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MacroModel Quick Start Guide

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2. 1 Selected shell 51 Radius 5 0 IX Complete residues Force constant 200 0 IEJ Freeze atoms Additional atoms for shell a II 30 IE Pick Atoms v Markers Read sbc File _ Write ASL formatted sbc file Write sbc File Write absolute atom coordinates Atoms 0 Substructure 0 Fixed 0 Frozen Start Write Close Figure 3 7 The Minimization panel showing the Substructure tab In the Molecule tab click the Proximity button The Proximity dialog box opens Under Proximity select Within and Angstroms and enter 5 0 in the text box Under Fill select Residues Click OK in the Proximity dialog box and in the Atom Selection dialog box The 1ig 5A set is now defined and you can proceed to set up the job Choose MacroModel Minimization from the Applications menu Choose Workspace included entry from the Use structures from option menu In the Potential tab choose OPLS_2001 from the Force field option menu In the Mini tab enter 5000 in the Maximum iterations text box In the Substructure tab see Figure 3 7 under Freely moving atoms substructure click the Atom Selections button and choose Select The Atom Selection dialog box opens Schr dinger Suite 2012 Update 2 Chapter 3 Energy Calculation and Minimization 17 18 19 In the Set tab select User defined from the list on the left then sel
3. Source of ligands Selected entries Input file Browse Receptor First selected entry Entry Choose Association energy mode O Energy difference mode Structures saved Complexes only Ligands only Receptor ligands and complexes Start Write Close Help Figure 5 1 The Embrace Minimization panel showing the Embrace tab Choose Applications gt MacroModel Embrace Minimization from the main window In the Potential tab choose OPLS_2001 from the Force field option menu and choose None from the Solvent option menu In the Mini tab enter 1000 in the Maximum Iterations text box Click the Embrace tab see Figure 5 1 Under Source of ligands select Selected entries Under Receptor select First selected entry Under Association energy mode select Interaction energy mode Under Structures saved select Complexes only In the Substructure tab click Read sbc file Select Embrace sbc from your working directory The atoms in the structure are highlighted white markers for the substructure orange markers for shell 1 and purple markers for shell 2 Click Start to open the Start dialog box Schr dinger Suite 2012 Update 2 Chapter 5 Other Calculations 14 15 16 Choose Append new entries from the Incorporate option menu Enter Embrace in the Name text box Click Start to launch the job This calculation may take 10
4. In the Substructure tab click the Clear button to clear any substructure Click Delete enough times to clear all shells From the Label atoms button menu on the main toolbar choose Atom Number All atoms in the workspace are labeled with their corresponding atom number In the Scan tab of the Coordinate Scan panel under Define coordinate to scan choose Dihedral from the Coordinate type option menu Choose Atoms from the Pick menu see Figure 5 3 MacroModel 9 9 Quick Start Guide 55 Chapter 5 Other Calculations 56 10 11 12 13 14 Coordinate Scan x Use structures from Workspace included entry IN Potential Constraints 0 Substructure Mini Scan 1 4 15 16 re Ja Delete Delete All Initial Final 360 0 Increment 30 0 m Define coordinate to scan Coordinate Type Pick Atoms r Dihedral Markers Figure 5 3 The Coordinate Scan panel showing the Scan tab In the order listed pick the atoms in the Workspace that define the two angles 1 14 15 16 and 6 25 26 27 Use the middle mouse button to rotate the structure if necessary Click Start to open the Start dialog box Choose Do not incorporate from the Incorporate option menu Enter Ddrive in the Name text box Click Start to launch the job Two files are produced Ddrive out grd contains the energetic
5. Y Axis Dihedral 5 6 25 26 y Select Color Black v Size 4 Symbol Filled square v 50 Line Style None _ Width 1 Color Black Ir Color by Ly Select Tr N Color map Rainbow hal Color scale 0 Symbol size by _ Select A C Best fit line IC Diagonal line with slope 1 r g 0 z _ Equal aspect Equalize axis range Legend None Jhd Plot title 7109 New Data Set Delete Data Set Axis Settings 150 o 2 4 6 8 10 12 Entry ID Manage Plots Cose Help Figure 2 14 The Scatter Plot panel MacroModel 9 9 Quick Start Guide 27 Chapter 2 Using Maestro 28 7 Choose your preferred plot and drawing styles 8 In the Scatter Plot panel click Rename 9 Change the name to Filter and click OK 10 Click the Pick to select entries button on the Scatter Plot toolbar IR Circles are placed around the plot symbols showing which entries are selected 11 Click or drag to select a set of points corresponding to a range of dihedral angle values The corresponding entries are selected in the Project Table and the plot symbols for are circled only for the selected entries Similarly you can include entries in the Workspace with the Pick to include entries button In E Schr dinger Suite 2012 Update 2 Chapter 3 Energy Calculation and Minimization 3 1 Current Energy Calculations Many types of energetic
6. You can also open the Import panel by choosing Project gt Import Structures in the main window or by choosing Table Import Structures in the Project Table panel MacroModel 9 9 Quick Start Guide 5 Chapter 2 Using Maestro BEE Look in E nfs zonel dyall macromodel 2012 Ne gt ee _ Minta mae ri lerr_htreatmae J MultMini mae Home Directory Ddrive mae _ Serial mae Ecalc out mae __ SubsAuto mae Ecalc out maegz SubsMini mae Ecalc mae Embrace mae Filter mae LigandMCMM mae LLMOD mae LogPmae MCMM mae MCSD mae Mini out maegz Mini mae Launch Directory EERERRERERRERTT Options lt lt Help Import all structures Replace Workspace Start X Fit to Workspace following import JEnd Total Include in Workspace First imported structure For Desmond files import only first structure Create groups for Files with multiple structures gt Import associated data files For SD files create titles from X For PDB files read alternate locations SD molecule name _ Open Protein Preparation Wizard after importing PDB file OSD property For pose viewer files turn on pose viewing File name 1err pdb Open Files of type Common mae maegz mae gz pdb ent sd sdf mol sdfgz sdf gz cn Mi X Cancel Figure 2 1 The Import panel 4 Select 1err pdb from the list of files 5
7. Choose Atoms from the Pick menu and select a few torsions from the structure in the Workspace e g 1770 1771 1779 1780 1789 1790 MacroModel 9 9 Quick Start Guide 45 Chapter 4 Conformational Searches 46 gt Torsion Rotations Molecule Trans Rot 1770 1771 1779 1780 Minimum rotation 0 0 Minimum rotation 0 0 Maximum rotation 180 0 Maximum rotation 180 0 Define torsions to rotate Minimum translation 0 0 x Pick Atoms X Markers Maximum translation 1 0 x x LE Delete Delete All X Show markers Define molecules to translate rotate Delete Delete All Close Figure 4 3 The Torsion Rotations panel left and the Molecule Trans Rot panel right 12 Close the Torsion Rotations panel 13 In the CSearch tab from the Search variables option menu choose Molecule Trans Rot then click Edit to open the Molecule Trans Rot panel see Figure 4 3 The Molecule Trans Rotation feature identifies molecules that are to be rotated and trans lated relative to each other Only the ligand needs to be specified in this example 14 In the Workspace select any atom in the ligand Use the default minimum and maximum values 15 Close the Molecule Trans Rot panel To freeze the protein and start the job This section uses the Substructure facility to freez
8. Click the Substructure tab In the Freely moving atoms substructure section choose Molecules from the Pick menu and click on an atom in the ligand in the Workspace Enter 3 0 in the Expand to atoms within radius of text box and select Complete residues You could achieve the same result by using the Atom Selection dialog box to select mole cule number 4 and the atoms within 3 or by entering the following expression in the ASL text box fillres within 3 mol num 4 Under the Shells list click New In the Selected shell section select Complete residues and enter 2 0 in the Radius text box This is the shell of fixed atoms with harmonic constraints of 200 kJ mol A applied Click New In the Selected shell section select Complete residues and Freeze atoms and enter 2 0 in the Radius text box This is the shell of frozen atoms The moving fixed and frozen regions have now been defined and are indicated in the Work space as white orange and purple regions To set up the search method and search variables In this example you will use the automatic setup features to define the MCMM conformational search variables You can set up variables either for the entire moving region the substructure or only for the ligand molecule Atoms in the fixed or frozen atom regions do not have confor mational search variables assigned to them when using Perform Automatic Setup Schr dinger Suite 2012 Update 2 Chap
9. Markers LYS52 Chil 1616 1617 1620 1621 70 2 Delete Delete All write Preferences _ Create property for selected entries ANN Figure 2 13 The Measurements panel showing the Dihedrals tab Schr dinger Suite 2012 Update 2 Chapter 2 Using Maestro You can then select a subset of entries with the desired range of properties These structures can be written to disk or investigated further 2 10 3 Filtering Using the Plot Facility This exercise demonstrates how to plot the dihedral angle generated in the previous section and select the desired entries from the plot 1 In the Project Table select the structures to be filtered 2 Click the Plot button on the toolbar 3 The Manage Plots panel opens 4 Click New Scatter Plot A Scatter Plot panel opens A new scatter plot is created with the name Scatter 1 see Figure 2 14 You can rename it by selecting it and clicking Rename in the Manage Plots panel 5 Choose Entry ID from the X axis option menu 6 Choose the recently defined dihedral angle from the Y axis option menu Once you have selected properties for the axes the points are plotted in the default style Scatter Plot Filter SEES i 3 D a u R hc ta H Hide Controls 100 X Axis EntryID 00 r Select
