaded into the Script window of the Command Script Editor panel 4 Click Run Script Command scripts cannot be used for Prime operations 22 FirstDiscovery 3 0 Quick Start Guide The Command History window displays a log of all commands issued internally within Maestr
35. Start The calculation is started and the Monitor panel is displayed This job should take about an hour to complete After it finishes the following items should appear in the workdir predict directory change_sgbparam_predict_sim predic predic simula t_sim t_sim mae te_predict_sim The predict_sim subdirectory should contain the following HO6_al HO6_al predic The directory tered tered stdout t_sim log predict_sim H06_altered contains data for the free and the bound versions of the corresponding ligand HO6_altered H06_altered H06_altered HO6_altered H06_altered H06_altered bound inp free inp bound ave bound log bound out free ave HO6_altered free log HO6_altered free out HO6_altered_lig mae HO6_altered_lig_min mae HO6_altered_rec mae HO6_altered_rec_min mae Now you are ready to begin the Predict analysis task 11 4 2 Predicting Binding Energy Using the LRM Model i 2 3 4 5 6 Enter HO FirstDiscovery 3 0 Quick Start Guide In the Liaison panel type predict_sim in the Job text box In the Settings folder select Analyze results of earlier simulations In the Analysis folder select Predict Under Binding energy model select LIA equation From the Specify ligands by option menu choose Enter list of ligand names 6_altered in the Comma separated list text box 89 Chapter 11 Analyzing Liaison Data 7 Use a text editor to open the file work
36. al functions described later in this chapter These functions assume that you have a three button mouse If you have a two button mouse ensure that it is configured for three button mouse simulation the middle mouse button is simulated by pressing or holding down both buttons simultaneously 3 2 Starting Maestro Before you start Maestro you must first set the SCHRODINGER environment variable to point to the installation directory You can set this variable by entering the following command at a shell prompt csh tesh setenv SCHRODINGER installation directory bash ksh export SCHRODINGER installation directory You might also need to set the DISPLAY environment variable if it is not set automatically when you log in To determine if you need to set this variable enter the command echo SDISPLAY FirstDiscovery 3 0 Quick Start Guide 5 Chapter 3 Introduction to Maestro If the response is a blank line set the variable by entering the following command csh tesh setenv DISPLAY display machine name 0 0 bash ksh export DISPLAY display machine name 0 0 After you set the SCHRODINGER and DISPLAY environment variables you can start Maestro using the command SCHRODINGER maestro options If the SSCHRODINGER directory has been added to your path you only need to enter the command maestro Options for this command are given in the Maestro User Manual The directory from which you started Maestr
37. allow you to perform functions on the entries in the Project Table The second set of buttons controls the ePlayer which plays through the selected structures each structure is displayed in the Workspace in sequence at a given time interval See Section 3 3 2 on page 8 for a description of the types of toolbar buttons The buttons are described below Project Table table test Table Select Entry Property ePlayer ba BY Lx Sel Bol of R 414 am DD 2 selected eooo mol_o004 imp1 jo QI mo1_0004 mol_oo04 impt inct O jo jo fo fo f Q mo1 0007 mol_ooor impt f2 jo o fo fo j 4 mo _0007 Q mol_ooos mol_ooos impt inet o fo jo fo fo 0 0 Oo 0 gt mo1_0018 Hidd Included Excluded Fixed or locked Selected entry entry entry entries Figure 3 2 The Project Table panel FirstDiscovery 3 0 Quick Start Guide 13 Chapter 3 Introduction to Maestro 14 Find Open the Find panel for locating alphanumeric text in any column of the Project Table except for the row number Sort Open the Sort panel for sorting entries by up to three properties Plot Open the Plot panel for plotting entry properties Import structures Open the Import panel for importing structures into the project Export structures Open the Export panel for exporting structures to a file Columns menu Display a menu for adjusting the column widths Entry selection Open the Entry Selection dialog box
38. and for pausing resuming or killing jobs the Monitor panel All jobs that belong to your user ID can be displayed in the Monitor panel whether or not they were started from Maestro The text pane shows some kinds of output from the job that is being monitored such as the contents of the log file The Monitor panel opens automatically when you start a job If it is not open you can open it by choosing Monitor from the Applications menu in the Maestro main window While jobs are running the Detach Pause Resume Stop Kill and Update buttons are active When there are no jobs currently running only the Monitor and Delete buttons are active These buttons act on the selected job By default only jobs started from the current project are shown To show other jobs deselect Show jobs from current project only When a job that is being monitored ends the results are automatically incorporated into the project If a job that is not currently being monitored ends you can select it in the Monitor panel and incorporate the results Monitored jobs are incorporated only if they are part of the project You can monitor jobs that are not part of the project but their results are not incorporated To add their results to the project you must import them FirstDiscovery 3 0 Quick Start Guide 25 Chapter 3 Introduction to Maestro 3 11 Getting Help Maestro comes with automatic context sensitive help Auto Help Balloon help tool tips an onl
39. anel from the Applications menu 2 Type lett in the Job text box 3 Choose a host for the job from the Host option menu If you use a different user name on the remote host you have selected enter that user name in the Login text box 4 Pick ligand and Show markers are selected by default Click an atom in the ligand The ligand is marked in blue green Anything in the complex structure that was not selected as the ligand will be treated as part of the receptor This includes any cofactors metals or other ligands if present ProteinPrep pprep Seix Job ppreptmp Login saunders Host localhost 1 Note Make sure that your ligand cofactors and nonstandard residues have appropriate bond orders and formal charges before starting a job r 1 E Pick ligand W Show markers i i Procedure Preparation and refinement y Preparation only YV Refinement only Neutralization zone around the ligand 10 20 A default Q 6 12 A recommended for Liaison QV Do not neutralize residues Stop minimization when RMSD reaches 0 30 A Incorporate results as Separate entries V Single entry Start Write Job Files Hide Help Figure 4 1 The Protein Preparation panel FirstDiscovery 3 0 Quick Start Guide Chapter 4 Protein Preparation 5 To redisplay the receptor choose All from the Also display button menu al 6 In the Procedure section of the ProteinPrep panel ensure th
40. anted Waters vciccs issssscasistssivscssseesust csaseesstsdesasiuias irt aa ea a 28 AA Adpostine the Ligand nipiiserres re osaa a EE Ea N Enia Ae E e iis 29 4 5 Running Protein Preparation on the Structure seseeesseseseeesiererrersrererrrerrresrsrens 32 4 6 Protein Preparation Output Structures 00 eee eeeeeeeeeeeeeseeneeseeseeseeseeseeseeaeens 34 FirstDiscovery 3 0 Quick Start Guide iii Contents Chapter 5 Introduction to Glide scccssscssssscsscssscsccscescesssccssscesceseessoees 35 Chapter 6 Creating Glide Grid Files cssccscssscssscsesscesscescsccssscesscseeseoees 37 6 1 Creating a Working Directory eceecceseescesscescesececeeseeesecaeeeseseesaeeeeeeseeneeeaeens 37 G2 PRC PORAt OG 2 setsteccc eset cievcsesd ogc cdenecbes E E 38 6 3 importing Maestro Files 3 ssscis ieis eerste aateinttdaccese rapi Esi ao aes 38 6 4 Saving a Scratch Project i 5 0s cidscrentetevisiieers ade nad cncaatiidesenaen 40 6 5 The Glide Panel Choosing and Naming a Grid Generation Job eee 41 6 6 Designating the Ligand Molecule cccccesccescssseeceeeeceseeeeeeseeeeeeseeeeeeaeeneeeaeens 43 6 7 Defining the Enclosing Box Center scsecnra 44 6 8 Starting and Monitoring the Grid Calculation ccccesceeceeseeeceeseeeeeeeeeeeeaeees 45 6 9 Exercise SUMMA y si sse2 ser ieks hance tide vegies eid os eatasstes anteaters 47 6 10 Running the Job With a Command Script 0 eee eeeeeeeeeeeeeneeeeeee
41. assevecsevteasceteccenss 97 13 5 Defining a QM REO esiisa anea aa a ES 98 13 6 Selecting a Basis Setsnsrnonni ennie noar ra E a onda 100 13 7 Including a Jaguar Keyword i2 isc0icsbs a2iiss iccacsesscecincaaistardeveadiaasctaniaaateecass 100 13 8 Writing QSite Job Piles nsina a eacheteses 100 FirstDiscovery 3 0 Quick Start Guide v Contents Chapter 14 Getting Help sniiccscccisccessesccsessesceescesssessoosscsscesoessoodseosiecsesssosssvoseoss 103 GOSS AY RA NE E E A EEN A 105 I r Ta E EESE E A A I EEES 109 vi FirstDiscovery 3 0 Quick Start Guide Chapter 1 Document Overview This manual contains tutorials designed to help you quickly become familiar with the functionality of the FirstDiscovery software suite In these tutorials protein preparation Glide Liaison and QSite module tasks are performed using the Maestro interface For information about other FirstDiscovery modules and about performing tasks from the command line see the FirstDiscovery User Manual and the FirstDiscovery Command Reference Manual Starting with FirstDiscovery 3 0 the FirstDiscovery Command Reference Manual is no longer printed as hardcopy and bound with the other FirstDiscovery manuals It is provided on disk with the FirstDiscovery distribution and is also available at Schr dinger s web site http www schrodinger com Support pdf html If you need help on a topic click the Help button in a Maestro panel open Maestro s help faci
42. at Preparation and refine ment the default is selected Each step can be run independently using the Preparation only or Refinement only options 7 Ensure that the default values of the following options are selected e Neutralization zone around the ligand 10 20 A Stop minimization when RMSD reaches 0 30 A This default value allows the refinement portion of the job to halt when the average RMSD of the heavy atoms reaches 0 30 A e Incorporate results as Separate entries This setting determines how the output structure is included in the Maestro Project Table upon completion Separate entries returns the protein and ligand as separate entries whereas Single entry does not Single entry may be more convenient if you want to run calculations on the complex with the existing ligand immediately 8 Click Start The Monitor panel is displayed and the preparation stage begins During the preparation stage hydrogen treatment is applied to the ligand and protein Residues within 10 20 A of the ligand are neutralized which may involve conformation changes to some residues When preparation is finished refinement begins The refinement portion of the job performs a series of restrained partial minimizations of the cocrystallized complex to opti mize the positions of the newly added hydrogens and relieve any strain due to unphysi cally short distances in the X ray structure Depending on the protein size machine speed and
43. ation facility is provided In addition the molecular mechanics program Impact provides general purpose modeling tools for FirstDiscovery The FirstDiscovery programs are operated from the Maestro graphical interface Protein Preparation for use in Glide Liaison and QSite can be performed for most protein and protein ligand complex PDB structures using the ProteinPrep panel in Maestro Command line utilities complete the protein preparation facility Glide is designed to assist you in high throughput screening of potential ligands based on binding mode and affinity for a given receptor molecule You can compare ligand scores with those of other test ligands or compare ligand geometries with those of a reference ligand Additionally you can use Glide to generate one or more plausible binding modes for a newly designed ligand Once you locate favorable structures and or bonding confor mations with Glide you can use Liaison to obtain binding energies for ligand receptor pairs Liaison is designed to predict ligand binding energies Ligands for which binding energies are known are used to calculate the Liaison SVD fitted parameters alpha beta and gamma These parameters are subsequently used to predict binding energies for other ligands with the same receptor QSite is a mixed mode Quantum Mechanics Molecular Mechanics QM MM program used to study geometries and energies of structures not parameterized for use with molec ular mechanics
44. bar Set element Pick atoms to change to the selected element default C Menu button with a list of target elements Menu button with a limited list of target elements Increment bond order Pick a bond to increase its bond order by one to a maximum of 3 Decrement bond order Pick a bond to decrease its bond order by one to a minimum of 0 Increment formal charge Pick an atom to increase its formal charge by one Decrement formal charge Pick an atom to decrease its formal charge by one Move Pick an atom to move in the xy plane or the z direction Menu button with a list of drec tions Moves in the xy plane are made by clicking the new location Moves in the z direc tion are made in 0 5 A increments Label Apply heteroatom labels as you build a structure The label consists of the element name and formal charge and is applied to atoms other than C and H Display Connect Fuse panel Open the Connect amp Fuse panel so you can connect structures create bonds between structures or fuse structures replace atoms of one structure with those of another Display Adjust panel Open the Adjust panel so you can change bond lengths bond angles dihedral angles or atom chiralities Add hydrogens Pick to apply the current hydrogen treatment Menu button with a pick menu and an item to open the Atom Selection dialog box Same as the Add hydrogens button on the main toolbar FirstDiscovery 3 0 Quick Start Guide Chapter 3 Int
45. cally illustrated in Figure 10 8 82 FirstDiscovery 3 0 Quick Start Guide Chapter 10 Liaison Simulations Liaison Directory Structure Maestro Working Directory Master Liaison Run Directory jobname ligand1 ligand2 ligand3 ligand4 Input Output analyze_jobname lt a simulate_jobname jJobname dat jJobname in jJobname 1og jJobname mae jJobname out change_sgbparam_jobname ligand5 ligand stdout ligand2 stdout ligand3 stdout ligand4 stdout ligand5 stdout jobname 1og ligand _structure ligand _lig_min mae receptor_structure ligand _rec_min mae ligand ree inp ligand free out ave amp log ligand bound inp ligand bound out ave amp log ligand _lig_fin mae ligand _rec_fin mae ligand free trj ligand bound trj cmpx rst Figure 10 8 The Liaison directory structure Files in brackets are created only with Liaison Dynamics and HMC jobs In Figure 10 8 the top level Maestro Working Directory contains the Master Liaison Run Directory the scripts used to run Liaison jobs and the receptor structure file In this tuto rial the Maestro Working Directory is workdir it and the Master Liaison Run Direc tory is workdir it it_sim Subdirectories contain the input and output files for jobs started by the simulate_jobname script If you want to stop working on the tutorial now choose Close Project from the Project menu in the main menu ba
46. cate and select the file workdir lia_structures liaison_ligands txt 5 Click Open The liaison_ligands txt path and filename appear in the Filename text box of the System folder In the next exercise you will view the default Liaison settings and change the number of steps in the minimization FirstDiscovery 3 0 Quick Start Guide 71 Chapter 10 Liaison Simulations 10 6 Setting Job Parameters The Minimization sampling method is the most desirable for quick fit and predict screen ings Hybrid Monte Carlo and Molecular Dynamics methods might produce better overall results but require more CPU time At times you will want to change some of the simula tion conditions for Liaison jobs To change the number of minimization steps 1 In the Liaison Parameters folder choose Minimization from the Sampling method menu 2 Ensure that Truncated Newton is selected in the Minimization algorithm menu 3 In the Ligand Simulation folder replace the default 500 in the Maximum minimiza tion steps text box with 800 Liaison Job fit_sim Login saunders Host localhost 1 settings System Parameters Constraints Analysis Sampling method Minimization Minimization algorithm Truncated Newton Shnulation temperate Ky 300 Temperature relaxation Une ips 0 01 Residue based cutoff distance 15 00 A Force field OPLS A amp L Use ligand input partial charges if they exist Ligand Sim