10. 2 Choose Workspace included entry from the Use structures from option menu 3 Click Start to open the Start dialog box 4 5 6 Under Incorporate select Append new entries individually In the Name text box type Mini Click Start to launch the job An intermediate structure is displayed in the Workspace with the atoms colored according to the energy gradient of the minimization at the time of monitoring After job completion the final minimized structure is incorporated into the project as a new entry If you wish to change the default minimization setting click the Mini tab MacroModel 9 9 Quick Start Guide 33 Chapter 3 Energy Calculation and Minimization 34 3 2 2 Comparing Structural Results by Superposition One useful way of comparing structural results is to superimpose them Maestro provides tools for superimposing molecules based on a selection of atoms For a pair of molecules you can select the corresponding atoms manually and Maestro superimposes them by minimizing the RMSD of the selected atom distances You can also select atoms in one structure using the Atom Selection dialog box or ASL and use this set as the basis of superposition The atom specification is applied to each entry included in the Workspace This is useful for groups of conformers but may have unintended results for non conformers Superposition is discussed in detail in Section 10 3 of the Maestro User Manual The following exercise
11. In the Molecule tab choose Molecule Number from the list on the left and enter 3 in the Molecule Number text box Click Add Click Proximity to open the Proximity dialog box Under Proximity select Within and Angstroms and enter 5 0 in the text box Under Fill select Residues and select Exclude source 10 11 Click OK in the Proximity dialog box and in the Atom Selection dialog box In the Hydrophobic philic Surfaces panel under Bounding box choose Molecules from the Pick menu and select an atom in the ligand Enter 6 0 in the Box margin text box and choose Standard from the Grid Spacing option menu Click Start to open the Start Job dialog box The Start dialog box opens You can keep the default settings Click Start to start the job Enter sitemap1SHD in the Name text box Click Start to launch the job When the job finishes the surface is displayed in the Workspace and the Manage Sur faces panel opens In the Manage Surfaces panel experiment with the transparency and the isovalue For example select the philic surface in the table and enter 15 0 in the Isovalue text box at the bottom of the panel Enter 0 3 for the phobic isovalue When you have finished close the Manage Surfaces panel and the Hydrophobic philic Surfaces panel Schr dinger Suite 2012 Update 2 Chapter 2 Using Maestro 2 9 Creating and Manipulating Atom Sets Defining subsets of atoms can be useful for many analysis and
12. Mult Input file Browse Minimization mode O Minimization of non conformers OMinimization of conformers not defined Eliminate redundant conformers using Maximum atom deviation Cutoff A ORMSD Cutoff A Retain mirror image conformations Energy window for saving structures kj mol 5 02 kcal mol Maximum number of structures to save LogP estimation Secondary solvent Figure 5 6 The Multiple Minimization panel showing LogP selected in the Mult tab Schr dinger Suite 2012 Update 2 Getting Help Information about Schr dinger software is available in two main places The docs folder directory of your software installation which contains HTML and PDF documentation Index pages are available in this folder The Schr dinger web site http www schrodinger com particularly the Support Center http www schrodinger com supportcenter and the Knowledge Base http www schro dinger com kb Finding Information in Maestro Maestro provides access to nearly all the information available on Schr dinger software To get information Pause the pointer over a GUI feature button menu item menu In the main window information is displayed in the Auto Help text box which is located at the foot of the main window or in a tooltip In other panels information is displayed in a tooltip If the tooltip does not appear within a seco
13. Pick Atoms Delete Delete All Figure 4 2 The Comparison Atoms panel In the CSearch tab of the Conformational Search panel deselect Perform automatic setup during calculation Click Reset All Variables From the Search variables option menu choose Comparison Atoms then click Edit to open the Comparison Atoms panel see Figure 4 2 The procedure below selects the non hydrogen atoms of the ligand You can also do this by clicking Heavy Atoms which is defined as all non hydrogen atoms 6 10 11 Under Define comparison atoms click the Atom selection button and choose Select to open the Atom Selection dialog box In the Molecule tab select Molecule Number from the list and type 4 in the Molecule Number text box or click on the molecule in the Workspace then click Add In the Atom tab select Element from the list on the left then select H from the Element list and click Subtract to remove the hydrogen atoms from the selection set Click OK then close the Comparison Atoms panel In the CSearch tab from the Search variables option menu choose Torsion Rotations then click Edit to open the Torsion Rotations panel see Figure 4 3 Torsion rotations specify the torsions that are randomly rotated during the search All non trivial C C and N C bonds except amide torsions could be selected It is only nec essary to choose the second and third atoms of the torsion
14. selected entries from the Use structures from option menu see Figure 3 6 9 Click Start to open the Start dialog box 10 Under Incorporate select Replace existing entries 11 In the Name text box type MultMini 12 Click Start to launch the job This job uses the selected entries as the input structure file and replaces the input entries in the Project Table with the resulting energy minimized structures at the conclusion of the job For multi conformer computations you can eliminate duplicate minima and reduce the output by using the tools in the Mult tab of the Multiple Minimization panel to define an energetic window and identify comparison atoms Schr dinger Suite 2012 Update 2 Chapter 3 Energy Calculation and Minimization 3 2 4 Energy Minimization of a Substructure The time required to minimize large structures can be drastically reduced by focusing on a particularly important section of the structure and restraining freezing or ignoring the rest This exercise uses the protein ligand complex from Section 2 1 to perform a substructure mini mization The ligand and all residues within 5 0 A of the ligand are freely minimized The atoms between 5 0 A and 10 0 A from the ligand are restrained while the atoms between 10 0 A and 15 0 A from the ligand are frozen The remaining atoms are ignored For more information on the Substructure facility see Section 4 3 3 of the MacroModel User Manual 1 Click the Clear Workspa
15. 5 2 Molecular Dynamics u sss0s 0ER 53 5 3 Creating Energy Profiles from Coordinate Scans ee 55 5 3 1 Performing a Coordinate Scan Calculation ssssersssssrserssrsrrorsrrrrssrsrrsnnnrrnt 55 5 3 2 Analyzing the Results of the Coordinate SCAN ssssssessrserssrsrrssrssrsrrsrsrsrnnnrnnn 56 5 4 MINTA Prediction of Free Energy sseesssssssssrsrsssrssrsrrsssssnrssssrsrss sr rsrs sars nns r nennen nennen 57 5 5 Partition Coefficient Between Two Solvent ennnennn 59 BERN NED nennen E 61 Schr dinger Suite 2012 Update 2 Document Conventions In addition to the use of italics for names of documents the font conventions that are used in this document are summarized in the table below Font Example Use Sans serif Project Table Names of GUI features such as panels menus menu items buttons and labels Monospace SSCHRODINGER maestro File names directory names commands envi ronment variables command input and output Italic filename Text that the user must replace with a value Sans serif CTRL H Keyboard keys uppercase Links to other locations in the current document or to other PDF documents are colored like this Document Conventions In descriptions of command syntax the following UNIX conventions are used braces enclose a choice of required items square brackets 1 enclose optional items and the bar symbol separates items in a list from which
16. Description An all atom treatment which does not include lone pairs This treatment is suitable for the MM3 AMBER94 MMFF MMFFs OPLSAA and OPLS2003 force fields Modify hydrogen treatment Pick atoms 00 Figure 2 6 The Add Hydrogens Advanced panel Schr dinger Suite 2012 Update 2 Chapter 2 Using Maestro Molecular Surface Atoms for surface display f Pick Entries _ Ir Markers og Surface context Selected atoms v Surface resolution Low vijo 8 Probe radius 1 4 A VDW radius sclae 1 0 A Boolean operation Union v Atoms for surface boolean operation X Pick Entries IN Markers ena Create Surface Figure 2 7 The Molecular Surface panel 2 8 Creating and Viewing Surfaces Examining the surface of a molecule frequently leads to valuable insights Maestro can create several surface types Surfaces can be rendered in different styles color schemes and transpar ency Maestro surfaces are associated with project entries This set of exercises uses the lerr prj project from the previous section If you are starting the tutorial at this point follow the instructions in Section 2 1 Section 2 2 Section 2 6 and Section 2 7 to set up the project for these exercises 2 8 1 Creating a Molecular Surface of a Complex Maestro can create molecular surfaces that represent solvent accessible reg
17. Linux command line SCHRODINGER diagnostics 2 When the diagnostics have run click Technical Support A dialog box opens with instructions You can highlight and copy the name of the file 3 Attach the file specified in the dialog box to your e mail message 4 Attach the file maestro_error txt to your e mail message This file should be in the following location e Windows LOCALAPPDATA Schrodinger appcrash Choose Start gt Run and paste this location into the Open text box e Mac Documents Schrodinger e Linux Maestro s working directory specified in the dialog box the location is given in the terminal window 5 On Windows also attach the file maestro EXE dmp which is in the same location as maestro_error txt Schr dinger Suite 2012 Update 2 120 West 45th Street 17th Floor New York NY 10036 155 Gibbs St Suite 430 Rockville MD 20850 0353 Quatro House Frimley Road Camberley GU16 7ER United Kingdom 101 SW Main Street Suite 1300 Portland OR 97204 Dynamostrafe 13 D 68165 Mannheim Germany 8F Pacific Century Place 1 11 1 Marunouchi Chiyoda ku Tokyo 100 6208 Japan 245 First Street Riverview II 18th Floor Cambridge MA 02142 8910 University Center Lane Suite 270 San Diego CA 92122 Zeppelinstra e 73 Potsdamer Platz 11 D 81669 M nchen D 10785 Berlin Germany Germany No 102 Ath Block 3rd Main Road 3rd Stage Sharada Colony Basaveshwaranagar Bangalore 560079 India SCHR DINGER
18. approaches to performing a subsequent conformational search on the complex Two methods are demonstrated in the following two sections This first exercise demonstrates how to perform a substructure conformational search on the protein ligand complex keeping the protein frozen The MCMM method is used for the ligand To set up the job 1 2 3 4 5 Import the minimized structure LigandMCMM mae from your working directory Display the structure in the Workspace Choose Applications gt MacroModel gt Conformational Search Choose Workspace included entries from the Use structures from option menu In the Potential tab choose OPLS_2005 from the Force field option menu and choose None from the Solvent option menu In the CSearch tab choose Torsional sampling MCMM from the Method option menu Deselect Multi ligand For a shorter computation enter 200 in the Maximum number of steps text box To set conformational search parameters manually for the ligand Note that this setup would not be adequate for a complete search of conformational space 1 2 Choose Ligands from the Display only toolbar button to display only the ligand molecule Click the Fit button on the Workspace toolbar Schr dinger Suite 2012 Update 2 Chapter 4 Conformational Searches Comparison Atoms 1791 1792 1793 1794 1795 Heavy Atoms O H S H Define comparison atoms
19. concerted conformational changes in the structure Specialized applications of LLMOD include protein loop optimization homology model refinement and fully flexible docking for induced fit modeling In addition LLMOD gener ated conformations can be used for subsequent rigid docking studies For this exercise you will use the crambin structure Icrn which is contained in the file LLMOD mae in your working directory This is a 14 amino acid sequence Large proteins can take multiple hours to complete the LLMOD conformational search Solvation should gener MacroModel 9 9 Quick Start Guide 49 Chapter 4 Conformational Searches 50 ally be used for LLMOD searches but it is not used in this exercise in order to speed the computation The example structure has been minimized with OPLS_2001 without solvation Any structure used in an LLMOD conformational search must be initially minimized to a low gradient with the same force field and solvation treatment that will be used in the conformational search l 2 3 4 5 Sr u ON 10 11 12 Import the protein in LLMOD mae from your working directory Choose Applications gt MacroModel Conformational Search from the main window Choose Workspace included entries from the Use structures from option menu In the Potential tab choose OPLS_2001 from the Force field option menu In the Constraints tab clear any previously set constraints by clicking Rese
20. demonstrates super position for two conformers 1 Click the Clear button on the Workspace toolbar d 2 Open the Project Table panel Table button on the Project toolbar choose Project gt Show Table or type CTRL T 3 Click the In column for the unminimized job input structure 4 Control click the In column for the minimized output structure The two structures are superimposed in the Workspace but do not necessarily have the best alignment 5 Choose Tools gt Superposition The Superposition panel opens 6 Click the ASL tab 7 In the Superimpose by ASL text box enter the expression not atom element H and press RETURN see Figure 3 5 The minimized structure is superimposed on the input structure using only the non hydrogen heavy atoms 8 Close the Superposition panel Schr dinger Suite 2012 Update 2 Chapter 3 Energy Calculation and Minimization Superposition EEE Entries to superimpose Included entries Selected entries _ Calculate in place no transformation Create RMSD property Atom Pairs ASL SMARTS Superimpose by ASL not atom element H B All Selection Select RMSD Mols 1 2 RMS 0 5305 Maximum Diff 1 2060 between atoms 17 amp 17 Close Help Figure 3 5 The Superposition panel 3 2 3 Energy Minimization of Multiple Structures A collection of structures either conformers or non conformers can b
21. glycine from the User defined list in the center 4 Click Add 5 In the Sets tab select User defined from the list on the left then select 1ig 5A from the User defined list in the center 6 Click Intersect then OK to define the lig and gly set 2 10 Filtering Structures Sorting and the Plot Facility It is often useful to identify subsets of a group of structures based on properties such as energy or dihedral angle which can be stored as properties in the Project Table Energetic properties are generated from the results of calculations and incorporated automatically into the Project Table In addition geometric properties can be created from the Measurements panel and applied to selected entries in the Project Table by selecting Create property for selected entries when making the measurement selection Once the properties have been incorporated into the Project Table there are two independent methods to filter the structures based on a range of the properties The first method is to use the Sort facility to sort the structures in the Project Table by property value in increasing or decreasing order The second method is to use the Plot facility and graphically select the struc tures based on the property values 2 10 1 Generating Data This exercise demonstrates how to create properties from measurements for a set of conformers The properties are automatically added to the Project Table 1 Import the structures in Filter m
22. minutes When the calculation is complete the results are placed in a table at the end of the Embrace log file and are incorporated into the Project Table 5 2 Molecular Dynamics Molecular dynamics calculations simulate molecular movement over time using Newton s equations of motion In this exercise you will run an MC SD dynamics calculation In the MC SD simulation an initial minimization is performed to ensure that the structure is at a minimum on the potential energy surface Geometric structural parameters can be monitored over the course of the dynamics simulation and structures can be sampled during the simula tion at constant intervals Since MC SD uses Monte Carlo methods it is also necessary to define the Monte Carlo parameters 1 Import the structure in MCSD mae from your working directory This structure has been minimized to a low gradient with MMFFs in the gas phase Choose Applications gt MacroModel gt MC SD from the main window Choose Workspace included entry from the Use structures from option menu In the Potential tab choose MMFFs from the Force field option menu and choose None from the Solvent option menu In the Constraints tab clear any previously set constraints by clicking the Reset All button in both the Constrain section and the Freeze section In the Substructure tab click the Clear button in both the Atoms for substructure section and in the Shells section to clear any previously
23. one item must be chosen Lines of command syntax that wrap should be interpreted as a single command File name path and environment variable syntax is generally given with the UNIX conven tions To obtain the Windows conventions replace the forward slash with the backslash in path or directory names and replace the at the beginning of an environment variable with a at each end For example SCHRODINGER maestro becomes SCHRODINGERS maestro Keyboard references are given in the Windows convention by default with Mac equivalents in parentheses for example CTRL H 8H Where Mac equivalents are not given COMMAND should be read in place of CTRL The convention CTRL H is not used In this document to type text means to type the required text in the specified location and to enter text means to type the required text then press the ENTER key References to literature sources are given in square brackets like this 10 MacroModel 9 9 Quick Start Guide v vi Schr dinger Suite 2012 Update 2 Chapter 1 Getting Started 1 1 About MacroModel MacroModel 9 9 is a general purpose force field based molecular modeling program with applicability to a wide range of chemical systems MacroModel provides multiple advanced methods to aid in the understanding of chemical structure energetics and dynamics A large selection of force fields is included along with the latest technical advances introduced into the OPLS force fiel
24. results of the calculation Ddrive out mae contains the structural output 5 3 2 Analyzing the Results of the Coordinate Scan You can create a contour diagram of Ddrive out grd in the Plot of Two Coordinate Scan panel see Figure 5 4 Schr dinger Suite 2012 Update 2 Chapter 5 Other Calculations Plot of Two Coordinate Scan a o x Minimum energy 440 0 o Maximum energy 384 2 i Oo z ka i Full Scale Number of contours 10 Contour width EN C Negative dashed 25 Ddrive out 390 _ Fill contours Show legend Label contours 395 401 Color map Rainbow Ir Energy units kj mol Okcal mol 407 412 Energy scale Absolute ORelative Decimal places X axis o Y axis 0 Contour labels 0 Labels 418 Coordinate 2 X axis Coordinate 1 Y axis Coordinate 2 3 Title Ddrive out Coordinate 1 Open Close Help mm 3G Figure 5 4 The Plot of Two Coordinate Scan panel 1 Choose Tools Plot Coordinate Scan Two Coordinates 2 Click Open and select Ddrive out grd from your working directory 3 Click Open The plot is displayed in the plotting area 4 When you have finished examining the plot close the Plot of Two Coordinate Scan panel and choose Project Close 5 4 MINTA Prediction of Free Energy MINTA is a powerful tool for estimatin
25. 9 3 1 1 Calculating the Gas phase Potential Energy uursurssnrsnnnnnnnnnnnnnnnnennn nn 29 3 1 2 Investigating Force Field Interactions u uuuunussusnnnnnnannnnnnnnnnnnnnnnnnnnnnnnnnnnnn 31 3 1 3 Calculating the Solution phase Current Energy m ssseserrserrsrssrrerssrserssrsrnnnnnrn 32 3 2 Energy Minimization u sa 4a 32 3 2 1 Energy Minimization of a Single Structure unrmerssurssennnnnnnnnnennnnon nennen nen 33 3 2 2 Comparing Structural Results by Superposition ssssserssrrseersrosrssrsrsrrenrenns nt 34 3 2 3 Energy Minimization of Multiple StruCtUreS ssssseeseresrssrssrsorsorsrrsrrsnrsnrenennrn 35 3 2 4 Energy Minimization of a Substructure eee eee eee cee eee tees teeeeeeeteeeenes 37 Chapter 4 Conformational Searches 41 4 1 MCMM Search te ree i brer err errr eeren 41 4 2 Serial MCMM Conformational Search nnnnnenennennennnn 42 4 3 Serial Low Mode Search 244244440n240nnennennnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 43 4 4 Ligand Conformational Search with a Frozen Receptor 44 4 5 Substructure Conformational Search with Automatic Setup 47 4 6 Large Scale Low Mode Conformational Search n 49 Chapter 5 Other GCaleul 20008 innen 51 5 1 Ligand Binding using Embrace rseneennnnennnnnnennennnnnnn nennen nennen 51