47. ce Display menu provides access to panels that control the display of the contents of the Workspace to commands for the display of panels and to options for the display of main window components Your choice of main window components displayed is persistent between Maestro sessions e Tools menu provides access to panels for grouping atoms for measuring for aligning and superpositioning structures and for viewing and visualizing data e Applications menu provides access to panels for setting up submitting and mon itoring jobs for all Schr dinger s computational programs Some products have a submenu from which you can choose the task to be performed e Help menu provides access to the Help panel and to a control for the display of Balloon Help tooltips 3 3 2 The Toolbar The main toolbar contains buttons for performing common tasks There are three kinds of buttons on the toolbar Those that perform simple tasks like clearing the Workspace Those that show and hide panels or open dialog boxes e Those that display a menu when you click and hold The third type of button is called a menu button and has a triangle in the lower right corner The menu is called a button menu There are two kinds of items on button menus and both kinds can be on the same menu e Actions which perform an action immediately e States which you set before an action is performed When you select a state it is stored and marked w
48. cking s cicccssacceieisrsvesiscssssosecive 106 POMS ois ses A E T 1 fragments building structures with 18 Frozen Atoms panel cece eee 80 G Glide analyzing data 0 ceeeeeeseeeeeeeeee 61 docking output files ee 58 enclosing DOX eeeeeeeeeeeeeeeeeeeeeeeees 44 introduction tO eee eee eeeeseeecseeeeeetseeeees 3 output options s ssssssssssesssssssesresrieseeeere 59 pose viewer files sssseeeeeeeeeeesee 62 Pose Viewer panel eee 106 reference ligands specifying 53 109 Index scoring preferences defining 54 starting JODS essiri aeisi 58 Glide constraints 0 cece eeeeeteeeeeeeeeeeeees 56 Glide panel Constraints folder cece 56 Ligand folder opening Output folder Scoring foldet sinisisi 54 Similarity folder ieee 56 Site TOlMEL ss sissdisisssse dissents wicarevsts 45 Glide Pose Viewer panel Contacts folder ieee 67 H Bonds folder 68 Poses folder resnais 63 Glide Sc fEn poai i RENE 106 in Glide Pose Viewer 62 i iais OM gesedeer 71 global transformations 0 0 00 cece 106 grid calculations EAn aT E E EE S specifying files starting and monitoring grid ilese S GLEAN O oree tear a tan EEEa EEEE specifying preexisting s TOW DONG wedi ei anet AESA EAEE G Score GlideScore c cssccsseeseeseeesees H H bonds displaying eee eeeeeeeeeeeees 68 WOM Pissssnsssecicssssssessve
49. corporate it into the project However you can use a scratch entry as input for some calculations The structures and their data are represented in the Project Table which displays a list of entries Each entry is represented by a row in the Project Table Each row contains the row number an icon indicating whether the entry is displayed in the Workspace the In 12 FirstDiscovery 3 0 Quick Start Guide Chapter 3 Introduction to Maestro column the entry title a button to open the Surfaces panel if the entry has surfaces the entry name and any entry properties The row number is not a property of the entry You can open the Project Table panel by choosing Show Table from the Project menu by clicking the Show Hide project table button on the toolbar or by pressing ALT T Ee The Project Table panel contains a menu bar a toolbar and the table itself You can use entries as input for all of the computational programs Glide Impact Jaguar Liaison LigPrep MacroModel Prime QikProp and QSite You can select entries as input for the ePlayer which displays the selected structures in sequence You can also duplicate combine rename and sort entries create properties import structures as entries and export structures and properties from entries in various formats 3 4 1 The Project Table Toolbar The Project Table toolbar contains two groups of buttons and a status display The first set of buttons opens various panels that
50. cted entry Incorporate output into project by Appending new entries Q Replacing existing entries lt Do not incorporate Potential Constraints Minimization Optimization QM Settings Method DFT B3LYP Charge 0 Multiplicity 1 QM options iacc 1 vshift 1 0 maxit 100 Number of processors to run job 1 QM regions Residues Ligands lons Start Write Job Files Hide Help Figure 13 2 The QM Settings folder of the QSite panel 98 FirstDiscovery 3 0 Quick Start Guide Chapter 13 Running a QSite DFT Job QM Residue Ligand iqmres EEE APR W Show markers r 1 Residue selection by backbone picking i j 1 _ Residue selection by sidechain picking j J Free ligands Basis set 6 31G Delete Figure 13 3 The QM Residue Ligand selection panel To define the QM region by backbone 1 In the QM Residue Ligand selection panel select Residue selection by backbone picking 2 In the Workspace pick the carbonyl carbon of residue 15 and the amino nitrogen of residue 18 to add residues 15 through 18 to the QM region The selected residues are added to the QM Residue Ligand panel list QM region size is the most influential factor in QSite calculation speed It is therefore not advantageous to work with smaller model proteins However you might want to mark as frozen atoms any portions of your system treated by the MM force field see the Constrai
51. ctive color to the ligand molecule on screen is helpful for visualizing large scale ligand receptor interactions To view atom types you must use a different coloring scheme In this exercise you will color only the carbons in the displayed mole cules by molecule number This will leave non carbon atoms colored by atom type so that you can more thoroughly investigate contacts and hydrogen bonds e On the toolbar click and hold the Color all atoms by scheme button and select Mole cule Number Carbons from the menu amp In the Workspace carbon atoms remain colored by molecule number but non car bon atoms are now colored by atom type 8 7 Changing Molecular Representations These instructions describe how to change the molecular representation of bonds in the displayed ligand to Tube Displaying some of the Workspace bonds in Tube representa tion can help you view intermolecular interactions more clearly 1 On the toolbar click the Draw bonds in tube button Q 2 Pick an atom in the ligand molecule The bonds in the ligand are displayed as tubes 8 8 Visualizing Bad and Ugly Contacts Since there are fewer disadvantageous than advantageous contacts in the structures selected by Glide visualizing only the former simplifies the interpretation of receptor ligand interactions Use the following instructions to visualize contacts that are Bad or Ugly according to default or user defined criteria 1 In the Poses fold
52. d hold the Label atoms button and choose Molecule Number from the menu D al The ligand is labeled 1 molecule 1 2 On the toolbar click and hold the Color by constant color button and choose Purple from the menu o a 3 Click on an atom in the displayed structure The ligand is colored purple 4 In the Poses folder of the Glide Pose Viewer panel select Display The receptor is redisplayed in the Workspace The molecule number is useful when you are manipulating the molecule s properties or defining sets of atoms using ASL Changing the color of the ligand can be helpful in visu alizing the large scale ligand receptor interactions In the next exercise you will use the molecule number of the ligand to selectively display only those receptor atoms that are within a specified distance of the ligand In subsequent exercises you will examine inter actions between the displayed ligand and receptor 64 FirstDiscovery 3 0 Quick Start Guide Chapter 8 Examining Glide Data 8 5 Displaying Atoms by Proximity In this section you will display only part of the receptor molecule to better examine contacts and hydrogen bonds between the displayed ligand and the binding pocket of the receptor 1 11 On the toolbar click Display only and choose Select from the menu lt a ail The Atom Selection dialog box ASD is opened with the heading Select to Display Only Click the Molecule tab and select Molecule Number
53. d in the lower right corner of the Workspace that displays an image of structures as viewed from above The Top View window contains two clipping planes The window can be hidden or displayed by selecting Topview Window from the Display menu Workspace The large open area in the center of the main window By default it is colored black Molecular structures whether built or imported are displayed and manipu lated here FirstDiscovery 3 0 Quick Start Guide 107 Glossary 108 FirstDiscovery 3 0 Quick Start Guide Index Symbols SCHRODINGER protprep ssseeees 33 A ASL undisplaying atoms with 65 atom labels applying 64 Atom Selection dialog box ASD 21 atoms COTONE esns OES fCZING sieros ri rinena nis EEE EE Eia MUM DELING eoii selecting seese undisplaying with ASL AUto He lp si tssccsccsscessteveeesscnsecs ccs B Balloon help cceeeseeeseeeeeees 26 103 105 DASE NAME ssesceccssstevccssesseassassacententencsseavassees 105 basis set selecting 100 binding energy file wee eee 86 105 binding free energy calculating bounding DOX ssr oenina ainar 44 105 Build panels iscsi cases aivnchtnc tian 19 building structures eects 18 20 b tton MENU sirsa 8 C clipping planecie 105 command input area command line running Protein Preparation ATOM esie peor aianei 33 Command Script Editor panel 23 97 command scripts for Gl
54. definitions In the following exercise you will visualize any existing ligand receptor hydrogen bonds FirstDiscovery 3 0 Quick Start Guide 67 Chapter 8 Examining Glide Data 8 9 Displaying Hydrogen Bonds Use the following instructions to display hydrogen bonds between the ligand and the receptor 1 In the Poses folder ensure that Display is selected 2 In the H Bonds folder ensure that Display H Bonds is selected 3 In the Poses folder select a ligand pose in the list 4 Click Visualize H Bonds to Receptor Hydrogen bonds are depicted in the Workspace as broken yellow lines 5 Rotate the Workspace structures to better view the hydrogen bonds In this exercise you displayed hydrogen bonds in the Workspace As with contacts you can change the atom sets for which hydrogen bonds are displayed When you finish viewing the hydrogen bonds click both Clear buttons in the H Bonds folder Poses H Bonds Contacts WE Display H bonds Maximum distance 2 50 Minimum donor angle 90 00 Minimum acceptor angle 60 00 O Pick Molecules Figure 8 3 The H Bonds folder of the Glide Pose Viewer panel 68 FirstDiscovery 3 0 Quick Start Guide Chapter 8 Examining Glide Data 8 10 Writing a File Containing a Single Ligand In the previous exercise you practiced using the Glide Pose Viewer s analytical tools to study ligand receptor interactions The instructions below describe how to create indi vi
55. dir it fit_sim out 8 In the Analysis folder under Prediction parameters enter the alpha beta and gamma values from the file in the corresponding text boxes 9 Click Start The Monitor panel is displayed and logs the job s progress When the job finishes the following items are written to the workdir predict directory analyze_predict_sim predict_sim dat predict_sim in predict_sim log predict_sim out Liaison Job predict_sim Login saunders Host localhost 1 settings system Parameters Constraints Analysis Analysis type Prediction parameters Fit Van der Waals alpha 9 Predict Electrostatic beta 0 Binding energy model CaVity gamma LIA equation Stepe brercepk Q GlideScore t l Specify ligands by Read ligand names from a text file File name of ligand names fo Browse Comme separated ish Filename of fend bindini energies SSS E HAY Start write Job Files Figure 11 1 The Analysis folder of the Liaison panel 90 FirstDiscovery 3 0 Quick Start Guide Chapter 11 Analyzing Liaison Data In predict_sim out you will find the binding energy of the HO6_altered ligand The binding energy reported in kcal mol can also be found in the upper window of the Monitor panel The predicted binding energy is calculated from the LRM equation AG a lt U gt lt U ay gt B KW arec gt lt Utec gt Y lt U ra gt lt UF oa gt
56. dual structure files for the top five poses in the pose viewer file You will use these struc ture files later as input for a Liaison job 1 on OA a In the Poses folder of the Glide Pose Viewer panel deselect the receptor Display option The receptor is removed from the Workspace Select the first pose in the pose list Click Write Displayed Poses The PoseWrite panel is displayed Ensure that Append is deselected and then click Write To The Write Pose File file selector is displayed Navigate to the workdir lia_structures directory After the text in the Selection text box type HO1_poses mae Click Save Repeat the previous steps to create five more files each containing one of the top five ligand poses starting again with pose 1 This time use the following file names replacing ig with the structure numbers of your five top poses e g H18 H06 and so on posel_lig mae pose2_lig mae pose3_lig mae pose4_lig mae pose5_lig mae These numbers represent both the poses ranks in the list and the numbers of the ligands within the multiple ligand structure file When you are finished you will have written six files five to use as input for Liaison jobs and one to use in the next exercise PoseWrite posewrite J Append File Figure 8 4 The PoseWrite panel FirstDiscovery 3 0 Quick Start Guide 69 Chapter 8 Examining Glide Data When writing files for use w
57. e 3 Resume the job by clicking Resume You can also start monitor and interrupt Glide jobs from the command line For more information see the FirstDiscovery User Manual and the Maestro User Manual The job takes approximately 10 minutes depending on your particular system configura tion and workload When the calculation is complete these files should appear in your grids directory grids_H01 inp Command input for grids job grids_H01 mae Receptor structure input for grids job grids_H01 log Log summary file from grids job grids_H01 out Output summary file from grids job as well as these output grid files for use in docking grids_H01 csc grids_H01 save grids_H01 greedy save grids_H01 grd grids_H01 site grids_H01 recep mae grids_H01 gsc grids_H01 coul2 fld grids_H01 vdw fld 46 FirstDiscovery 3 0 Quick Start Guide Chapter 6 Creating Glide Grid Files When you run multiple calculations with the same job name Glide overwrites some of the created files and preserves others by appending incremented numbers to the existing file names 6 9 Exercise Summary When you calculate grid files the files are saved to disk allowing you to use them in subsequent docking jobs with additional ligands In the next chapter you will dock ligands using the grid files you calculated in this chapter If you want to stop working on the tutorial now choose Close Project from the Project menu in the main menu bar 6 10 Running the Job With a
58. e ligand 4 TAPAP shown in orange In the terminal window where Maestro was started you should see these messages WARNING check_residue no template for residue 1 TOS chain T WARNING check_residue no template for residue 2 PAP chain T WARNING check_residue no template for residue 3 PIP chain T The ligand 4 TAPAP comprises three PDB HET groups p toluene sulfonate TOS amidophenylalanine PAP and piperidine PIP None of these is a standard amino acid residue which means that there is no standard connection template to supply information about bond order or formal charges Without this information Maestro creates a ligand structure using only single bonds and assigns no formal charges which is far from correct for 4 TAPAP The ligand structure must be corrected before it can be used in Glide and other FirstDiscovery applications Bond order correction of the ligand is covered in Section 4 4 4 3 Deleting Unwanted Waters There are hundreds of water oxygen atoms in this structure as there are in most PDB structures Because water molecules vary in relevance to the binding mode of interest the Protein Preparation workflow allows you to decide in each case whether to keep all water molecules delete some or delete all If cocrystallized water molecules are coordinated to metal ions or are forming hydrogen bond bridges between the ligand and protein and you want to search for ligands that bind in the