26. Click Open The Import panel closes and a warning dialog box appears but it isn t critical for this exercise Click OK When Maestro imports a PDB file problematic parts of imported structures such as non stan dard functional groups are colored orange red green or blue For this exercise it is not neces sary to correct the protein structure However when you begin to work on other proteins you may want to investigate and manually adjust marked portions See Section 3 1 6 of the Maestro User Manual for more information Schr dinger Suite 2012 Update 2 Chapter 2 Using Maestro 2 2 Identifying Labeling and Deleting Structure Elements This exercise demonstrates how to use Maestro s display tools to inspect the protein ligand complex and delete parts of the structure that are not needed for a calculation The protein ligand complex imported in the last exercise was obtained from the Protein Data Bank repository The structure contains crystallographic water molecules which need to be removed Also the structure is dimeric and for most purposes only the monomer is required To label the water molecules with the PDB name 1 In the Workspace right click on an atom in one of the outlying water molecules to spot center on the atom 2 Zoom in on the water molecules by scrolling with the mouse wheel or by dragging with the middle and right mouse buttons until you have a good view of the water molecules 3 Choose
27. Composition from the Pick to Label button menu on the Labels toolbar ii The Atom Labels panel opens see Figure 2 2 Atom Labels alx Composition Fields Element Atom number Remove Remove All Pick to Add labels replace v Label atoms Pick atoms O0 Update Existing Labels Clear All Labels Label Preferences Cose Help Figure 2 2 The Atom Labels panel MacroModel 9 9 Quick Start Guide 7 Chapter 2 Using Maestro Click Remove All to remove the current properties from the Fields list Click Add select Residue name in the Atom Properties tab and click OK Choose Molecules from the Pick option menu in the Label atoms section Sar Fey Se cn In the Workspace select one of the outlying water molecules of the structure to display its label HOH 8 Close the Atom Labels panel To delete unwanted atoms 1 Choose Waters from the Delete button menu on the Edit toolbar x All the water molecules are deleted 2 Click the Fit button on the Workspace toolbar The entire protein is now visible 3 Pause the pointer over various atoms in the protein until you find one that is in chain B Information on an atom is displayed in the status area at the bottom of the main window when the pointer pauses over the atom beginning with the chain name 4 Choose Chains from the Delete button menu and click on an atom in chain B x The ent
28. M The serial_split utility can be used to divide the results of a serial search into individual output files for the individual input structures See Section 18 7 of the MacroModel User Manual for more information 4 3 Serial Low Mode Search Low mode searching explores the low frequency eigenvectors of the system to generate new conformations A low mode calculation does not require the designation of ring structures and variable torsion angles 1 Import Serial mae from your working directory 2 In the Project Table select the three imported entries 3 Choose Applications gt MacroModel Conformational Search from the main window 4 Choose Project Table selected entries from the Use structures from option menu 5 In the CSearch tab choose Low mode sampling from the Method option menu and select Multi ligand Enter 100 in the Number of steps text box Click Start to open the Start dialog box Choose Do not incorporate from the Incorporate option menu 19 SO L Enter SerialLMOD in the Name text box MacroModel 9 9 Quick Start Guide Chapter 4 Conformational Searches 44 10 Click Start to launch the job The output structure file Serial LMOD out mae contains a collection of minimized configu rations for each input structure 4 4 Ligand Conformational Search with a Frozen Receptor In Section 3 2 4 a protein ligand complex was minimized using the OPLS_2001 force field There are multiple
29. MacroModel 9 9 Quick Start Guide O Schr dinger Press MacroModel Quick Start Guide Copyright 2012 Schr dinger LLC All rights reserved While care has been taken in the preparation of this publication Schr dinger assumes no responsibility for errors or omissions or for damages resulting from the use of the information contained herein BioLuminate Canvas CombiGlide ConfGen Epik Glide Impact Jaguar Liaison LigPrep Maestro Phase Prime PrimeX QikProp QikFit QikSim QSite SiteMap Strike and WaterMap are trademarks of Schr dinger LLC Schr dinger and MacroModel are registered trademarks of Schr dinger LLC MCPRO is a trademark of William L Jorgensen DESMOND is a trademark of D E Shaw Research LLC Desmond is used with the permission of D E Shaw Research All rights reserved This publication may contain the trademarks of other companies Schr dinger software includes software and libraries provided by third parties For details of the copyrights and terms and conditions associated with such included third party software see the Legal Notices or use your browser to open SSCHRODINGER docs html third_party_legal html Linux OS or SCHRODINGER docs htmi third_party_legal html Windows OS This publication may refer to other third party software not included in or with Schr dinger software such other third party software and provide links to third party Web sites linked sites Refere
30. ace Surface Molecular Surface in the main window Under Atoms for surface display click the Clear button to clear the ASL text box Click the Atom Selection button and choose Select to open the Atom Selection dialog box 5 In the Molecule tab select Molecule Number from the list on the left and enter 4 in the Molecule Number text box Click Add Click Proximity The Proximity dialog box opens see Figure 2 10 Under Proximity select Within and Angstroms and enter 5 0 in the text box Under Fill select Residues and select Exclude source Click OK in the Proximity dialog box and in the Atom Selection dialog box In the Molecular Surface panel under Surface context select Molecule Click Create Surface The resulting surface clearly defines the topology of the binding site Proximity Within Angstroms Beyond 5 9 Bonds Fill None Residues O Molecules x Update Markers OK Cancel Figure 2 10 The Proximity dialog box Schr dinger Suite 2012 Update 2 Chapter 2 Using Maestro 12 Close the Molecular Surface panel In the Manage Surfaces panel you can click Display Options and color the surface by partial charge or residue charge to visualize the electrostatics topology You can also change the style or transparency to see the atoms under the surface When you are fin ished close the Display Options panel and the Manage Surface
31. ae using the directions in Section 2 1 on page 5 The structures are imported as a new entry group and are selected 2 Include one of the entries in the Workspace click the In column 3 Choose Tools gt Measurements to open the Measurements panel MacroModel 9 9 Quick Start Guide 25 26 Chapter 2 Using Maestro 4 Select Create property for selected entries see Figure 2 13 5 Choose Atoms or Bonds from the Pick menu and select the four atoms or the three bonds that define the torsion of interest When the torsion is defined Maestro calculates the dihedral angle for each selected entry and transfers the data to the Project Table as a new property 6 Close the Measurements panel 2 10 2 Filtering by Sorting This exercise demonstrates how to sort the structures based on the dihedral angle generated in the previous section 1 In the Project Table select the entries to be sorted You can use shift click and control click to select a range of items Select the entries for which you created properties in the previous section these should already be selected 2 Right click on the column heading of the Dihedral property that you created and choose Sort Selected Rows The entries in the Project Table are reordered based on the sort criteria Measurements Distances Angles Dihedrals IH NMR Coupling BCE r Define atoms for dihedral measurement Atoms Dihedral
32. ammonium group In this exercise you will convert single bonds to double bonds and adjust the formal charges In the next exercise the hydrogen atoms will be added 1 Choose Molecules from the Display Sel button menu and select an atom in the ligand nat You can choose Molecule Number from the Color Scheme button menu on the Represen tation toolbar to help distinguish the ligand 2 If the molecule is not displayed in wire representation choose Molecule from the Wire button menu on the Representation toolbar and pick an atom in the ligand O 3 Choose Element from the Color Scheme button menu at bE A 4 Click the Build button on the Manager toolbar or choose Window Toolbars Build Schr dinger Suite 2012 Update 2 Chapter 2 Using Maestro Figure 2 5 The raloxifene molecule after fixing bond orders and formal charge 5 Click the Bond Order button on the Build toolbar CC 6 Click on the aryl C C bonds that need to be converted to double bonds There are two phenyl rings and a fused ring 7 Click on the carbonyl C O bond 8 Click the Formal Chg button on the Build toolbar fall LL 4 9 Click on the nitrogen atom of the piperidine in the Workspace The formal charge of the nitrogen atom is now 1 and the atom type is automatically adjusted To check the formal charge choose Formal Charge from the Label All button menu Choose Delete Labels from the Label All button menu to remove
33. apter 3 Energy Calculation and Minimization 1 2 Stretch energy 0 437 i Force constant 5 829 2 3 Ideal length 1 369 H Actual length 1 385 3 8 Origin Original ri Quality High 5 6 a Alternate No Alternates Used for MMFF 3 18 Comment MMFFBOND PAR 3 10 C94 Define stretch sort by energy Show All parameters Show force field Pick Atoms x Figure 3 3 The Stretch panel 3 1 2 Investigating Force Field Interactions Pe Choose Tools Force Field Viewer Click Browse select Ecalc out mmo from the Files list and click Open Click Stretch to open the Stretch panel see Figure 3 3 Click on a numbered pair in the list on the left to select a stretching interaction and dis play it in the Workspace with a magnifying glass icon To sort the stretching interactions select Sort by Energy in the lower center portion of the panel The list of stretching interactions is re sorted so that the stretch with the lowest energy that is the least strained atom pair is at the top of the list To investigate a particular stretching interaction choose Bond from the Define Stretch pick menu and click on the desired bond in the Workspace To view stretching interactions by parameter quality select the desired quality level from the Show option menu View relevant force field parameters by clicking Show force field This feature has limited utility for t