59. e panel is displayed with the Settings folder open 2 In the Settings folder choose Set up grids from the Choose Glide function option menu 3 In the Job text box enter grids_H01 Note that HO1 contains a zero When you assign a name to a grid generation job Maestro copies the job name into the Base name for grid files text box FirstDiscovery 3 0 Quick Start Guide 41 Chapter 6 Creating Glide Grid Files When you choose Set up grids Maestro sets the Directory for grid files to the current working directory If this is where you want to write the grid files you do not need to change the grid file directory setting However if you want to write the files to an alterna tive directory you must specify the new directory in the Directory for grid files box For this exercise if you did not start Maestro from your workdir grids directory enter the path to this directory in the Directory for grid files text box Now that the new job has a name you need to specify which molecule is the ligand You will do so in the next exercise By default the name you enter in this text box becomes the base name for the job output files 42 Glide glide Host localhost 1 Settings site ugana Searing output constraints simitarity Choose Glide function Set up grids choase Hecki mode y Displayed structure is Receptor alone J kin Byands vith so alos Skip buands wiih 1s retatabie hont
60. ec mae e posel_lig _lig mae 2 Confirm that the Monitor panel is displayed as the job starts If the Monitor panel does not appear automatically open it by selecting Monitor Jobs from the Maestro Applications menu For information on job monitor commands and options click Help in the Monitor panel 3 When the job finishes confirm that stdout and 1log files for each ligand have been written to the it_sim directory The bound and free simulations write multiple output files to each ligand s subdirec tory In the pose1_lig directory confirm that the following files have been added e posel_lig bound ave e posel_lig bound log e posel_lig bound out e posel_lig free ave e posel_lig free log e posel_lig free out e posel_lig _lig_min mae e posel_lig _rec_min mae 10 9 Exercise Summary In this chapter you set up and started Liaison simulation calculations After the calcula tions are completed the ligand free ave files and ligand bound ave files contain the terms in the angular brackets used in the LRM equation and the GlideScore equation on page 71 These job results are used in the next chapter for a Liaison fitting calculation The fitting calculation determines the alpha beta and gamma coefficients in the LRM equa tion which can then be used to predict ligand binding energies Inside the fit_sim directory a subdirectory for each ligand has been created The Liaison directory structure is schemati
61. eeserseesseeserssesseeseesseesreseesese 13 3 4 2 The Project Table Menusissi 5535s 2 520505 sgesehdh cioes a n E 15 34 3 Selecting BAES sosie crentar AE A eaves R IEE R atest 15 3 4 4 Including Entries in the Workspace s sssseeseeeeeesesseseeeressseseseessreseesersese 16 3 4 5 Mouse Functions in the Project Table eee ceeseeseeseceeeceneeseaeeeseeesaes 16 3 4 6 Project Table Shortcut Keys ci 085sischcs weesssiscssepecscgessspssteabesessaserteecesasebudees 17 33 Bailing d SUW sacs ceeds ches icise vs sdevaedaccaavaenedesa E E EE 18 3 6 Selecting Atoms viisc15iis ccsccieeveciieee listens naciaki E E E E E een ales 21 3 1 Maestro Command Scripts eccna eria ranea o a Aae a 22 3 8 Specifying a Maestro Working Directory ssesssricssriessirersisrissssesserersessnsrssuressses 23 3 9 Updoins am Operation osc ceedc ins ice cedensssctcyssehvatesiaceiactdensesscanendece seven ycdanveadeedeerveres 24 3 10 Running and Monitoring Jobs ce eeeceseeceneceseeeeeeeeseeeeeeeeeeceaeeeeessaeeeteeesaes 24 3 11 Goett Help ensor a a ch evs eves devisees ededeads 26 3 12 Ending a Maestro Sessioner nenret iine n AEE EK a aai nite 26 Chapter 4 Protein Preparation csccscscsccssccssscssessesscescsssssssssesscsessssseserees 27 4 1 Preparing Proteins for FirstIDIsCOVELY i 050 sssvesscsssssedecorteetatesetcoscavansceseceasntesse 27 4 2 Importing the Protein Complex Structure eeeeseeseeseceneeseseneeeeseseeeenens 27 4 3 Deleting Unw
62. er of the Glide Pose Viewer panel ensure that Display is selected 2 In the Contacts folder make sure Display contacts is selected The default behavior for this option is equivalent to selecting Bad contacts and Ugly contacts but not the more numerous Good contacts Note that you can modify the Contact cutoff Ratios for the displayed contacts 66 FirstDiscovery 3 0 Quick Start Guide Chapter 8 Examining Glide Data Glide Pose Viewer pose Poses H Bonds Contacts W Display contacts Mark contacts Contact cutoff ratios I Good contacts 1 30 W Bad contacts 0 89 WE Ugly contacts 0 75 Select W Pick Molecules Figure 8 2 The Contacts folder of the Glide Pose Viewer panel 3 In the Poses folder select a ligand pose in the list 4 Click Visualize Contacts to Receptor The contacts are shown as dashed lines connecting Workspace atoms e Ugly contacts red are interactions with van der Waals radii closer than those possible in real systems e Bad contacts orange are less close than Ugly ones but are still unlikely in real systems e Good contacts green are not currently displayed Contacts are considered Good if they are allowed according to empirical values for the particular atom type interaction 5 Return to the Contacts folder Note that you can select alternative atom sets for which to display contacts and H bonds 6 Click both of the Clear buttons to remove the atom set
63. eration is being performed Balloon Help Automatic help that appears in a floating text box when the mouse pointer is over an interface item Base Name The name entered in the Base name for grid files text box that is used to write grid files during a grid file calculation or to find pre existing grid files during a docking job Binding Energy File A text document specified during a Liaison Fit task that contains the experimental binding energies for the ligands on which the job is being run You must create this file manually The correct format for the document is two columns The first column contains the name of the directory in which Liaison placed the data for the ligand of interest during the corresponding Simulate job The second column contains the ligand s experimental binding energy in kcal mole Bounding Box tThe green cube shaped marker that appears in the Workspace during Glide docking job setup after you select active site residues coordinates or a ligand to be used as the box s center The box represents the space in which ligands are allowed to move during docking Increasing the size of the bounding box increases the space that can be sampled by the docked ligands and consequently increases the CPU time required for the calculation Clipping Planes Two horizontal lines in the Top View window When moved onto the Top View image of the Workspace structure the clipping planes cause portions of the Workspace str
64. es writing ligand poses displaying ligand source file SPOCILYVIND serinin eais Linear Response Method eseceeseeeees local transformations log file saving in Maestro M Maestro NiG Pisces cee escsa an a E 103 interface behavi0l cccccccccesseceeseees 5 introduction tO eeccccccessseeessceesseeesseees 3 main WINKOW cccceescceessceeseeeetseeeeee 6 7 MENUS Ses ssssaessseecsca recesses E 7 8 QUITS os itsncssssasecetendeavesdieatereciectassesnets 26 running jobs from 24 25 FirstDiscovery 3 0 Quick Start Guide scratch Projects ceceseseseeseeeeeteeeeees 12 Stata NE O avcieds Cresta enccedeenseats 6 undoing Operations 24 Maestro command input area 29 Main Menu Bat cece eeeereeeeneeeeees 106 M in WING OW sssr sei Aa 7 MENU DUTON wisscciesecescsscssassssssesscssodsssnssassessa ses 8 molecular representation changing 66 molecules COLONS sssscus cts nralesvedaetiiintvisiaete 64 coloring by number cee 66 UMETNE sieve sisctivcbececseenzcerssastersstawsees 64 Monitor panel ca ssscateies aussitateseisrss 25 46 MOUSE FUNCTIONS 00 eee eeeeeeteeeteeeeeeeteeeeeaeeee 5 Project Table panel eee 16 17 WOKS ACE vaeiesvisssisatscostqeeesinincestiveaseises 11 multiple ligand files writing 70 O online Hel pics iisssctiseseksassdesisscsseeaceassldvesiescaess 26 option menu output Glide docking s0 5 secscste
65. es are supplied for comparison and for use as job input if you want to complete only some of the exercises in this guide As you perform the exercises you will create your own job files so you must first create a directory in which to write these files To create your working directory 1 Ata shell prompt change to a directory in which you have write permission 2 Create a new directory by entering the command mkdir workdir In the text this directory is referred to as the working directory 3 In the working directory create subdirectories named glide grids fit predict lia_structures and gsite The fit predict lia_structures and qsite directories are used in the Liaison and QSite tutorials 4 In the working directory create a soft link to the SCHRODINGER impact vversion tutorial structures directory by entering ln s SSCHRODINGER impact vversion tutorial structures In the distribution a directory called SCHRODINGER impact vversion tutorial maestro_cmd contains command scripts that automatically perform tasks described in the exercises The command scripts are provided so that you have the option of manually FirstDiscovery 3 0 Quick Start Guide 37 Chapter 6 Creating Glide Grid Files or automatically configuring the jobs in this guide and so that you will have examples for creating your own command scripts You do not need to copy these scripts you can run them from the distribution directory Look for f
66. essesesesreseesssesrensesssenrenere 65 8 6 Coloring Carbons by Molecule Numbet c cceccesceeseeeeeeseeeeeeseeeeeeeeneeeaeens 66 8 7 Changing Molecular Representations ceccesceeseeseeeceeeeeeceessenseeeenseeseenseeaes 66 8 8 Visualizing Bad and Ugly Contacts ccccecceceeseeeceeseeeseeseceeeeseceeeeaeeeneeerenaeeaes 66 9 Displaying Hydrogen BOndS 4 cexs chssdcensecbactendeecuevtevedansesteestndvsdneguaeedvasaoneayeece 68 8 10 Writing a File Containing a Single Ligand eee eeeeeeeeeeteeeneeeaee 69 iv FirstDiscovery 3 0 Quick Start Guide Contents 8 11 Saving Multiple Ligand Poses to a Single File eee eeeeeeeereeeeeeeeeeee 70 8 12 Exercise SUMMAT Y sseni eiin rge ne eieiei EE E EE 70 Chapter 9 Introduction to Liaison soesossessoesessoesossessossoseesoosseseossosseseossss 71 Chapter 10 Liaison Simulations ccccsscscsscccscscccsccssssesssscesscesseessscessseses 73 10 1 Prepatation n eai Ean eE E ai Ea oaea Aaa 73 10 2 Specifying Jop Seti iscsccccscc chess asasccnescasdhcyuerd cs sevtuesiegdanesedbisvaieavdeaseaniecercbeases 74 10 3 Loading a Recepto ienen oeo notea i E EE E ee Ro ies 75 10 4 Creating a Ligand Source File ccceeceecessceseeeeeeseceeeeseceeeeseeeeeseeeeeeaeeneeeaeens 76 10 5 Specifying a Ligand Source File and File Format seesseeesesesseeresrerrereeerrrer Vd 10 6 Settine Job Paramete Ssss iieii oae aa aaas 78 10 7 Specifying Atoms to Free2ersns
67. evbisdtentsscesusostes nini 103 Help buttonuna nis 103 Help panelis isores teresina 26 103 Hide Buttons s cissssccisissitdevecsaticcditisssstsausaatessuss 5 hydrogen bonds displaying 0 00 0 68 I Impact introduction t0 seeen 4 Import panel 3 5 seedseaseseescossnecesnesasonevesoseon s 39 Included enthiess isisesceceds cteieesstvsesestiees 16 interface behavior of Maestro 0 0008 5 J Jaguar DASIS SOUS sssceccesstecsivaeissvecteas sebsaneevees 100 Key WOTS sssissiosecstcccsssccteencdestavsnesnsontees 100 job name assigning 41 110 jobs monitoring and stopping ee 45 running in Maestro cee 24 25 K Keep At Most n Pose s setting in Glide 55 keywords Jaguar 100 L Liaison binding energy file oo eee 86 directory structure oo cles 83 fittaS Kerisi 82 86 89 introduction toO sssessseseeesesrsesrererererererere 3 job paramMeterS ssesssssiserssnisiiiiirsisisissssss 78 job type specifying eee 74 master directory sssseseeseeeeerereeeeeee 107 predict task aiaiai 87 89 simulation type specifying 74 Startins JODSisssieesseidasiessessssiesiesivednesi tes 81 See also ligand source file Liaison panel Analysis folder ccccceseeseeseeseeseeseeeees Constraints folder Parameters folder ieee Settings folder ee sseceeeseeeseseereere System folder sirosis ligand centroid s sssseeeeeeeeeeseesseesreeserseee ligand pose fil
68. ference ligand are conformers Glide computes and reports the RMS deviation in atomic coordinates between the reference ligand and the poses generated for the docked molecule s The RMS deviation is based on a comparison of heavy atoms The steps below describe how to designate a reference ligand 1 In the bottom section of the Ligand folder select Define a reference ligand 2 Click Specify Ligand The Reference Ligand panel is displayed 3 Select Use ligand from external file and ensure that the Format menu option is Mae stro 4 Click Browse A file selector is displayed 5 Locate and select the file workdir structures H01_H20_lig mae 6 Click Open In the Reference Ligand panel you can leave the Structure number in ligand file value set to 1 since the first structure in the multi structure file is the cocrystallized ligand for the HO1 receptor 7 Click Hide In this exercise you specified a reference ligand for the docking of molecules in the struc ture file HO1_H20_lig mae This completes the necessary adjustments to settings in the Ligand folder In the next exercise you will view the Scoring folder settings eference Ligand refligand Specify reference ligand Select to use a gt Use displayed ligand ligand currently included in the Workspace as Use ligand from external file Format Maestro the reference Ligand file name rial tutorial structures H01_H20_lig mae Click to dis ligand Structure number in l
69. first of the new entries the refined receptor structure with all hydro gens is the first structure in the lett_prot_ref mae file and is automatically included in the Workspace Exclude the receptor and include the second new entry to inspect the refined ligand struc ture The extra hydrogen has been added to the charged nitrogen and the guanidine group is planar It is a good idea to examine prepared refined protein and ligand structures in the Work space checking for obvious structural problems making sure that the ligands and any cofactors were properly hydrogen treated that the correct formal charges if any were added still exist and that the structures look properly minimized If any problems exist you can correct them in the input structure and then run the appropriate preparation and or refinement jobs again 34 FirstDiscovery 3 0 Quick Start Guide Chapter 5 Introduction to Glide Glide is a fast and accurate docking program that addresses a number of problems ranging from database screening to highly accurate docking The process has two main steps receptor grid generation followed by ligand docking and scoring Each step is set up using the Maestro graphical user interface In grid generation the shape and properties of the receptor are represented on a grid by several sets of fields that govern evaluation of the ligand poses A ligand pose includes both the internal conformation and the position and orientation rela
70. for selecting entries based on criteria for entry properties Go to start Display the first selected structure Previous Display the previous structure in the list of selected structures Play backward Display the selected structures in sequence moving toward the first Stop Stop the ePlayer Play forward Display the selected structures in sequence moving toward the last Next Display the next structure in the list of selected structures Go to end Display the last selected structure ePlayer loop menu Display a menu of options for repeating the display of the structures Single direction displays structures in a single direction then repeats Oscillate reverses direction each time the beginning or end of the list is reached FirstDiscovery 3 0 Quick Start Guide Chapter 3 Introduction to Maestro The status display shows the number of selected entries When you pause the cursor over the display the Balloon help shows the total number of entries the number shown in the table the number selected and the number included 3 4 2 The Project Table Menus e Table menu provides tools for finding text sorting entries and plotting properties importing and exporting structures and configuring the Project Table e Select menu provides commands and access to the Entry Selection dialog box and the Filter panel so that you can select entries e Entry menu provides tools for including and excluding entries controll
71. he item Move the mouse pointer over the element If there is Balloon help for the element it appears within a few seconds If you do not find the help you need using the steps above click the Help button in the panel for whose settings you are seeking help The Help panel is opened and a relevant help topic is displayed For help with a concept or action not associated with a panel open the Help panel from the Help menu on the main menu bar or by using the key combination ALT H If you do not find the information you need in the Maestro help system check the following sources The Maestro User Manual for questions about Maestro The FirstDiscovery User Manual for questions about FirstDiscovery and FirstDis covery panels in Maestro The FirstDiscovery Command Reference Manual for information about command line tasks and options The Command Reference Manual is provided with the First Discovery distribution but is not included in the printed FirstDiscovery Operating Manual and is also available with the other manuals and release notes at Schr dinger s web site see below The FirstDiscovery Technical Notes for information about technical or scientific issues The Maestro Release Notes The FirstDiscovery Release Notes The Frequently Asked Questions page located at http www schrodinger com Support faq html FirstDiscovery 3 0 Quick Start Guide 103 Chapter 14 Getting Help These manuals and release notes are avai
72. he use of Glide constraints is optional In the Glide grid generation exercise see Chapter 6 no Glide constraints were specified and none will be applied to the docking job set up here For more information on Glide constraints see the FirstDiscovery User Manual Glide glide Job dock_confgen Login saunders Host localhost 1 settings site Ligand Scoring output Constraints simitarity In order to apply docking constraints select the receptor sites in the list below Display Receptor Receptor constraint sites W Show markers Ligand atoms interacting with receptor metal sites Must be charged Start write Job Files Hide Help Figure 7 5 The Constraints folder of the Glide panel 56 FirstDiscovery 3 0 Quick Start Guide Chapter 7 Docking Atom pair similarity scoring can be used in docking to increase the likelihood that high ranking ligands will be similar to or different from known actives If similarity scoring is selected a file of known actives must be specified Similarity scoring is optional and will not be used in this exercise 1 In the Glide Similarity folder make sure that Use similarity score in docking is not selected 2 Optionally read the online help topic for the folder For more information on similar ity scoring in Glide see the FirstDiscovery User Manual Glide glide Job dock_confgen Login saunders Host localhost 1 Settings Site
73. ick Start Guide Chapter 3 Introduction to Maestro Maestro is the graphical user interface for all of Schrddinger s products FirstDiscovery Glide Impact Liaison and QSite Jaguar LigPrep MacroModel Prime and QikProp It contains tools for building displaying and manipulating chemical struc tures for organizing loading and storing these structures and associated data and for setting up monitoring and visualizing the results of calculations on these structures This chapter provides a brief introduction to Maestro and some of its capabilities For more information see the Maestro User Manual 3 1 General Interface Behavior Most Maestro panels are amodal more than one panel can be open at a time and a panel need not be closed for an action to be carried out Instead of a Close menu option or button each Maestro panel has a Hide button so that you can hide the panel from view Maestro supports the mouse functions common to many graphical user interfaces The left button is used for selecting choosing menu items clicking buttons and selecting objects This button is also used for resizing and moving panels The right button displays a context sensitive menu Other common mouse functions are supported such as using the mouse in combination with the SHIFT or CTRL keys to select a range of items and select or deselect a single item without affecting other items In addition the mouse buttons are used for speci
74. ide docking cee eeeeeeeeeee 59 for Glide grid setup wee 47 for Liaison fit we 84 for Liaison predict sos Dl for QSit ses cscssetsttiicicdsccncsatcrcee 96 Maestro cvssscsssssssssssssssssssocsocsonsossossss cesses 22 command line application PIOUDLSP sivcsesiss cesstussvensatiiissssactassi dese 27 constraints Glide c cccccessceeseceesseeetseees 56 CONACS senares sss 66 105 current working directory 0 0 eee 6 FirstDiscovery 3 0 Quick Start Guide D directory Current WOrkIN go eee eeeeeeeeeees 6 23 OUT Ub sexs ss coscerelssveciaesseh T 23 for tutorial os sicvseeweisasccacabesieneiesestiesscieets 37 docking reference ligands for 0 0 eeeee eee a3 scoring preferences for 54 selecting ligands for eee 50 specifying grid files for 50 starting JODS iieii oiia 58 E enclosing BOK ccsccescsscsscesessccsveabodsedseeees 44 106 entries Project Table cceeeeeceeseeseeseeteees 12 including excluding and fixing 16 SCLC CHING erisso erisin 15 16 SOUNE ca scucsushexesss tes cvs svaccssoasszcsuincies tested 14 environment variables DES PLAY etnisite eann Eain SCHRODINGER ePlay eTa a E ais een ete excluded entries aiccnicnsioniiiaiiaiens F fil T O GITECHOTY econ aia 23 files IMPOTtiNg oe inteston 38 75 FIETS iiris 15 16 fit CASK ssasssccssszsssevssves caxetsvsatsodsstbassenteousateercens 86 PIXE entie weiss cess assess eestistas 16 flexible do
75. ie i niniin E EEE leet 79 10 8 Startins the Liaison JOD sipsineinccm esee aiia nares an iea ne aas 81 10 9 Exercise SUMMA LY srsenirrinrnsnm eea a ar a E E EiS 82 10 10 Running the Job With a Command Script sssesesseesesessssesresesresresesresreresresese 84 Chapter 11 Analyzing Liaison Data scssccssccsscsscsssssssscessscsssscessecessceses 85 MI Preparanoneanesen na e e Ei E E E E O 85 11 2 Creating a Binding Energy Pile ss sccsesssssstessosssxsduazvosssseivezadeiviosessceestass tos sactesas 86 11 3 Fitting Empirical Data Using the LRM Equation eee eeeeeeeseeeeeneee 86 114 Predicting Binding Energies cuimirce sanen nena E Listes audies 87 11 4 1 Performing the Predict Simu latiOn ncccsscr 88 11 4 2 Predicting Binding Energy Using the LRM Model ee 89 11 5 Exercise Summary oes chbs eevee vee cdc veedtuvecs sabe a aae a a iE an Sei iaa 91 11 6 Running the Job With a Command Script sssseseeeeeseesesesesrssserrsrersrersrrsrsrerereses 91 Chapter 12 Introduction to QSite esseesesererososoeseseeeseeeeosorcroeororereeeososoreeereseeee 93 Chapter 13 Running a QSite DFT Job essessesssessesecosseseeoosoesesosoesesossoseocssossse 95 13 1 Preparation sneinen Ea E E 95 13 2 Importing a SUCUT ennnen ara a e cbnedas 95 13 3 Preparing for QM Region Selection s eseseressressereesseressesssesessesestnesresesresssnene 96 13 4 Selecting the OSite Job Type ssssssicsecessscs ssdeatscsvesdsaseesgceaspecsocca
76. igand file 1 play a file selector Hide Help Q Use entry name Figure 7 2 The Reference Ligand panel FirstDiscovery 3 0 Quick Start Guide 53 Chapter 7 Docking 7 5 Reviewing Options for Scoring and Output The default values for Glide ligand scoring and output are appropriate for most jobs so you do not need to change them for this exercise but you might want to examine them Scoring 1 In the Scoring folder view the controls and their default settings 2 Optional Click Help to open the Glide Panel help topic In the Contents click Glide Panel Features then choose Scoring from the list of folders Glide glide Job dock_confgen Login saunders Host localhost 1 Settings Bie Ligand Scoring output Constraints simitarity Refinement of initial poses on coarse grid Keep 5000 initial poses per ligand for refinement Scoring window for keeping initial poses 100 0 Keep 400 refined poses per ligand for energy minimization Energy Minimization Distance dependent dielectric constant 2 0 Maximum number of conjugate gradient steps 100 Final Scoring Reject pose unless Coulomb vdW score lt 0 0 Hydrogen bond score lt 0 0 Metal ligand score lt 0 0 Start write Job Files Hide Help Figure 7 3 The Scoring folder of the Glide panel 54 FirstDiscovery 3 0 Quick Start Guide Chapter 7 Docking Output 1 In the Output
77. ill displayed in the Workspace go to Step 4 Otherwise continue with Step 3 Click Clear workspace then import the file tutorial structures H01_rec mae In the Liaison panel type predict _sim in the Job text box In the Settings folder select Simulate In the System folder set the simulation type to Single ligand single receptor In the Name to use for this ligand text box type HO6_altered In the Parameters folder a Choose Minimization from the Sampling method menu b In the Ligand Simulation folder replace 500 with 800 in the Max minimization steps text box Set up frozen atoms a In the Liaison panel s Constraints folder click Frozen Atoms b In the Frozen Atoms panel click Select to open the Atom Selection dialog box ASD c In the ASL field of the ASD type beyond 18 res 120 and click OK Open the Import panel deselect the Replace workspace option and import the file tutorial structures H06_altered mae Use the Color by constant color toolbar button to color the ligand purple h Choose purple from the Color by constant color button menu Then click on the ligand in the Workspace The ligand molecule is now purple FirstDiscovery 3 0 Quick Start Guide 12 13 Chapter 11 Analyzing Liaison Data In the System folder select Select ligand molecule by picking an atom Pick an atom in the ligand A blue green trace is superimposed onto the selected molecule 14 Click
78. ine help facility and a user manual To get help follow the steps below Check the Auto Help text box below the title bar of the main window If help is avail able for the task you are performing it is automatically displayed there It describes what actions are needed to perform the task If your question concerns a GUI element such as a button or option there may be Balloon help for the item Pause the cursor over the element If the Balloon help does not appear check that Show Balloon Help is selected in the Help menu of the main window If there is Balloon help for the element it appears within a few seconds If you do not find the help you need using either of the steps above click the Help button in the lower right corner of the appropriate panel The Help panel is displayed with a relevant help topic For help with a concept or action not associated with a panel open the Help panel from the Help menu or press ALT H If you do not find the information you need in the Maestro help system check the following sources The Maestro User Manual The Maestro Release Notes The Frequently Asked Questions page found at http www schrodinger com Support fag html 3 12 Ending a Maestro Session To end a Maestro session choose Quit from the Maestro menu To save a log file with a record of all operations performed in the current session click Quit save log file in the Quit panel This information can be useful to Schr dinger supp
79. ing files from SCHRODINGER impact vversion tutorial lia_structures to the workdir lia_structures subdirectory replacing lig with the actual number in the files provided posel_lig mae pose4_lig mae pose2_lig mae pose5_lig mae pose3_lig mae liaison_ligands txt FirstDiscovery 3 0 Quick Start Guide 73 Chapter 10 Liaison Simulations 10 2 Specifying Job Settings Before you can run a Liaison job you must specify basic job settings like job name job type and the number of processors you want to use Follow the instructions below to assign a job title and to specify that you want to run a new Liaison simulation on a single processor 74 1 a oe ee In the main window choose Liaison from the Applications menu The Liaison panel is displayed In the Settings folder ensure that Simulate is selected Confirm that the value in the Number of processors to use text box is 1 Type it_sim in the Job text box In the System folder verify that the Simulation type is set to Multiple ligands single receptor Liaison Host localhost 1 Settings System Parameters Constraints Analysis Job type Simulate Analyze results of earlier simulations Number of processors to use 1 Start Write Job Files Hide Help Figure 10 1 The Settings folder of the Liaison panel FirstDiscovery 3 0 Quick Start Guide Chapter 10 Liaison Simulations Liaison Host localhost 1 Setti
80. ing job When the job has finished these additional items appear in fit_sim analyze_fit_sim fit_sim dat fit_sim in fit_sim log fit_sim out Included in it_sim out are the coefficients from the fit Chi square values and RMSD error In this exercise you have performed a Liaison fitting analysis to determine the coefficients used in the LRM equation In the next exercise you will learn how to use these calculated coefficients to produce binding energies for ligands that are structurally similar to those in the training set 11 4 Predicting Binding Energies These exercises describe how to use o B and y coefficients calculated from the training set to estimate the binding energy for a new structurally similar ligand Before you can predict the binding energy of a new ligand you must run a Liaison simulation on the new ligand The simulation for the new ligand must be set up with the same parameters as in the earlier simulation used to derive the coefficients for the LRM equation Since simula tions were covered in Chapter 10 simplified instructions will be provided in Section 11 4 1 FirstDiscovery 3 0 Quick Start Guide 87 Chapter 11 Analyzing Liaison Data 11 4 1 Performing the Predict Simulation 1 2 oN A a A 10 11 88 Make a directory called predict in the workdir Enter the following command in the command input area of the main window cd predict If the HO1 receptor with its frozen atoms is st
81. ing the display of entries in the Project Table and performing various operations on the selected entries e Property menu provides tools for displaying and manipulating properties e ePlayer menu provides access to the play controls and the ePlayer options 3 4 3 Selecting Entries Many operations in Maestro are performed on the entries that are selected in the Project Table The Project Table functions much like any other table you select rows by clicking shift clicking and control clicking However because clicking in an editable cell of a selected row enters edit mode you should click in the Row column to select entries See Section 3 4 5 on page 16 for more information on mouse actions There are shortcuts for selecting classes of entries on the Select menu In addition to selecting entries manually you can select entries that meet a combination of conditions on their properties Such combinations of conditions are called filters Filters are Entry Selection Language ESL expressions and are evaluated at the time they are applied For example if you want to set up a Glide job that uses ligands with a low molec ular weight say less than 300 and that has certain QikProp properties you can set up a filter and use it to select entries for the job If you save it you can use it again on a different set of ligands that met the same selection criteria You can create filters in the Entry Selection dialog box which you can open f