34. ared earlier The final search is a large scale low mode search with another protein 4 1 MCMM Search The first conformational search is a Monte Carlo Multiple Minimum MCMM which gener ates trial conformations by randomly adjusting rotatable bonds 1 Import MCMM mae from your working directory 2 Choose Applications gt MacroModel Conformational Search in the main window Ww Choose Workspace included entries from the Use structures from option menu see Figure 4 1 on page 42 In the Substructure tab clear any previously defined substructures and shells In the CSearch tab choose Torsional sampling MCMM from the Method option menu Deselect Multi ligand and Perform automatic setup during calculation ao a SE Click the Perform Automatic Setup button The parameters of the calculation should be displayed as markers on the structure If they are not click the Display All Markers button in the Search Variables section Many of the variables define conformational comparisons which govern how the generated structures are compared and duplicates eliminated They can be individually examined from the parameter panels which you open by clicking the respective parameter buttons in the center of the tab The defaults are sufficient for this exercise 8 Enter 200 in the Maximum number of steps text box 9 Click Start to open the Start dialog box 10 Choose Append new entries as a new group from the Incorporate option
35. calculations are available using MacroModel This section introduces the MacroModel energetic panels and basic energetic parameters These exercises calculate the current molecular mechanics energy of a structure in gas phase then in solution phase Before starting the calculations import the substituted thymine structure from Ecalc mae which you copied to your working directory in Section 1 3 on page 2 If you have not copied these files do so now See Section 2 1 on page 5 for instructions on importing structures 3 1 1 Calculating the Gas phase Potential Energy 1 Choose Applications gt MacroModel Current Energy Choose Workspace included entries from the Use structures from option menu In the Potential tab choose MMFFs from the Force Field option menu and choose None from the Solvent option menu In the ECalc tab choose Complete from the Energy Listing option menu Click Start The Start dialog box opens see Figure 3 1 Choose Replace existing entries from the Incorporate option menu Enter Ecalc in the Name text box Current Energy Start Output Incorporate Append new entries as a new group v Job Name Ecalc Compose Host localhost 4 Ir Cancel Help Figure 3 1 The Start dialog box MacroModel 9 9 Quick Start Guide 29 Chapter 3 Energy Calculation and Minimization Current Energy IGE Use struct
36. ce button on the toolbar d 2 Import the structure in SubsMini mae from your working directory The ligand in this complex is molecule number 4 First you will create an atom set for use in the definition of the substructures 1 Choose Tools Sets The Sets panel opens 2 Click New in the lower portion of the panel 3 Enter 1ig 5A in the Set name text box and click OK A new set is created named lig 5A 4 In the Sets panel under Atoms for set select Markers 5 Choose Molecules from the Pick menu 6 In the Workspace select an atom in the ligand If you need to identify the ligand color the atoms by molecule number or use the Find Atoms panel described in Section 2 3 on page 9 If you do use Find Atoms deselect Mark found atoms once you have selected the desired atom 7 In the Sets panel under Atoms for set click the Atom Selection button and choose Select 3 The Atom Selection dialog box opens MacroModel 9 9 Quick Start Guide Chapter 3 Energy Calculation and Minimization 38 10 11 12 13 14 15 16 BCE Use structures from Workspace included entry MI Potential Constraints 0 Substructure Mini Freely moving atoms substructure set lig 5A ena Pick Atoms X Markers Expand to atoms within radius of 0 0 Complete residues _ Calculate constrained atom mutual interactions Shells constrained and frozen atoms
37. ction of the entry 1 In the table click the V field of the first row to display the surface 2 Click Limit in the lower portion of the Manage Surfaces panel to open the Limit panel 3 Enter mol num 1 in the ASL text box 4 Click Apply to see the changes The surface is limited to the part that is generated for molecule number 1 5 Click the Atom Selection button and choose Select to open the Atom Selection dialog box 6 In the Molecule tab choose Molecule Number from the list and enter 2 in the Molecule Number text box 7 Click Add then click OK 8 In the Limit panel click OK The surface is extended to include molecule number 2 9 In the Manage Surfaces panel deselect the Limit box for the first row to remove the sur face limit and redisplay the entire surface Limit Limit to ASL mol num 1 Soma XPick Entries v XMarkers Distance 2 0 Apply Cancel Help Figure 2 9 The Limit panel MacroModel 9 9 Quick Start Guide Chapter 2 Using Maestro 18 2 8 3 Generating a Surface for One Molecule in a Complex An entry can be composed of multiple molecules such as a co crystallized receptor ligand complex Maestro is capable of generating a surface using a subset of atoms in the entry In this example you will use the 1err entry to create a surface of just the atoms near the binding site ignoring the ligand 1 2 10 11 Choose Worksp
38. defined substructures and shells In the Shells section click Delete Shells until all shells are deleted In the Mini tab enter 5000 in the Maximum iterations text box and enter 0 002 in the Con vergence threshold text box These parameters are required for the initial minimization MacroModel 9 9 Quick Start Guide 53 Chapter 5 Other Calculations 54 10 11 12 13 14 15 BCE Use structures from Workspace included entry Ihr ntial Constraints 0 Substructure Mini Monitor Dynamics MC SD Bg Perform Automatic Setup Reset All Variables Ratio of SD to MC steps 1 Minimum number of torsions to vary io Maximum number of torsions to vary 1 Torsion Rotations Molecule Trans Rot Start Write Close Figure 5 2 The MC SD panel showing the MC SD tab In the Monitor tab enter 10 in the Number of structures to sample text box You can use the buttons in this tab if you want to conduct additional structural monitoring In the Dynamics tab choose Stochastic dynamics from the Method option menu and choose Nothing from the SHAKE option menu SHAKE is not recommended for MC SD simulations In the MCSD tab click Perform Automatic Setup see Figure 5 2 To view the selected torsions click Torsion Rotations in the middle of the panel Click Start to open the Start dialog box Choose Append new entries as a
39. ds Numerous minimization methods are available enabling geometry optimi zations for a broad selection of structural classes A wide range of methods is available for conformational searching which allows efficient sampling of the potential energy surface for low energy structures including entire proteins Solvation effects can be accounted for using the efficient continuum solvation model in MacroModel Additional advanced features include molecular dynamics simulations free energy perturbation simulations and pure and mixed ensemble sampling methods 1 2 About this Manual This manual contains exercises designed to help you learn the basic tasks for preparing and initiating MacroModel calculations from Maestro Once you have worked through these exer cises you will have an understanding of the basic MacroModel features The exercises are divided into groups e Chapter 2 contains exercises on a number of basic operations in Maestro e Chapter 3 contains exercises on the calculation and minimization of the energy e Chapter 4 contains exercises on conformational searching e Chapter 5 contains exercises on various other MacroModel capabilities The exercises contain only the information required for basic understanding and to complete the task at hand For more information about a particular MacroModel feature see the Macro Model User Manual To learn more about the command line MacroModel and MacroModel operation codes see the MacroM
40. e Project Table with the total potential energy as a property You can use the output in the Monitor panel or in the output Ecalc log and EcalcSolv log files to examine the details of the energies for the gas phase and solution phase calculations 3 2 Energy Minimization MacroModel energy minimizations are set up from the Minimization and Multiple Minimization panels within Maestro Minimization calculations can be performed on single structures and multi structure collections In addition for single structure calculations the MacroModel substructure facility can be used to select fixed and frozen atoms for the minimization of a subset of atoms within a large structure For the next two exercises you can either use the structure from Section 3 1 3 or import Mini mae from your working directory The entry title is Ecalc See Section 2 1 on page 5 for instructions on importing structures Schr dinger Suite 2012 Update 2 Chapter 3 Energy Calculation and Minimization BCE Use structures from Workspace included entry v Potential Constraints 0 Substructure Mini Method PRCG v Maximum iterations 500 Converge on Gradient r sense Convergence threshold 0 05 Start Write Close Figure 3 4 The Minimization panel showing the Mini tab 3 2 1 Energy Minimization of a Single Structure 1 Choose Applications gt MacroModel Minimization
41. e diagnostics have run click Technical Support A dialog box opens with instructions You can highlight and copy the name of the file 3 Attach the file specified in the dialog box to your e mail message If your job failed 1 Open the Monitor panel in Maestro Use Applications gt Monitor Jobs or Tasks Monitor Jobs 2 Select the failed job in the table and click Postmortem The Postmortem panel opens 3 If your data is not sensitive and you can send it select Include structures and deselect Automatically obfuscate path names 4 Click Create An archive file is created in your working directory and an information dialog box with the name of the file opens You can highlight and copy the name of the file 5 Attach the file specified in the dialog box to your e mail message 6 Copy and paste any log messages from the window used to start Maestro or the job into the email message or attach them as a file e Windows Right click in the window and choose Select All then press ENTER to copy the text e Mac Start the Console application Applications Utilities filter on the applica tion that you used to start the job Maestro BioLuminate Elements copy the text MacroModel 9 9 Quick Start Guide 63 Getting Help 64 If Maestro failed 1 Open the Diagnostics panel Windows Start gt All Programs gt Schrodinger 2012 Diagnostics e Mac Applications gt Schrodinger2012 Diagnostics e