82. ipt to set up the files a If you choose to copy the necessary items copy the file it_sim mae and the directory fit_sim from SCHRODINGER impact vversion tutorial fit to workdir fit b If you want to run the Simulation job now using a command script to set up the job follow the instructions in Section 10 10 on page 84 Start the simulation job and let it run to completion This job takes approximately one hour 3 Follow the instructions above for continuing with a new Maestro session FirstDiscovery 3 0 Quick Start Guide 85 Chapter 11 Analyzing Liaison Data 11 2 Creating a Binding Energy File To run a Liaison Fit calculation you must use as input a text file containing empirically determined binding energies for the ligands in your training set The Fit calculation will determine the coefficients in the LRM equation You can then use these coefficients with Liaison to predict the free energy of binding for ligands that are structurally similar to the ligands in the training set To create the file containing experimental binding energies for the structures to which you are going to fit Liaison data 1 In a text editor open the file SSCHRODINGER impact vversion tutorial fit bindE expt 2 Open another text editing session and create a new file 3 In the first line of the new file type pose1_lig and replace lig to match the name you specified for your first pose in liaison_ligands txt Type one or more spaces
83. is Base name for grid files arias si Seiegd Directory for grid files home saunders Documentation Fi rstDiscov Start write Job Files Hide Help Figure 6 4 The Settings folder of the Glide panel FirstDiscovery 3 0 Quick Start Guide Chapter 6 Creating Glide Grid Files 6 6 Designating the Ligand Molecule To calculate a grid file Glide must know the approximate conformational space that you want to sample during the subsequent docking run The simplest method of defining the search space dimensions is by using the receptor s cocrystallized ligand if it is available Follow the instructions below to specify which Workspace molecule is the HO1 ligand 1 In the Settings folder of the Glide panel choose Receptor plus a single ligand from the Displayed structure is option menu 2 If Choose an atom in the ligand molecule is not selected select it 3 In the Workspace pick an atom in the ligand molecule The ligand molecule is colored aquamarine from the previous exercise Bounding box X 3 Atoms 1921 1921 Entries 2 21 Res 123 Chn 8 Mol 8 Chg 2 protein_ protein_ QLGIPXPAGLKKKXSYT LXQSSHTXILXPFXXQNPXIVIYQYMXDLYY Figure 6 5 The marked ligand with bounding box FirstDiscovery 3 0 Quick Start Guide 43 Chapter 6 Creating Glide Grid Files Once you pick an atom the ligand molecule is marked with blue green markers and a bounding box with axes is displayed in green
84. ith Liaison you must place only one structure in each file Then you create a file called a ligand source file that lists the names of these structure files Instructions for creating this ligand source file are given in the exercise in Section 10 4 on page 76 8 11 Saving Multiple Ligand Poses to a Single File There are two ways to save multiple ligand poses to a single file select multiple ligands from the list simultaneously or append structures to an existing file To save multiple structures to the same file simultaneously use the steps for writing displayed poses outlined in Section 8 10 except you select multiple poses simultaneously in the list by holding down SHIFT while clicking on the first and last pose entries To append multiple structures to an existing file one at a time follow the instructions below When you import either file type into Maestro the structures are placed in separate entries in a project 1 In the Poses folder select the second entry in the Pose List 2 Click Write Displayed Poses 3 In the PoseWrite panel select Append Click Write To 4 5 Select HO1_poses mae in the Files list 6 Click Save 7 Hide the PoseWrite and Glide Pose Viewer panels 8 12 Exercise Summary After you finish the exercises in this chapter you will have completed the Glide portion of the tutorial and will have written out the pose structure files that you will use in the Liaison exercises that follow
85. ith a red diamond on the menu Most states on button menus are pick states see Section 3 6 on page 21 which means you must pick an atom in the Workspace before the action is performed If you click a menu button that has pick states the button is indented to indicate that picking with the selected pick state is in effect If you double click a menu button that has pick states the action is applied to all atoms Some other menu buttons support double clicking to apply an action this support is explicitly mentioned in the button description 8 FirstDiscovery 3 0 Quick Start Guide Chapter 3 Introduction to Maestro You can show or hide the toolbar using the collapse button at the top or by selecting Toolbar from the Display menu You can hide it or move it to the right or left side of the Workspace by right clicking in the toolbar and selecting the appropriate option The buttons are described below Some descriptions refer to features not described in this chapter See the Maestro User Manual for a fuller description of these features Open a project Open the Open Project dialog box Show Hide project table Show the Project Table panel or hide it if it is displayed Create entry from workspace Create an entry in the current project using the contents of the Workspace Show Hide Build panel Show the Build panel or hide it if it is displayed Local transformation Pick the object to transform Menu but ton with a pick menu and a
86. job settings the let t preparation and refinement job takes about 20 to 40 minutes Instead of starting the job immediately you can click Write Job Files then run the job from the command line by entering SCHRODINGER protprep This command has options that allow fine control over the refinement section of the procedure See the First Discovery User Manual for details on the protprep command line application FirstDiscovery 3 0 Quick Start Guide 33 Chapter 4 Protein Preparation 4 6 Protein Preparation Output Structures Once the lett job is complete examine the output structure files in Maestro There will be either one or two new entries in the Project Table depending on whether you chose Single entry or Separate entries as the incorporation mode These files should exist after the job is complete lett_lig mae The input ligand structure file lett_lig_prep mae The post preparation ligand structure file lett_lig_ref mae The post refinement ligand structure file lett_prot mae The input receptor structure file lett_prot_prep mae The post preparation receptor structure file lett_prot_ref mae Contains both the post refinement receptor and ligand structures lett log The log file for the complete preparation and refinement job a This file has the ligand structure appended so that Maestro can incorporate both struc tures Because the Separate entries option was chosen there are now two new entries in the Project Table The
87. l However the job could take between one and five hours to complete If you want to examine the job input files without running the job write them out by clicking Write Job Files The following files appear in your current working directory workdir qsite HO6_dft inp HO6_dft jaguar in HO6_dft mae Note that saved job files can be used to run QSite jobs only from the command line See the FirstDiscovery Command Reference Manual for more information and syntax for running jobs from the command line 100 FirstDiscovery 3 0 Quick Start Guide Chapter 13 Running a QSite DFT Job If you choose to run the QSite DFT job the following additional files are written to your qsite directory HO6_dft out HO6_dft_out mae HO6_dft jaguar log HO6_dft jaguar out HO6_dft jaguar 01 in FirstDiscovery 3 0 Quick Start Guide 101 Chapter 13 Running a QSite DFT Job 102 FirstDiscovery 3 0 Quick Start Guide Chapter 14 Getting Help For help installing and setting up licenses for Schr dinger software see the Schr dinger Product Installation Guide The Maestro help facility consists of Auto Help Balloon Help tooltips and online help To get help follow the steps below Check the Auto Help window below the title bar of the main window If help is avail able for the task you are performing it is automatically displayed there If your question concerns an interface element e g a button or option menu there may be Balloon Help for t
88. lable in PDF format from the Schr dinger web site at http www schrodinger com Support pdf html Information on additions and corrections to the manuals is also available from this web page If you have questions that are not answered from any of the above sources contact Schr dinger using the information below Schr dinger E mail help schrodinger com USPS 1500 SW First Ave Suite 1180 Portland OR 97201 Phone 503 299 1150 Fax 503 299 4532 WWW http www schrodinger com FTP ftp ftp schrodinger com Generally e mail correspondence is best because you can send machine output if neces sary When sending e mail messages please include the following information most of which can be obtained by entering SCHRODINGER machid at a command prompt e All relevant user input and machine output e FirstDiscovery purchaser company research institution or individual e Primary FirstDiscovery user e Computer platform type e Operating system with version number e FirstDiscovery version number e Maestro version number e mmshare version number 104 FirstDiscovery 3 0 Quick Start Guide Glossary Auto Help cContext sensitive hints on how to perform operations associated with the operation for which picking is currently taking place The Auto Help window is located in the main window between the Maestro title bar and the main menu bar The Auto Help window displays the version number of the program when no op
89. lder Default directory for job startup and file i o Maestro s current working directory V Parent of project directory Y Project directory vy Project jobs directory vy Other specify below reptery gt currentdir Figure 3 6 The Directory folder of the Preferences panel 3 9 Undoing an Operation To undo a single operation click the Undo button in the toolbar choose Undo from the Edit menu or press ALT Z The word Undo in the menu is followed by text that describes the operation or operations to undo Not all operations can be undone for example global rotations and translations are not undoable operations For such operations you can use the Save view and Restore view buttons in the toolbar which save and restore a molecular orientation If you think that you might want to undo a series of operations later you can start an undo block by selecting Begin Undo Block from the Edit menu When you have completed the group of operations you want to undo end the block by selecting End Undo Block from the Edit menu Then to undo the operations in the block choose Undo from the Edit menu Undo is not supported for all Maestro operations An undo block can be created only if at least one undoable operation has been performed since the Begin Undo Block command was issued 3 10 Running and Monitoring Jobs While FirstDiscovery jobs can be run from the command line we suggest that you use the Maestro GUI to set up and s
90. lick Remove File 4 Click Add File The Add Ligand Structure Files file selector is displayed 5 Navigate to the workdir structures directory and select the HO1_H20_lig mae file in the Files list 6 Click Add The file appears in the Specify one file in Maestro format list 7 Under Docking scoring mode verify that Generate conformations for each input structure flexible docking is selected To specify ligands from the Project Table 1 In the Project Table click the ligand entry H01 then shift click the ligand H20 All ligands from HO1 to H20 are selected 2 In the Ligand folder of the Glide panel ensure that Dock selected entries from project table is selected A file named dock_confgen entries mae containing structures for the entries is created in the glide directory along with the input command file Depending on the number of entries you select the file written to disk could be large 3 In the Docking scoring mode section verify that Generate conformations for each input structure flexible docking is selected In this exercise you chose one of two options for selecting ligands either you specified the name and format of the file that contains the ligands to be docked or you selected entries from the Project Table for docking In the last step you specified that Glide sample various conformations for each ligand before docking the ligand with the receptor FirstDiscovery 3 0 Quick Start Guide 51 Chapter
91. lity from the Help menu on the main menu bar or see the FirstDiscovery User Manual or the FirstDiscovery Technical Notes For more information see Chapter 14 In addition to the normal use of italics for names of documents the font conventions used in this manual are summarized in Table 1 1 Table 1 1 Font conventions Font Example Use Sans serif Project Table Names of GUI features such as panels menus menu items buttons labels Monospace SSCHRODINGER maestro File names directory names commands and environment variables Italics filename Text that the user must replace with a value Sans serif ALT H Keyboard keys uppercase In descriptions of command syntax the usual UNIX conventions are used square brackets enclose optional items and the pipe symbol separates items in a list from which one item must be chosen In this document to type a command means to type the required text in the specified loca tion and to enter a command means to type the required text and then press the RETURN key FirstDiscovery 3 0 Quick Start Guide 1 Chapter 1 Document Overview 2 FirstDiscovery 3 0 Quick Start Guide Chapter 2 The FirstDiscovery Suite FirstDiscovery is a powerful protein modeling suite that consists of the program modules Glide Liaison and QSite Each module is designed to perform a specific drug discovery or design task To ready protein structures for use in FirstDiscovery a protein prepar
92. n item to open the Advanced Transformations panel Fit to screen Scale what is displayed to fit into the Workspace and reset the center of rota tion Set fog display state Menu button Automatic means on when there are more than 40 atoms in the Workspace off when there are fewer Rotate around X axis by 90 degrees FirstDiscovery 3 0 Quick Start Guide les ii Bs va 2 eu x Import structures Show the Import panel Save as Open the Save Project As dialog box to save the project with a new name Delete Choose an object to delete Menu button with a pick menu a section to delete hydrogens and waters and to open the Atom Selection dialog box and a sec tion to delete other objects associated with the structures in the Workspace Add hydrogens Pick atoms for hydrogen treatment Menu button with a pick menu and an item to open the Atom Selection dialog box Undo Redo Undo or redo the last action Performs the same function as the Undo item on the Edit menu and changes to an arrow pointing in the opposite direction when an Undo has been performed indicating that its next action is Redo Clear workspace Clear all atoms from the Workspace Enhance depth cues Optimize fogging and other depth cues based on what is in the Workspace Rotate around Y axis by 90 degrees Chapter 3 Introduction to Maestro Tile entries Arrange entries in a rectangular grid in the Workspace Save vie
93. nates are the mean of the minimum and maximum x y and z coordinates of all the atoms in the ligand Ligand Source File A manually created text document used in Liaison simulation calculations that contains the path and file names for each ligand and also the names for the directories in which Liaison will place ligand specific job files The directory names should appear in the left column and the path and file names on the right It is acceptable for the directory names to correspond with the file names Local Transformation Translation or rotation of a subset of Workspace atoms Main Menu Bar The menu bar at the top of the main window below the Auto Help window The main menu bar contains menu titles Maestro Project Edit etc that when clicked display menus from which selections can be made 106 FirstDiscovery 3 0 Quick Start Guide Glossary Master Liaison Directory tThe repository for the files and directories created during a Liaison job After a Liaison Simulate calculation the master Liaison directory will contain subdirectories corresponding to each analyzed ligand The name of the master directory corresponds to the name entered in the Liaison panel Job text box Option Menu A list of choices displayed when a button containing a raised square on its right side is clicked Panel The window that appears when an item is selected from a menu on the main menu bar Panels contain controls for performing various o
94. nd source file If you were running a single ligand single receptor job you could load the desired ligand into the Workspace along with the receptor or you could specify the ligand as a structure file somewhat like in Glide 10 4 Creating a Ligand Source File To perform a multiple ligand Liaison calculation you must create a ligand source file This is a text file that contains a name and a path to the ligand structure file for each ligand to be evaluated To create a ligand source file for the five ligand poses that you wrote out in the previ ous chapter 1 Open a text editor 2 Open a terminal window and list the contents of your workdir lia_structures directory 3 In the first line of the file type pose1_lig replacing lig with the number whose ligand appears in your first pose file Type one or more spaces and on the same line type the path name for the first ligand file as indicated below Replace tutorial_directory with the path to your tutorial lia_structures directory On a new line type the directory name and path for the next ligand repeating this for the final three ligands Your file should have the same format as the text below posel_lig tutorial_directory lia_structures posel_lig mae pose2_lig tutorial_directory lia_structures pose2_lig mae pose3_lig tutorial_directory lia_structures pose3_lig mae pose4_lig tutorial_directory lia_structures pose4_lig mae pose5_lig tutorial_directory lia_structures po
95. neeseeseeeeees 47 Chapter 7 DOCK 8 iic5ciccis ciscsctoccecsescsecaecetedpoesavcsteeescstestecsdecssesecesseaeseesesoececeseoes 49 Dell Preparation nensis rane ee E e a a E ERE Ea EEES 49 7 2 Specifying a Pre Existing Grid File for Docking seseseeeseeeseeresrereerrresrreesrrsrsee 50 T3 Selecting Ligands for Docking irie rnaen iner EE EE Ra EE 50 TA Specifying a Reference Ligand cceecccscesceeseeeceeseeeeeeseeeeeeseeeeesseeeeeeseeneeeaeens 53 7 5 Reviewing Options for Scoring and Output eee eeceeseeseeeneeeseeeeaeeeseeeeeeeee 54 7 6 Glide Constraints and Similarity cccceccesceeseeseeeceseceseceeeeseeeeeeseeeeeeaeeneeeaeens 56 T1 Starine the Docking VOD cciss cdes cthesteesievietscssetedetaaccaeestsdaadeaassataaeeeeeedenoesee ee 58 7 8 TEROTCISE Summary saecs dhe seh Sv scacsets ninine iaa ai a NE EE a 58 7 9 Running the Job With a Command Scripts cccsscis scss vscciss coassessisctssseasterisavesevins 59 Chapter 8 Examining Glide Data cssccssssscssscssscscescccsccsssccssscssscseesseees 61 8 1 Ppa MELT ss Sareea erie eae SEE eE iEn Ee E a EE A EAE E ADEE ENE EE 61 8 2 Displaying Pose Data si iredi anesson cenene are neea a EESE E k EE aE ESE 62 8 3 Viewing POSES 3 cccaraczesuesiagssvanaduiesinatesvessdesaad E N EEPE EE EE 62 8 4 Coloring and Labeling the Ligand s ssseseesesessesesserserseseessssrseeseseesessessesessesee 64 8 5 Displaying Atoms by Proximity seosesseeoeeseseeeseseeese
96. nel The lett structure is not a multimer and does not include cofactors or metal ions See the FirstDiscovery User Manual for information on preparing systems with these features To begin the tutorial 1 If itis not already running start Maestro 2 In the Project menu select New 3 Name the new project lett 4 2 Importing the Protein Complex Structure Download the lett complex structure from the Protein Data Bank 1 In your browser go to http www rcsb org pdb 2 Search the Archive by PDB ID for 1ETT 3 Click Download Display File and download the appropriate PDB file 4 Uncompress the file if necessary FirstDiscovery 3 0 Quick Start Guide 27 Chapter 4 Protein Preparation Import 1ETT pdb into Maestro 1 On the Maestro toolbar click the Import structures button Es Ei The Import panel is displayed 2 From the Format options select PDB 3 Navigate to the directory in which you saved 1ETT pdb 4 Select LETT pdb in the Files list and click Import The protein complex appears in the Workspace colored according to the PDB Maestro structure conversion color scheme which reports structural errors missing atoms and nonstandard residues The light gray that colors nearly all of the 1ETT structure indicates standard residues Orange indicates anything that is not a standard amino acid residue such as a ligand cofactor or metal ion The lett structure consists of two protein chains and a singl
97. ngs System Parameters Constraints Analysis Simulation type Multiple ligands single receptor These options are unavailable because multi ple ligands must Format of ligand files Maestro come froma Source of ligand structures ligand source file File containing a list of ligand names and associated structure files Filename Browse Mane ta tse for Wis yand Lig Start Write Job Files Figure 10 2 The System folder of the Liaison panel You have now established the general Liaison job settings The next step in the job setup is to load the receptor into the Workspace 10 3 Loading a Receptor Liaison simulations use the contents of the Workspace as the receptor structure In this exercise you will import the receptor for the simulation and place it in the Workspace To load the receptor 1 On the toolbar click the Clear workspace button to exclude any structures that might be in the Workspace D FirstDiscovery 3 0 Quick Start Guide 75 Chapter 10 Liaison Simulations 2 On the toolbar click the Import structures button Gs El The Import file selector is displayed 3 Under Format choose Maestro 4 Navigate to the tutorial structures directory 5 Select HO1_rec mae in the Files list and click Import 6 Click Hide to close the Import file selector In the multiple ligand single receptor job that you will set up in the next section the ligands are specified using a liga
98. nt to be placed There are several options for adding to a fragment that you have placed e Place another fragment and connect them using the Connect amp Fuse panel which you open from the Edit menu on the main menu bar or with the Display Connect Fuse panel on the Build toolbar yK e Replace one or more atoms in the existing fragment with another fragment by select ing a fragment and clicking in the Workspace on the main atom to be replaced e Grow another fragment by selecting Grow and clicking the fragment you want to add in the Fragments folder Grow mode uses predefined rules to connect a fragment to the grow bond The grow bond is marked by a green arrow The new fragment replaces the atom at the head of the arrow on the grow bond and all atoms attached to it You can change the grow bond by clicking on the desired grow bond in the Workspace The arrow points to the atom nearest to where you clicked 18 FirstDiscovery 3 0 Quick Start Guide Chapter 3 Introduction to Maestro Build build El f x AX tod eR sl adah Atom Residue Properties Properties H N H Kew ad OH whole wont H Grow Direction forward Joining Geometry anti Figure 3 3 The Build panel You can also draw a structure freehand by choosing an element from the Draw button menu on the Build panel toolbar and then drawing the structure In the Atom Properties folder you can change the properties of
99. nts folder The undisplayed residues need to be redisplayed prior to starting the job 1 On the toolbar click and hold the Also display button and select the option All al All residues should be redisplayed 2 If your preferences are not set to save Workspace changes automatically click Create Entry from Workspace in the Project menu to update the entry FirstDiscovery 3 0 Quick Start Guide 99 Chapter 13 Running a QSite DFT Job 13 6 Selecting a Basis Set A variety of basis sets is available for use with QSite To change basis sets for the ligand molecule 1 From the list at the top of the QM Residue Ligand panel select the ligand molecule listed as 8 1 2 From the Basis Set option menu select lacvp 3 Click Hide to close the QM Residue Ligand panel 13 7 Including a Jaguar Keyword Some Jaguar keywords can be used in QSite calculations For example to improve conver gence in difficult cases you can use the keyword for finer grids in the SCF calculations To use the keyword for level shifting e In the QM Settings folder add the following to the default options in the QM Options text box lacscf 2 For other Jaguar keywords see the Jaguar User Manual This concludes the setup for the QSite DFT job In the next exercise you will write out job files containing the settings you have specified 13 8 Writing QSite Job Files You may proceed with the QSite job by clicking Start in the QSite pane
100. o when you interact with a panel menu or structure Chapter 3 Introduction to Maestro rmmand Script Editor script Command History ganic Methyl nic Carbonyl Select All Deselect All Show Hide Selection T W Log commands place 1 396908 0 649130 0 000000 fragment organic Amine attach 4 fragment organic Methy attach fragment organic Methy attach 3 fragment organic Carbony attach 11 undo T Run Script 3H ipi f Expand Command Aliases Open Local Open Global Save As Hide Help Figure 3 5 The Command Script Editor panel Opens the Show Hide Command panel used to determine which commands are logged in the Command History list 3 8 Specifying a Maestro Working Directory When you use Maestro to start FirstDiscovery jobs Maestro writes job output to the direc tory specified in the Directory folder of the Preferences panel By default the directory to which Maestro writes files the file i o directory is the directory from which you started Maestro To change this directory 1 Open the Preferences panel from the Maestro menu 2 Click the Directory tab 3 Select the option for the directory you want files to be read from and written to FirstDiscovery 3 0 Quick Start Guide 23 Chapter 3 Introduction to Maestro Preferences prefer Bex Delete Markers Font Size Project Directory Label Mouse File suffix Bui
101. o is Maestro s current working directory and all data files are written to and read from this directory unless otherwise specified see Section 3 8 on page 23 You can change directories by entering the following command in the command input area of the main window cd directory_name where directory_name is either a full path or a relative path 3 3 The Maestro Main Window The Maestro main window is shown in Figure 3 1 on page 7 The main window compo nents are as follows e Title bar displays the project name and the current working directory e Auto Help automatically displays context sensitive help e Menu bar provides access to panels e Workspace displays molecular structures e Clipping planes window displays a small top view of the Workspace and shows the clipping planes and viewing volume indicators e Toolbar contains buttons for many common tasks and also provides tools for dis playing and manipulating structures and organizing the Workspace e Status bar displays the number of atoms entries residues chains and molecules in the Workspace e Sequence viewer shows the sequences for proteins displayed in the Workspace e Command input area provides a place to enter Maestro commands You can control the display of any of the last five components from the Display menu 6 FirstDiscovery 3 0 Quick Start Guide Chapter 3 Introduction to Maestro Title bar Auto Help text area Menu bar Workspace aest
102. only if you have set up your tutorial directory as specified and are running from your workdir it directory Before running the script you must first create the bindE expt file as instructed in Section 11 2 on page 86 FirstDiscovery 3 0 Quick Start Guide 91 Chapter 11 Analyzing Liaison Data 92 FirstDiscovery 3 0 Quick Start Guide Chapter 12 Introduction to QSite Like Liaison QSite is a free energy calculation program However QSite uses a QM MM approach and is powered by the Jaguar QM and Impact MM computational engines Mixed mode QM MM free energy calculations will produce more accurate results but will require more CPU time To perform a QSite job you must specify not only a receptor ligand pair to be studied but you must define a QM region a small number of atoms encompassing the ligand and prominent atoms in the binding pocket of the receptor The instructions in the next chapter will lead you through setting up an example QSite job FirstDiscovery 3 0 Quick Start Guide 93 Chapter 12 Introduction to QSite 94 FirstDiscovery 3 0 Quick Start Guide Chapter 13 Running a QSite DFT Job For consistency and convenience the protein drug candidate structures used in the Glide and Liaison sections of this guide will also be used to demonstrate QSite functionality However keep in mind that QSite might be most valuable for modeling other types of systems particularly enzymatic systems involving transition
103. ort staff when responding to any problem you report 26 FirstDiscovery 3 0 Quick Start Guide Chapter 4 Protein Preparation 4 1 Preparing Proteins for FirstDiscovery The quality of the results obtained from Glide Liaison and QSite depends on starting structures that include all hydrogens have correct charge states near the binding site and are reasonably free of major steric clashes A typical PDB protein complex structure as downloaded from the Research Collaboratory for Structural Bioinformatics RCSB web site http www rcsb org has no hydrogens and may have residues in unusual charge states Schr dinger offers a Protein Preparation facility for use with FirstDiscovery that is designed to ensure chemical correctness and to optimize protein structures The full Protein Preparation facility includes the ProteinPrep panel the protprep command line application and other utilities See the FirstDiscovery User Manual for a description of all the steps and options available For most structures however including the one used in this tutorial Protein Preparation can be performed in a few steps with Maestro and the ProteinPrep panel This tutorial carries out a Protein Preparation for lett bovine thrombin with cocrystallized ligand 4 TAPAP Ligand bond orders are corrected using the Maestro Build panel The remaining preparation and refinement tasks run automatically as a job that is set up and started from the ProteinPrep pa
104. oximity dialog box is displayed 7 Ensure that Beyond and Angstroms are selected 8 In the text field type 18 Click OK to close the Proximity dialog box 9 Note the ASL expression you have generated in the ASL field of the ASD Click OK to close the ASD In the Workspace red padlock markers indicate frozen atoms 10 Click Hide to close the Frozen Atoms panel In this exercise you specified that all of the atoms of the receptor molecule farther than 18 from residue number 120 located in the active site be treated as a frozen shell Therefore only the atoms closest to the receptor site will be able to move during the Liaison calculations This will reduce the CPU time required for the job 10 8 Starting the Liaison Job You are now ready to start the Liaison simulation job fit_sim 1 Click Start on the Liaison panel The following files and directories are written e change_sgbparam_fit_sim e fit_sim mae the receptor structure file used for each ligand s bound state simulation FirstDiscovery 3 0 Quick Start Guide 81 Chapter 10 Liaison Simulations e simulate_fit_sim the script that starts the simulation e fit_sim The it_sim directory contains one subdirectory for each structure in the ligand source file Each subdirectory contains bound and free input files and soft links to the structure files used as input For example pose1_lig contains e posel_lig bound inp e posel_lig free inp e posel_lig _r
105. perations Unlike dialog boxes panels can be left open while you perform other operations in other panels or in the main window Picking Clicking right clicking for left handed mice on an atom or other structural element in a Workspace structure Pick Options that control how a click on structural elements in the Workspace will be interpreted Available pick options are Atoms Bonds Residues Chains Molecules Entries Sets and Pick All Atoms Reference Ligand In Glide a user specified structure whose ligand receptor docking score will be compared with all other docked ligands Rigid Docking In Glide a job type in which only supplied conformations of the speci fied ligands will be docked scored and displayed in a pose view file This job type is useful if you have already performed a conformational search on the ligands that you want to dock Toolbar tThe array of icon buttons located by default along the left side of the main window which provides tools for common tasks such as moving structures in the Work space changing what is displayed opening a project or undoing the most recent Maestro operation Move the mouse over the button for a tooltip describing the button s function Buttons with triangles in the lower right hand corner display an option menu when you click them and hold down the left mouse button Without releasing the mouse button move to the option you want to select Top View The window locate