42. e following command SSCHRODINGER maestro profile Maestro amp e Windows Double click the Maestro icon on the desktop You can also use Start gt All Programs Schrodinger 2012 Maestro e Mac Click the Maestro icon on the dock If it is not on the dock drag it there from the SchrodingerSuite2012 folder in your Appli cations folder or start Maestro from that folder Now that Maestro is running you can start the setup 1 Choose Help Tutorials The Tutorials panel opens 2 Ensure that the Show tutorials by option menu is set to Product and the option menu below is labeled Product and set to All 3 Select MacroModel Quick Start Guide in the table Schr dinger Suite 2012 Update 2 Chapter 1 Getting Started 4 Enter the directory that you want to use for the tutorial in the Copy to text box or click Browse and navigate to the directory If the directory does not exist it will be created for you on confirmation The default is your current working directory 5 Click Copy The tutorial files are copied to the specified directory and a progress dialog box is dis played briefly If you used the default directory the files are now in your current working directory and you can skip the next two steps Otherwise you should set the working directory to the place that your tutorial files were copied to 6 Choose Project gt Change Directory 7 Navigate to the directory you specified for the tutorial
43. e minimized in one computation using the Multiple Minimization panel 1 Click the Import button on the Project toolbar S The Import panel opens 2 Ifthe options are not displayed click Options 3 Ensure that Import all structures is selected 4 Select MultMini mae from the list of files and click Open This file contains 10 small molecular structures which are imported as a new group named MultMini 5 Open the Project Table panel MacroModel 9 9 Quick Start Guide 35 Chapter 3 Energy Calculation and Minimization Multiple Minimization lolx Use structures from Potential Constraints 0 Substructure Mini Mult Input file Browse Minimization mode Minimization of non conformers Minimization of conformers Comparison Atoms not defined Eliminate redundant conformers using Maximum atom deviation Cutoff 0 5 A ORMSD Cutoff 0 5 A x Retain mirr or image conformations Energy window for saving structures 21 0 kj mol 5 02 kcal mol _ Maximum number of structures to save 100 I LogP estimation Secondary solvent Water v Start Write dose Help Figure 3 6 The Multiple Minimization panel showing the Mult tab 6 Ensure that all 10 structures are selected in the Project Table 7 Choose Applications gt MacroModel Multiple Minimization in the main window 8 Choose Project Table
44. e the receptor atoms that are within 6 A of the ligand MacroModel automatically ignores any remaining atoms in the computation 1 Display all atoms by double clicking the Display Sel button on the Display Atoms toolbar kk 2 In the Substructure tab of the CSearch panel clear any previously defined substructures and shells 3 In the Freely moving atoms substructure section enter the following in the ASL text box mol n 4 Schr dinger Suite 2012 Update 2 Chapter 4 Conformational Searches 4 Click New in the Shells constrained and frozen atoms section 5 Select Complete residues and enter 6 0 in the Radius text box 6 Select Freeze atoms Maestro colors the frozen atoms orange the remainder are ignored in the computation 7 Click Start 8 In the Start dialog box choose Append new entries as a new group from the Incorporate option menu 9 Enter LigandMCMM in the Name text box 10 Click Start to launch the job This computation will take one to three hours depending on your computer When the calculation is complete the output structures are incorporated as a group named LigandMCMM 11 Use the ePlayer to view the different low energy orientations For more information on the ePlayer see Section 9 7 of the Maestro User Manual 4 5 Substructure Conformational Search with Automatic Setup The last exercise demonstrated a computation in which the ligand was manually assigned Monte Carlo conformational s
45. earch parameters while the entire receptor was held frozen This exercise demonstrates a modified conformational search that enables increased receptor flexi bility using Perform Automatic Setup to define the MCMM search variables The steps below prepare a substructure conformational search calculation in which the receptor is divided into freely moving fixed and frozen regions Computations using substructures use less resources than full receptor simulations Automatic Setup recognizes substructures and assigns the MCMM conformational search parameters only to functional groups in the substructure and not to those in the restrained or frozen part of the structure To set up the job 1 Import the structure in SubsAuto mae from your working directory 2 Display the structure in the Workspace 3 Choose Applications gt MacroModel Conformational Search from the main window MacroModel 9 9 Quick Start Guide 47 Chapter 4 Conformational Searches 48 6 Choose Workspace included entries from the Use structures from option menu In the Potential tab choose OPLS_2001 from the Force field option menu and choose None from the Solvent option menu In the Mini tab enter 5000 in the Maximum iterations text box To set up the substructure and shells that define moving fixed and frozen atoms In this example the freely moving portion includes the ligand as well as all residues within 3 A of the ligand 1 2
46. ect 1ig 5A from the User defined list in the center Click Add then click OK Select Markers to highlight the atoms in the substructure This is the section of the structure that is minimized without restraints Next you will define a shell of restrained atoms and another shell of frozen atoms 20 21 22 23 24 25 26 27 28 29 Click New in the middle part of the Substructure tab below Shells constrained and frozen atoms Under Selected shell select Complete residues Enter 5 0 in the Radius text box The restrained atoms are highlighted in orange in the Workspace Click New again Under Selected shell select Complete residues and Freeze Atoms Enter 5 0 in the Radius text box The frozen atoms are labeled in red in the Workspace Click Start The Start dialog box opens Choose Append new entries individually from the Incorporate option menu Enter SubsMini in the Name text box Click Start to launch the job This job may take several minutes to finish MacroModel 9 9 Quick Start Guide 39 40 Schr dinger Suite 2012 Update 2 Chapter 4 Conformational Searches The goal of conformational searching is to locate the low energy configurations of a molecular structure MacroModel includes a number of conformational searching algorithms as well as mixed methods This exercise first explores three standard conformational searches then explores searches with the ligand protein system prep
47. ed multiple structures in the output file The entire set of conformers can be used as input to MINTA or to shorten the computation a subset of the lowest energy structures can be used 1 Import the structures in Minta mae from your working directory Select all entries in the Project Table or just a subset of the lowest energy structures 2 3 4 Choose Applications gt MacroModel MINTA from the main window Choose Project Table selected entries from the Use structures from option menu see Figure 5 5 on page 58 In the Potential tab choose the same force field that you used to perform the conforma tional search The Minta mae file was generated using MMFFs Click Start to open the Start dialog box Choose Append new entries as a new group from the Incorporate option menu Schr dinger Suite 2012 Update 2 Chapter 5 Other Calculations 8 Enter Minta in the Name text box 9 Click Start to launch the job The MINTA free energy and other information is written at the end of the log file and is included as a set of properties in the Project Table 5 5 Partition Coefficient Between Two Solvents MacroModel can estimate the logarithm of the partition coefficient of a solute between two solvents The GB SA parameterized solvents available are water octanol and chloroform Multiple solutes can be used as input by selecting entries in the Project Table The input struc tures are minimized in each s
48. enerate the same surface with High image quality This calculation takes longer to generate but the resulting surface has superior quality Also the resulting high quality surface may be slower to rotate depending on your work station resources In the Manage Surfaces panel click Display Options and experiment with different styles and color schemes The Partial Charge color scheme uses white until a calculation is performed The struc ture was imported from a PDB record which has no information about the fractional atomic charges Therefore these must be calculated before Maestro can render the partial charge values on the surface To use the partial charges from the OPLS_2005 force field you can choose Assign Partial Charges from the Tools menu Molecular Surf molecular S 14255 8 T Tr Kasten E delsten SAL aden aa ancien TE a Isovalue Q C Display at most 10 A fr EET Help J Figure 2 8 The Manage Surfaces panel Schr dinger Suite 2012 Update 2 Chapter 2 Using Maestro 2 8 2 Limits to a Surface Frequently the entire surface of an entry is not required Instead of creating another surface with a smaller subset of atoms you can display a portion of a generated surface using the Limit panel This exercise demonstrates how to limit the surface generated in the previous exercise from the entire entry to a smaller se
49. energy difference mode In the first the receptor and the ligand are individually treated as separate sets and only the energy components between sets are evaluated and recorded The Embrace energy difference mode reports the minimized energy of both the individual ligand and receptor subtracted from the minimized energy of the complex It is also possible to perform Embrace calculations using conformational searches Embrace calculations can be accelerated by using substructures with constraints applied to atom positions The substructure need only include elements of the protein not any ligands This exercise demonstrates how to import a receptor and a group of ligands and import a substructure and run the calculations with constraints 1 Import Embrace mae from your working directory If you are not sure how to import a structure use the directions in Section 2 1 on page 5 This file contains a single protein and four pre positioned ligands Only the first structure the receptor is displayed in the Workspace In the Project Table select all of the entries The structural input to an Embrace calculation must contain the receptor first followed by the pre positioned ligands In Maestro the receptor must be the first selected entry MacroModel 9 9 Quick Start Guide 51 Chapter 5 Other Calculations 52 SO po eS VB a 10 11 12 13 Embrace Minimization IGE Potential Substructure Mini Embrace