106. played Use the steps below to select ligand poses from the table and display the corre sponding structures in the Workspace 1 Add pose 2 to the selection by shift clicking the second entry in the pose list 2 Click Next to select and display only pose 3 62 FirstDiscovery 3 0 Quick Start Guide Glide Data ining Chapter 8 Exam jaund 1 M 1 A SOd Apl D ay fo 4apjof S SOd YL T ainsi snolAad fejdsig mt 091030884 uoydasay aeu Ad7uabjuod yop ap L B Le L404ny Le Luoyny hsaaods 10354 Ly uo Lyequawnzog ssapunes awoy apy uso staeuey spuog H sasod 63 FirstDiscovery 3 0 Quick Start Guide Chapter 8 Examining Glide Data 3 Reselect pose 1 by clicking twice on the Previous button Instead of using the Glide Pose Viewer to examine the docked ligand structures you can import the pose viewer file into the Project Table and use the ePlayer However the ePlayer cannot show contacts and hydrogen bonds For information on using the ePlayer see Section 3 4 1 on page 13 or the Maestro User Manual 8 4 Coloring and Labeling the Ligand This section describes how to redisplay the receptor molecule used in the grid file calcula tion and to apply color and molecule number labels to the displayed ligand The color change will help distinguish the ligand molecule from the receptor and the molecule number labels will allow you to later manipulate the molecule using ASL 1 On the toolbar click an
107. r FirstDiscovery 3 0 Quick Start Guide 83 Chapter 10 Liaison Simulations 10 10 Running the Job With a Command Script A command script called fit_lia cmd has been provided in the SCHRODINGER impact vversion tutorial maestro_cmd directory This script uses Maestro command language and Atom Specification Language ASL to accomplish the tasks described in this chapter When you use the provided command script to set up the job you should note the following First the script will call a file named liaison_ligands txt If you did not create this file you must copy it from SCHRODINGER impact vversion tutorial lia_structures into the workdir lia_structures directory Then you must edit the file and replace tutorial_directory to reflect the path of your working tutorial direc tory and replace the specific pose file names with the names of the new files that you created in the previous chapter Finally note that the script does not start the job it only writes the input files To start the job you must click Start on the Liaison panel after the script has finished running For information on how to run a command script see Section 3 7 on page 22 84 FirstDiscovery 3 0 Quick Start Guide Chapter 11 Analyzing Liaison Data In this chapter you will run a Liaison Analysis job to fit the simulation results to experi mental data using the LRM equation shown on page 71 For information about using the GlideScore equation
108. ript applies color to different residues undisplays the residues that do not interact with docked ligands and orients the receptor in the Workspace so that you can easily define the QM region of the receptor with backbone cuts 96 FirstDiscovery 3 0 Quick Start Guide Chapter 13 Running a QSite DFT Job The Command Command History History text area showpanel ligprep aN displays a log of cript Editor script EIEE hidepanel ligprep showpanel pprep all Maestro com hideranel pprep howpanel script f mands issued Select All Deselect All Show Hide internally when you interact with a panel menu or structure E Log commands rotate rotate rotate rotate rotate 9 y 0 z 5 y 0 75 2 0 xx xxx io wt ow i SCOOwW a aue n a 7 This script is only to be used along with the FirstDiscovery Quick Start Guide Running a QSite DFT Job text and should be run from the tutorial qsite directory a Run Script siog pi Expand Command Aliases Open Local Open Global Save As Hide Help Figure 13 1 The Command Script Editor panel 13 4 Selecting the QSite Job Type Like other Schr dinger computational programs QSite has its own panel in Maestro Follow the instructions below to display the QSite panel assign a jobname and specify the DFT job type 1 3 4 In the main window choose QSite from the Applications menu The QSite panel is displayed
109. ro zonel c yall Tutorials QuickTopics Maestro version 6 5 00 Maestro Project Edit Display Tools Applications Toolbar Atoms 1716 1716 Entries 1 1 Res 106 Chn 3 Mol 3 AllAtom1 gt Al 1Atom1 SIQAEEWYFGKITRRESERLLLNAENPRGTFLYRESEAYCLSVSDFDNA AllAtom1 All Atom1 EET ari F Viewing volume indicator Sequence viewer Status bar Command inputarea Clipping plane Figure 3 1 The Maestro main window When a distinction between components in the main window and those in other panels is needed the term main is applied to the main window components e g main toolbar 3 3 1 The Menu Bar The menus on the main menu bar provide access to panels allow you to execute some commands and control the appearance of the Workspace The main menus are as follows e Maestro menu allows you to save or print images in the Workspace execute sys tem commands save or load a panel layout set preferences set up Maestro com mand aliases and quit Maestro FirstDiscovery 3 0 Quick Start Guide 7 Chapter 3 Introduction to Maestro e Project menu provides access to many project related actions such as opening and closing a project and importing and exporting structures These actions can also be performed from the Project Table panel For more information see Section 3 4 on page 12 e Edit menu allows you to undo actions build and modify structures define com mand scripts and macros and find atoms in the Workspa
110. roduction to Maestro 3 6 Selecting Atoms Maestro has a powerful set of tools for selecting atoms in a structure that takes advantage of chemical information about the structure These tools are embedded in each panel in which you might need to select atoms to apply some operation Once you have chosen an operation you can use the tools to select or pick the atoms to apply the operation to To select all atoms in a molecule a chain a residue or an entry you can choose a pick state using the Pick list Once you have chosen the pick state you can click on an atom in the Workspace and all the atoms that belong to the same structural unit as defined by the pick state are selected For example if you choose Residue and click on any atom in a glycine residue all the atoms in that glycine residue are selected To select individual atoms choose Atoms from the Pick list The Pick list varies from panel to panel because not all pick states are appropriate for a given operation For example some panels have only Atoms and Bonds in the Pick list To make atom selections based on more complex criteria such as all carbon atoms in a protein backbone you can use the Atom Selection dialog box To open this dialog box click the Select button You can select an atom group from any of the folders in the dialog box Atom Residue Molecule Chain Entry Substruct Notation or Set You can then Atom Selection Select To Delete atom resiue
111. rom docking job dock_confgen_raw mae Unranked ligand poses dock_confgen rept Table of ranked poses dock_confgen_pv mae Receptor structure followed by ranked poses To confirm that these files have been written open a terminal window and list the contents of the current working directory which was changed at the beginning of the chapter to workdir g1ide see the title bar of the Maestro window By default the current working directory is used for job startup and file i o This default can be changed using options in the Directory folder of the Preferences panel When you are finished checking the files close the terminal window and hide the Monitor panel 7 8 Exercise Summary The most meaningful result of this docking job is generating the pose file dock_confgen_pv mae In pose viewer files such as this which you can examine with the Glide Pose Viewer panel ligands are placed in a list and arranged so that poses with the highest scores i e most favorable interactions with the receptor appear at the top This allows you to see at a glance which of the saved ligand poses should be studied further In the next chapter you will learn how to open and navigate in a pose viewer file and how to save the top scoring structures to separate files so that you can use them as input for Liaison jobs 58 FirstDiscovery 3 0 Quick Start Guide Chapter 7 Docking If you want to stop working on the tutorial now choose Close from the Project menu
112. rom the Select menu Only Add Deselect from the Edit Filter dialog box or by clicking the Entry selection button on the toolbar i FirstDiscovery 3 0 Quick Start Guide 15 Chapter 3 Introduction to Maestro To create a filter choose a property from the property list choose a condition and combine it with the current filter by clicking Add Subtract or Intersect These buttons perform the Boolean operations OR AND NOT and AND on the corresponding ESL expressions Once you have created a filter you can click OK to apply it immediately or name and save it for later use 3 4 4 Including Entries in the Workspace In addition to selecting entries for various tasks you also control which entries are displayed in the Workspace from the Project Table An entry that is displayed in the Work space is said to be included in the Workspace likewise an entry that is not displayed is excluded Included entries are marked by an X in the diamond in the In column excluded entries are marked by an empty diamond Entry inclusion is completely independent of entry selection To include or exclude entries you can click shift click and control click in the In column or select entries and then include or exclude them from the Entry menu Inclusion with the mouse works just like selection when you include an entry by clicking all other entries are excluded It is sometimes useful to keep one entry in the Workspace and include others one by one
113. ructures button Gx El The Import panel is displayed 2 Select Maestro from the Format menu 3 Navigate to workdir structures and select the file HO6alt_qsite mae 4 Ensure that Replace workspace is selected 5 Click Import 6 Click Hide to close the Import panel The HO1 receptor and HO6_altered ligand now appear in the Workspace and constitute the scratch entry In the next exercise you will use these structures to define a QM region for the QSite calculation 13 3 Preparing for QM Region Selection Before designating the QM region in a QSite job you might need to manipulate the struc ture so that you can better view the residues that come into closest contact with the ligand This can include undisplaying parts of the structure changing the molecular representa tion and applying atom labels The command script used in this exercise adjusts the color and molecular representation of the HO1 receptor active site and undisplays uninteresting parts of the receptor structure in order to simplify the designation of the QM region To execute the supplied preexisting command script 1 In the main window choose Command Script Editor from the Edit menu 2 Click Open Local The Open Local Script Files file selector is displayed 3 Navigate to the directory SCHRODINGER impact vversion tutorial maestro_cmd and select the file gsiteprep cmd 4 Click Open 5 In the Command Script Editor panel click Run Script The sc
114. se5_lig mae 76 FirstDiscovery 3 0 Quick Start Guide Chapter 10 Liaison Simulations 4 Save your ligand source file as workdir lia_structures liaison_ligands txt Note that the ligand source file is given a different name from the job because it contains information about ligands only and could be used for more than one simulation Liaison creates a directory corresponding to each name entered in the left column of the file and looks for the corresponding structure files using the path names in the right column For example if you enter pose1_H06 in the left column Liaison creates a subdi rectory called pose1_H06 ina directory named after your job name it_sim workdir fit fit_sim The information in the right column of the ligand source file workdir lia_structures pose1_H06 mae is used to locate the input structure file In the next exercise you will specify that Liaison use the ligand source file you have just created 10 5 Specifying a Ligand Source File and File Format In the previous exercise you created a ligand source file Now you must specify the name of the file and indicate the format of the referenced structure files To select the Liaison ligand source file and source file format 1 In the main window choose Liaison from the Applications menu and open the Sys tem folder 2 Ensure that Maestro is selected in the Format of Ligand Files menu 3 Click Browse The Open File file selector is displayed 4 Lo
115. section If you are continuing from the previous chapter with Maestro running If you have done the exercises in the previous chapter and Maestro is still running you should already be in the workdir glide directory Proceed to Clearing the Workspace below If you are continuing but with a new Maestro session If Maestro is not currently running open a new shell move to the workdir glide subdi rectory and start Maestro according to the instructions in Section 3 2 on page 5 If you are starting the tutorial with this chapter If you have not completed the exercises in Chapter 6 and Chapter 7 but want to work through the exercises in this chapter create a working directory and subdirectories as described in Section 6 1 on page 37 Then copy the file dock_confgen_pv mae from the directory SCHRODINGER impact vversion tutorial glide to the workdir glide directory Clearing the Workspace If any structures are currently included in the Workspace remove them by clicking the Clear workspace toolbar button If there are no structures in the Workspace the Clear workspace button is not available Clearing the Workspace before opening a pose viewer file is necessary because the structure is read into the Workspace and placed on top of any currently included structures FirstDiscovery 3 0 Quick Start Guide 61 Chapter 8 Examining Glide Data 8 2 Displaying Pose Data The following instructions describe how to use the
116. ssssrvescssassssaioress 58 Liaison fit files sinisisi 89 Liaison simulation cccce 82 89 Site flO wisi cccsterstscecciccescaseptiaveces 100 output options selecting oo eee 55 P PANS Paaa E S 107 PiK StatE Seine en 8 21 107 PICKINE arein oeiia 107 POSE Sear erae EES EEEE EAEE EET 62 Pose Write panel csiicesssscdesussseesserssresssssrsevecs 69 Predict tasken 87 Preferences panel 0 0 ccceeceeeeeeeeeees 23 24 processor number specifying for Liaison PODS AE E ET 74 product installation eects 103 PLOJECECMUMES Joes escetisssdseiesisccnteahionessesaeveres 12 Project Facility introduction cceeeee 12 Project Table panel 13 40 MENUS wieren aan a i 15 mouse functions 16 17 ShorteUt KEY Skirienn 17 PrOJEC S eee eeeeeeee _ 12 Protein Preparation incorporate results aS cece 33 PAD avs acess sees cevsts Asati ES 32 FirstDiscovery 3 0 Quick Start Guide Index protein preparation seesseeeereseseersersreees 27 Protein Preparation facility ceseeeeee 27 ProteinPrep panel csceeceeseeceeseeseeteeeeee 27 protprep command line application 27 33 protprep SCHIP i i ecni aiiis 33 Proximity dialog DOX 0 eee eeeeeeeeeeeeees 81 Q QM region defining by backbone eee 99 defining by ligand oo eee 98 SOLE CHON dscssessesie sstsssteossanssevesteonansversens 96 QM Residue Ligand panel eee 99 QM Settings folder QSite panel 98 QM MM defined uu
117. states or metal atoms that are poorly treated by empirical force fields such as OPLS AA The exercises in this chapter demonstrate how to set up a QSite DFT job 13 1 Preparation Before you start the exercises in this chapter follow the appropriate instructions in this section If you are continuing from the previous chapter with Maestro running To prepare to write job files to your workdir qsite directory this needs to be your current Maestro directory Clear the Workspace and then change to the proper directory by typing the following in the command input area of the main window cd qsite Proceed to Section 13 2 If you are starting with a new Maestro session Whether or not you have completed any other section in this guide if you are not currently running a Maestro session open a terminal window move to the workdir qsite direc tory and start Maestro according to the directions in Section 3 2 on page 5 Then proceed with the exercises below 13 2 Importing a Structure To run a QSite job you need to include in the Workspace the structure pair to be analyzed Use the following instruction set to import the combined structures of the HO receptor you have worked with in the other sections of this guide and the HO6_altered structure for which you calculated the binding energy in the Liaison Predict task FirstDiscovery 3 0 Quick Start Guide 95 Chapter 13 Running a QSite DFT Job 1 On the toolbar click the Import st
118. structures displayed in the Workspace enter the command cd glide in the command input area of the main window This command puts you in the workdir glide directory which you will use for the docking files you create in this chapter If you are continuing but with a new Maestro session Enter the command cd glide in the command input area of the main window If Maestro is not running start Maestro from the glide subdirectory in the working directory you created If you are starting the tutorial with this chapter 1 Create a working directory see Section 6 1 on page 37 2 Copy or create a soft link to the grid files that you will need to complete the docking exercise in this chapter or use the command script provided to set up the job files and then run the grid file calculation a To begin by copying the provided grids copy the grids_H01 files from SCHRODINGER impact vversion tutorial grids to the grids sub directory in the working directory b To use the command script to set up the grid file calculation use the instruc tions in Section 6 10 on page 47 FirstDiscovery 3 0 Quick Start Guide 49 Chapter 7 Docking 7 2 Specifying a Pre Existing Grid File for Docking In this section you specify that the grid files you calculated in Chapter 6 be used for the ligand docking job that will be run in this chapter 1 Click the Clear workspace toolbar button tb Open the Glide panel and click the
119. tart these jobs at least until you have some experience with the programs and understand the directory structure and the input file requirements Maestro has dedicated panels for each product for preparing and submitting jobs To use these panels make the appropriate choice for the product and task from the Applications menu and its submenus 24 FirstDiscovery 3 0 Quick Start Guide Chapter 3 Introduction to Maestro Monitor monitor Dex Monitoring job grids_H01 SIMPACT I Copenwt Request to open FORMATTED file grids_HO1 out on unit 2 Host Linux nahid schrodinger com 2 4 18 24 7 x 1 Fri Jan 31 07 06 03 EST 2003 i686 JobId nahid 0 40b78c7d SCHRODINGER directory software archive 2004 1_pb2 IMPACTLEXEC directory software archive 2004 1_pb2 impact v30508 bin Linux x86 MMSHARE_EXEC directory software archive 2004 1_pb2 mmshare v13005 bin Linux x86 SIMPACT I foldmain calling opls2001 atomtyping S IMPACT I foldmain finished parameter assignment VdW radii of protein atoms scaled by 1 000000000000000 Charge cutoff for polarity 0 2500000000000000 IMPACT I Cxdrwt File home saunders Documentation FirstDiscovery_Tutorial tutorial grids grids CALCSITES calling blduserlig for CM range Monitor Detach W Show jobs from current project only fhome saunders Documentation FirstDisco Figure 3 7 The Monitor panel Maestro also has a job control panel for monitoring the progress of jobs
120. tesevesenedussds cxiesaisseneecenetentys i 112 U undoing Maestro operations 24 W working directory creating 0 eee 37 WOLKSPACO sicsce ccsassstsstise deck tasisei sess clearing description including excluding and fixing entries 16 MOUSE FUNCTIONS 00 eee eect eteeete tees 11 placing fragments scratch entries FirstDiscovery 3 0 Quick Start Guide 120 West 45th Street 1500 SW First Avenue 3655 Nobel Drive Dynamostrafe 13 32nd Floor Suite 1180 Suite 430 68165 Mannheim New York NY 10036 Portland OR 97201 San Diego CA 92122 Germany SCHRODINGER
121. then without pressing ENTER copy the experimental binding energy in kcal mol from bindE expt for the first ligand Use a preceding minus sign if the value is negative On the next four lines type the information for the other four ligands Your file should have the same format as the text below posel_lig HEHH pose2_lig HEHH pose3_lig HHHH pose4_lig HEHH pose5_lig HHHH 4 Name your new file bindE expt and save it to the directory workdir fit In the next exercise you will use controls on the Liaison panel to specify bindE expt as your ligand binding energy file 11 3 Fitting Empirical Data Using the LRM Equation In this exercise you will fit empirical data using the LRM equation 1 In the Liaison panel type it_sim in the Job text box 2 In the Settings folder select Analyze results of earlier simulations 3 In the Analysis folder under Analysis type select Fit 86 FirstDiscovery 3 0 Quick Start Guide Chapter 11 Analyzing Liaison Data 4 Make sure that Binding energy model is set to LIA equation 5 Click Browse to the right of the Filename of ligand binding energies text box 6 In the Open Ligand Binding Energy File dialog box locate and select the file workdir it bindE expt 7 Click Open You have now adjusted the settings needed to fit empirical data using the LRM method 8 To start the fitting job click Start in the Liaison panel The Monitor panel appears showing the results of the fitt
122. tiple ligands e How to perform a Liaison fitting calculation to determine the a B and y coefficients for the LRM equation e How to perform Liaison prediction tasks to calculate the binding energy for a new ligand using the LRM method FirstDiscovery 3 0 Quick Start Guide 71 Chapter 9 Introduction to Liaison 72 FirstDiscovery 3 0 Quick Start Guide Chapter 10 Liaison Simulations In this chapter you will set up and start a Liaison simulation job that will calculate the ensemble average energy terms and GlideScores used in the equations on page 71 10 1 Preparation Before you start the exercises in this chapter follow the appropriate instructions in this section If you are continuing from the previous chapter and Maestro is open To perform the exercises in this chapter you should make the fit directory your current Maestro directory Change to this directory by typing the following line in the command input area of the main window cd fit Proceed to Section 10 2 on page 74 If you are continuing but with a new Maestro session If you are not currently running Maestro open a new terminal window change to the workdir fit directory and start Maestro according to the directions in Section 3 2 on page 5 Then proceed with Section 10 2 on page 74 If you are starting the tutorial with this chapter If you have not completed the Glide tutorial but want to do the exercises in this chapter copy the follow
123. tive to the receptor Grid generation setup can include defining Glide constraints required hydrogen bond donor acceptor or metal ligand interactions This step also includes weighting calculations if you want to do similarity scoring of ligands using a weighted algorithm During docking Glide performs an efficient systematic search of conformational space The best binding mode for a ligand is then identified by thoroughly exploring the active site using a series of hierarchical filters to select acceptable binding positions and orienta tions rapidly Flexible minimization and Monte Carlo sampling then yield the final ligand poses for accurate scoring Optionally ligand similarity scores can be used in docking even if weighting calculations were performed in grid generation There are two docking modes standard precision and extra precision Extra precision docking is used to refine the results of a standard precision docking job To allow you to evaluate the scored ligands Glide calculations can produce as output either a library file Gobname_1ib mae containing just the docked ligand structures or a pose viewer file jobname_pv mae which also contains the receptor structure You can view either file in the Maestro Project Table or you can view the pose viewer file in the Glide Pose Viewer panel You can also save the top poses to individual files for further evaluation The exercises in the next three chapters demonstrate how to e
124. toms Start Write Job Files Hide Help Figure 10 4 The Constraints folder of the Liaison panel FirstDiscovery 3 0 Quick Start Guide 79 Chapter 10 Liaison Simulations Frozen Atoms ifatom Define frozen atoms W Pick Atoms a All Select W Show markers Delete Delete All Hide Help Figure 10 5 The Frozen Atoms panel 3 In the Frozen Atoms panel click Select The Atom Selection dialog box ASD is displayed 4 Click the Residue tab and select Residue Number from the list on the left 5 In the Residue Number field type 120 Click Add Atom Selection Define frozen atoms stom Resite wotcue cnain entry Susie sa Residue Number a mau 1 ificati e classification f Subtract E Backbone Side Chain Secondary Structure Examples lt 12 or 3 5 20 34 Range In Workspace Update Markers 2 123 Atoms Matching a ASL WE Show markers i anji r Matching 0 atoms fa REN Figure 10 6 The Residue folder of the Atom Selection dialog box 80 FirstDiscovery 3 0 Quick Start Guide Chapter 10 Liaison Simulations Proximity Within Angstroms vy Beyond vy Bonds Fill None vy Residues V Molecules _ Exclude source Update Markers OK Help Cancel Figure 10 7 The Proximity dialog box 6 Click Proximity in the lower right of the ASD to open the Proximity dialog box The Pr
125. tus 1 Start the grids_H01 Glide job by clicking the Start button on the Glide panel The Monitor panel is displayed While the job is in progress the panel s Status col umn displays the word running When the job is complete the status is changed to incorporated FirstDiscovery 3 0 Quick Start Guide 45 Chapter 6 Creating Glide Grid Files Monitor monitor mi Monitoring job grids_H01 ZIMPACT I Copenwt Request to open FORMATTED file grids_HO1 out on unit 2 Host Linux nahid schrodinger com 2 4 18 24 7 x 1 Fri Jan 31 07 06 03 EST 2003 i686 JobId nahid 0 40b78c7d SCHRODINGER directory software archive 2004 1_pb2 IMPACT_EXEC directory software archive 2004 1_pb2 impact v30508 bin Linux x86 MMSHARE_EXEC directory software archive 2004 1_pb2 mmshare v13005 bin Linux x86 SIMPACT I foldmain calling opls2001 atomtyping SIMPACT I foldmain finished parameter assignment VdW radii of protein atoms scaled by 1 000000000000000 Charge cutoff for polarity 0 2500000000000000 S IMPACT I xdrwt File home saunders Documentation FirstDiscovery_Tutorial tutorial grids grids CALCSITES calling blduserlig for CM range 7 mi Monitor Pause Stop Update Detach Resu Kill Copiety W Show jobs from current project only fhome saunders Documentation FirstDisco Figure 6 7 The Monitor panel 2 Pause the Glide job by clicking on the job name in the list and then clicking Paus
126. ucture to be hidden Command Input Area The text box labeled Commands that appears by default along the bottom of the main window You can enter Maestro commands here You can undis play the command input area from the Display menu Contacts Graphical representations of the van der Waals interactions between the atoms of two or more molecules Within Maestro contacts are categorized as Good Bad and Ugly Good contacts are those that have van der Waals radii consistent with the experimentally determined values for the involved atom types Bad contacts depict those interactions that are experimentally improbable Ugly contacts represent van der Waals interactions that are disallowed in experimental systems FirstDiscovery 3 0 Quick Start Guide 105 Glossary Enclosing Box tThe purple cube shaped marker that appears in the Workspace after you specify active residue sites coordinates or a ligand to be used as a bounding box center using the Glide panel The enclosing box represents the space that any part of any specified ligand can sample during a docking calculation Compare this with the green bounding box which represents the space that the center of each specified ligand must be confined to during a docking calculation Flexible Docking lIn Glide a job type in which alternate conformations for each ligand are generated during the docking process and then the interactions between the receptor and the conformers
127. ulation Ligand Receptor Simulation Maximum minimization steps 500 RMS gradient for convergence 0 01 Heatauy fine ps 5 00 Shnulation ime ios 5 00 fine steps betygen data collections 10 Update long range forces every 10 steps Long range force cutoff gt 10 000 A Start write Job Files Hide Help Figure 10 3 The Parameters folder of the Liaison panel 78 FirstDiscovery 3 0 Quick Start Guide Chapter 10 Liaison Simulations In this exercise you changed the maximum number of steps in the ligand minimization portion of the job to 800 Although the ligand minimizations in this job will probably not take even 500 steps to converge in future jobs you might want to change this setting or the analogous one in the Ligand Receptor Simulation folder which specifies the maximum number of minimization steps for the bound ligand 10 7 Specifying Atoms to Freeze When you set up Liaison calculations immobilizing freezing receptor atoms that do not interact with the ligand is advantageous because it reduces the CPU time required for simulations Use the instructions below to freeze selected atoms 1 In the Liaison panel click the Constraints tab 2 In the Constraints folder click Frozen Atoms The Frozen Atoms panel is displayed Liaison Job fit_sim Login saunders Host localhost 1 Settings System Parameters Constraints Analysis Frozen Atoms Buffered A
128. urther instructions on using the scripts at the conclusion of each chapter 6 2 Preparation Before you begin the exercises shown below you must first have created a working direc tory as described in the previous section If you have not yet set up your working directory do so now then proceed with the instructions in the appropriate subsection below If you are starting with an active Maestro session Close any open project If there are still atoms in the Workspace remove them by clicking the Clear Workspace button in the toolbar In the command input area enter the following command to change into the correct directory cd workdir grids Proceed with the exercises below If you are starting with a new Maestro session Start Maestro from the workdir grids subdirectory you have created and proceed with the exercises below 6 3 Importing Maestro Files Before you submit a Glide job you must have at least the receptor displayed in the Work space In this exercise you will import ligand and receptor structures into a Maestro scratch project and then change the color of the ligand so that it is distinguishable from the receptor You will then use the imported structures to continue the exercises in this chapter To import ligand and receptor structures and distinguish the ligand from the recep tor by color 1 Click the Import structures button on the toolbar E The Import panel is displayed 38 FirstDiscovery 3
129. w Save the current view of the Workspace orientation location and zoom Display only picked atoms Pick atoms to display Menu button with a pick menu Also display Add the selected atoms to the display Menu button with a list of predefined atom categories and an item to open the Atom Selection dialog box Display residues within N angstroms of currently displayed atoms Menu button with a list of values and an item to open a dialog box to set a value Draw bonds in wire Pick atoms for representation Menu button with a pick menu and an item to open the Atom Selection dialog box Draw atoms in ball and stick Pick atoms for representation Menu button with a pick menu and an item to open the Atom Selection dialog box Color all atoms by scheme Menu button with a list of schemes Label atoms Label all atoms with the selected label Menu button with a list of label types and an item to delete labels 10 A P Reset workspace Reset the rotation translation and zoom of the Workspace to the default state Restore view Restore the last saved view of the Work space orientation location and zoom Display only Display only the selected atoms Menu button with a list of predefined atom cat egories and an item to open the Atom Selection dialog box Undisplay Undisplay the selected atoms Menu a button with a list of predefined atom cat amp a R egories and an item to open the

FirstDiscovery3.0

Contents

Download Pdf Manuals

Related Search

Related Contents