50. estro User Manual 1 2 Choose Select from the Display Only button menu on the Display Atoms toolbar The Atom Selection dialog box opens see Figure 2 4 In the Molecule tab choose Molecule Number from the list on the left and enter 4 in the Molecule Number text box MacroModel 9 9 Quick Start Guide 9 Chapter 2 Using Maestro 10 Atom Selection FIER Select To Display Only Atom Residue Molecule Chain Entry Substructure Set Molecule number Add Molecule number in entry e Molecular weight Subtract Size number of atoms Intersect Molecule type Molecule list Atoms matching Examples J lt 12 or 3 5 20 34 Range in workspace 1 109 ASL Show markers mol num 4 Create Set Al Undo Redo Clear Invert Previous Selection Atom Num Res Num Matching 34 atoms OK Cancel Help Figure 2 4 The Atom Selection dialog box Molecule tab 3 Click Add then click OK The ligand molecule number 4 is displayed and the remaining atoms are undisplayed 4 Choose Protein Backbone from the Also Display button menu Repeat for Protein Side Chains and for Waters D You have now redisplayed the entire protein However the crystallographic water molecules have not been redisplayed because they were deleted not undisplayed in the exercise in Section 2 2 on page 7 You can also display
51. files and click OK You can close the Tutorials panel now and proceed with the exercises MacroModel 9 9 Quick Start Guide 3 4 Schr dinger Suite 2012 Update 2 Chapter 2 Using Maestro The exercises in this section present a quick tour of some aspects of the Maestro interface including the following e Importing a structure file e Deleting portions of a Workspace structure e Using the Find feature to locate particular structural elements e Displaying undisplaying and labeling atoms and molecules e Generating and displaying surfaces e Defining atom sets for use when selecting atoms You can find additional information about Maestro in the Maestro User Manual Most of the exercises in this chapter use the structure in lerr pdb which you copied to your working directory 2 1 Importing a Structure To display an existing structure in the Workspace you must import the structure into the current project Follow the instructions below to import the lerr protein ligand complex into a named project You can work in a scratch project but using a named project enables you to organize the results of your calculations 1 Click the Save As button on the Project toolbar je CH 2 In the File name text box enter lerr prj then click Save 3 Click the Import button on the Project toolbar The Import panel opens see Figure 2 1 It should display the common structure files in your working directory Maestro PDB SD MOL2
52. g free energies from individual conformations or collections of conformations Many common methods for estimating the free energy of a conformation do so based on a single point in conformation space i e the exact coordinates provided A key feature of MINTA is that an integration is performed over the normal modes for each conformation in order to accurately estimate the free energy of the local potential minimum as a whole As with other free energy methods performing multiple MINTA calcula tions and taking the appropriate differences among them can yield estimates of binding free energies Note that while MINTA and MacroModel are tightly coupled additional licensing is needed to run MINTA MacroModel 9 9 Quick Start Guide 57 Chapter 5 Other Calculations 58 BCE Use structures from MINTA Input file Browse Potential Substructure Mini Number of MINTA iterations 5 Number of energy evaluations per MINTA iteration 2000 Temperature K 1300 0 Hard limit for sampling along normal modes 1 0 Soft limit for sampling along normal modes st dev 3 Start Write Close Help Figure 5 5 The MINTA panel showing the MINTA tab This exercise uses MINTA to estimate the free energy of the substituted thymine structure based on the results of the conformational search in Section 4 1 on page 41 The MCMM computation contain
53. he BMFF force fields MMFF and OPLS_2001 The other panels opened from the Force Field Viewer panel are similar to the Stretch panel You can experiment with bond angle electrostatic and other parameters 8 9 When you have finished close the Stretch panel and the Force Field Viewer Click the Clear Workspace button on the toolbar MacroModel 9 9 Quick Start Guide 31 Chapter 3 Energy Calculation and Minimization 32 3 1 3 Calculating the Solution phase Current Energy 1 Include the Ecalc entry in the Workspace Choose MacroModel Current Energy from the Applications menu Choose Workspace included entry from the Use structures from option menu P e gt In the Potential tab choose MMFFs from the Force Field option menu and choose Water from the Solvent option menu 5 Enter 1 0 in the Dielectric constant text box For all calculations using the GB SA solvation model the constant dielectric treatment is automatically used for the electrostatic part of the calculation We recommend using a low molecular dielectric constant for example 1 0 Click the ECalc tab and choose None from the Energy Listing option menu Click Start to open the Start dialog box Under Incorporate select Append new entries as a new group ern Aa In the Name text box type EcalcSolv 10 Click Start to launch the job Because you selected the Append new entries option when the job finishes a new entry is added to th
54. ions of an entry The molecular surface is a Connolly surface where a probe typically with a radius of 1 4 A is rolled over the molecule The surface is defined by the contact of the probe s outer radius and the molecule s van der Waals radius To generate a molecular surface for all atoms in the entry 1 Open the Project Table panel Table button on the Project toolbar TITT 2 Click the In column for the 1err entry to include it in the Workspace MacroModel 9 9 Quick Start Guide 15 Chapter 2 Using Maestro 16 Choose Workspace Surface Molecular Surface in the main window The Molecular Surface panel opens see Figure 2 7 Under Atoms for surface display choose Entries from the Pick menu Choose Entry from the Surface Context option menu The surface context describes the atoms for which the surface is created The surface dis play describes the atoms for which the resulting surface is displayed You can change the atoms for which the surface is displayed after surface generation by using the Limit fea ture which you will do in the next exercise In the Workspace select any atom in the entry Click Create Surface When the surface generation is complete the surface is displayed in the Workspace If you have the preference set for it the Manage Surfaces panel opens see Figure 2 8 You can experiment with the surfaces by doing any of the following Manage Surfaces G
55. ire chain including the ligand is deleted leaving chain A Schr dinger Suite 2012 Update 2 Chapter 2 Using Maestro Find Element SE N Plo of o x Fit Figure 2 3 The Find Toolbar 2 3 Using the Find Toolbar to Identify Molecules The imported structure contains three discrete molecules Find and visualize the three separate molecules with the Find toolbar 1 a A N If the Find toolbar is not displayed choose Edit gt Find or press CTRL F See Figure 2 3 From the Find option menu choose Specified atoms Enter mol num 1 in the text box and press ENTER The view zooms to molecule number 1 and the atoms in the molecule are selected Change the number in the text box to 2 and press ENTER to find molecule 2 Repeat for molecules 3 and 4 Molecule 4 is the ligand When you have finished finding the molecules clear all the options in the lower left of the panel and close the Find panel 2 4 Displaying and Undisplaying Atoms By undisplaying atoms that do not contribute to active site functionality you can more easily examine the active site Atoms can be displayed and undisplayed in the Workspace using the toolbar the Display Undisplay Atoms panel or by entering an undisplayatom command with an appropriate Atom Specification Language ASL expression in the command input area Below are instructions for using the toolbar For information on the other methods see Section 7 5 of the Ma
56. jobs see the Job Control Guide Using Maestro see the Maestro User Manual Maestro commands see the Maestro Command Reference Manual Contacting Technical Support If you have questions that are not answered from any of the above sources contact Schr dinger using the information below E mail help schrodinger com USPS Schr dinger 101 SW Main Street Suite 1300 Portland OR 97204 Phone 503 299 1150 Fax 503 299 4532 WWW http www schrodinger com FTP ftp ftp schrodinger com Generally e mail correspondence is best because you can send machine output if necessary When sending e mail messages please include the following information All relevant user input and machine output MacroModel purchaser company research institution or individual Primary MacroModel user Installation licensing and machine information as described below Schr dinger Suite 2012 Update 2 Getting Help Gathering Information for Technical Support This section describes how to gather the required machine licensing and installation informa tion and any other job related or failure related information to send to technical support For general enquiries or problems 1 Open the Diagnostics panel Maestro Help Diagnostics Windows Start gt All Programs gt Schrodinger 2012 Diagnostics e Mac Applications gt Schrodinger2012 Diagnostics Command line SSCHRODINGER diagnostics 2 When th
57. m Types and Formal Charges 12 2 7 Adding Hydrogens to a United Atom Structure eeeeennne 14 2 8 Creating and Viewing Surfaces 442404nnnennnnnnnnnnnnnnnennnnnnnennnnnn 15 2 8 1 Creating a Molecular Surface of a Complex s ssssssserserserssrsrrsnsssrsnensrsrrsnrsnrnnnn nr n 15 2 8 2 LimilS toa Surface nei ee 17 2 8 3 Generating a Surface for One Molecule in a COMPICX ssserssersrrsssrsrrssssrrnrsrnt 18 2 8 4 Creating a Map of the Binding Site s s1sssesteserssisssorissirsnsensostssitsssnbessdbrsdsssskensd s 19 2 9 Creating and Manipulating Atom Sets nnnenennnnennnnnnennnn 21 2 9 1 Defining an Atom Set by Selecting Atoms umrssurssnnnnnnnnnnnonnnnnnnnnn nennen 21 2 9 2 Defining an Atom Set with the Atom Selection Dialog Box 22 2 9 3 Defining Atom Sets With Boolean Operations nurssurssernnnnnnnnnnnnnnnn nennen 23 2 10 Filtering Structures Sorting and the Plot Facility 25 2101 Generating Data an an a A aes A eS 25 2 10 2 Fillefing DY SOKING a nnn Ge eRe aoe 26 2 10 3 Filtering Using the Plot Facility s sss ssssernssestinisispiisssesisarsirspsssnissssnssssnsninssssssa 27 MacroModel 9 9 Quick Start Guide Contents Chapter 3 Energy Calculation and Minimization esses 29 3 1 Current Energy Calculations 42444440nnnsennnnennnnnnnnnnnnennnnnennnnnn 2
58. m the Pick menu In the Workspace select an atom in the ligand to define the ligand set If you need to identify the ligand color the atoms by molecule number or use the Find Atoms panel described on page 9 If you do use Find Atoms deselect Mark found atoms once you have selected the desired atom Maestro highlights the atoms in the ligand set in green Highlights are displayed as lines and dots or as boxes depending on the molecular representation of the atoms and bonds 2 9 2 Defining an Atom Set with the Atom Selection Dialog Box Thi s exercise uses the Atom Selection dialog box to define more complex sets of atoms Set 2 Glycine residues Create a set that contains all glycine residues in the structure 1 2 3 9 Create anew setnamed glycine In the Sets panel select Markers Under Atoms for set click the Atom Selection button then click Select a The Atom Selection dialog box opens In the Residue tab select Residue Type from the list on the left then select GLY from the Residue Type list in the center Click Add then click OK You can switch between sets by selecting a set from the list at the top of the Sets panel Set 3 All residues with atoms within 5 of the ligand Create a set containing the ligand and all atoms in complete residues within 5 0 A of the ligand 1 Create a new set named lig 5A Schr dinger Suite 2012 Update 2 Chapter 2 Using Maestro Under A
59. menu 11 Enter MCMM in the Name text box MacroModel 9 9 Quick Start Guide 41 Chapter 4 Conformational Searches 42 Conformational Search lol Use structures from Workspace included entries v Potential Constraints 0 Substructure Mini CSearch Method Torsional sampling MCMM ly Multi ligand _ Perform automatic setup during calculation Perform Automatic Setup Reset All Variables r Customize the search Torsion sampling options Intermediate XRetain mirror image conformations Search variables Ring Closures iv Edit Display All Markers I Undisplay All Markers Maximum number of steps f200 x Use 100 steps per rotatable bond Number of structures to save for each search 0 Energy window for saving structures 21 0 kj mol 5 02 kcal mol Eliminate redundant conformers using Maximum atom deviation Cutoff 0 5 A ORMSD Cutoff 0 5 JA Probability of a torsion rotation molecule translation 0 5 Minimum distance for low mode move Maximum distance for low mode move Start write dose Help Figure 4 1 The Conformational Search panel showing the CSearch tab 12 Click Start to launch the job This calculation takes a couple of minutes to finish The Workspace is updated with the current low energy structure during the calculation The output s
60. nces to such other third party software or linked sites do not constitute an endorsement by Schr dinger LLC or its affiliates Use of such other third party software and linked sites may be subject to third party license agreements and fees Schr dinger LLC and its affiliates have no responsibility or liability directly or indirectly for such other third party software and linked sites or for damage resulting from the use thereof Any warranties that we make regarding Schr dinger products and services do not apply to such other third party software or linked sites or to the interaction between or interoperability of Schr dinger products and services and such other third party software Revision A September 2012 Contents DOCUMENELORVENBON See v Chapter 1 Getting Selen 1 1 1 About MacroM del 2 u 23 4 1 1 2 About this Manual cisneros aaa a inao 1 1 3 Preparing for the Exercises s ssssssssinvissersnsasisb stessssnsdn iipsorsasesia bivded ssnsn b npesttsnsikts 2 Chapter 2 Using Masse 5 2 1 Importing a Structure soeone ai n aiiai 5 2 2 Identifying Labeling and Deleting Structure Elements T 2 3 Using the Find Toolbar to Identify Molecules m nen 9 2 4 Displaying and Undisplaying Atoms 0 000 000 eee eeeee nennen nennen nennen nenn 9 2 5 Applying and Removing Atom Labels cece nennen nennen 11 2 6 Adjusting Bond Orders Ato
61. nd check that Show tooltips is selected under General Appearance in the Preferences panel which you can open with CTRL Not all features have tooltips Click the Help button in a panel or press F1 for information about a panel or the tab that is displayed in a panel The help topic is displayed in your browser Choose Help Online Help or press CTRL H 3H to open the default help topic in your browser When help is displayed in your browser use the navigation links or search the help in the side bar Choose Help gt Manuals Index to open a PDF file that has links to all the PDF docu ments Click a link to open the document Choose Help Search Manuals to search the manuals The search tab in Adobe Reader opens and you can search across all the PDF documents You must have Adobe Reader installed to use this feature MacroModel 9 9 Quick Start Guide 61 Getting Help 62 For information on Problems and solutions choose Help Knowledge Base or Help gt Known Issues gt product Software updates choose Maestro gt Check for Updates New software features choose Help New Features Scripts available for download choose Scripts gt Update Python scripting choose Help Python Module Overview Utility programs choose Help gt About Utilities Keyboard shortcuts choose Help Keyboard Shortcuts Installation and licensing see the Installation Guide Running and managing
62. new group from the Incorporate option menu Enter MCSD in the Name text box Click Start to launch the job Schr dinger Suite 2012 Update 2 Chapter 5 Other Calculations The ten sampled structures are incorporated into the Project Table at the completion of the computation After incorporation you can view the sample trajectory using Maestro s ePlayer The incorporated structures should already be selected in the Project Table Click the Play forward button on the ePlayer toolbar to view the trajectory in the Workspace For more information on the ePlayer see Section 9 7 of the Maestro User Manual 5 3 Creating Energy Profiles from Coordinate Scans A contour diagram describing the molecular mechanics potential energy of a structure relative to the value of either one or two coordinates distances angles or dihedrals can be generated with MacroModel These exercises demonstrate how to produce a contour diagram describing the variation in energy of a molecule with respect to rotation of two dihedral angles 5 3 1 Performing a Coordinate Scan Calculation 1 2 Import the structure in Ddrive mae from your working directory Choose Applications gt MacroModel Coordinate Scan from the main window The Coordinate Scan panel opens Choose Workspace included entry from the Use structures from option menu In the Potential tab choose MMFFs from the Force Field menu and choose None from the Solvent option menu
63. new set named frozen Under Atoms for set click the Atom Selection button and choose Select g The Atom Selection dialog box opens In the Sets tab select User defined from the list on the left then select 1ig 5A from the User defined list in the center Click Subtract Click OK to define the frozen set This set could be used to specify those atoms to be fixed or frozen in a MacroModel calcula tion Set 6 The ligand and all the glycine residues Create a set containing the atoms in the ligand and in the glycine residues 1 2 6 Create a new set named lig or gly Under Atoms for set click the Atom Selection button and choose Select The Atom Selection dialog box opens In the Sets tab select User defined from the list on the left then select ligand from the User defined list in the center Click Add In the Residue tab select Residue Type from the list on the left then select GLY from the Residue Type list in the center Click Add then OK to define the lig or gly set Set 7 All glycine residues in the lig 5A set Create a set containing only atoms in the glycine residues within the lig 5A set Schr dinger Suite 2012 Update 2 Chapter 2 Using Maestro 1 Create a new set named lig and gly 2 Under Atoms for set click the Atom Selection button and choose Select The Atom Selection dialog box opens 3 In the Sets tab select User defined from the list on the left then select
64. odel Reference Manual Maestro comes with automatic context sensitive help Auto Help Balloon Help tool tips an online help facility and a set of manuals For information on using Maestro see the Maestro online help or the Maestro User Manual MacroModel 9 9 Quick Start Guide Chapter 1 Getting Started To perform the exercises you must have access to an installed version of Maestro 9 3 and MacroModel 9 9 For installation instructions see the Installation Guide The MacroModel installation contains the structure files used in the following exercises The installation also contains sample input files which you can use to run exercises without having to complete all of the preceding exercises 1 3 Preparing for the Exercises To run the exercises you need a working directory in which to store the input and output and you need to copy the input files from the installation into your working directory This is done automatically in the Tutorials panel as described below To copy the input files manually just unzip the macromodel zip file from the tutorials directory of your installation into your working directory On Linux you should first set the SCHRODINGER environment variable to the Schr dinger soft ware installation directory if it is not already set csh tesh setenv SCHRODINGER installation path sh bash ksh export SCHRODINGER installation path If Maestro is not running start it as follows e Linux Enter th
65. olvent and the resulting difference in solvation energies is used for the logP calculation The octanol water partition coefficient logP o w is often used as a measure of molecular hydrophobicity and other environmental parameters In this exercise you will run a logP o w calculation from Maestro 1 Import the structure in LogP mae from your working directory 2 Choose Applications gt MacroModel Multiple Minimization from the main window 3 Choose Workspace included entries from the Use structures from option menu 4 In the Potential tab choose MMFFs from the Force field option menu and select Octanol from the Solvent option menu 5 In the Mini tab enter 5000 in the Maximum iterations text box and enter 0 02 in the Con vergence threshold text box 6 In the Mult tab select LogP estimation and choose Water from the Secondary solvent option menu see Figure 5 6 7 Click Start to open the Start dialog box 8 Choose Append new entries as a new group from the Incorporate option menu 9 Enter logP in the Name text box 10 Click Start to launch the job The logP o w value is written to the log file and is added to the output structure file as a property which you can view in the Project Table MacroModel 9 9 Quick Start Guide 59 60 Chapter 5 Other Calculations Multiple Minimization Use structures from Workspace included entries v Potential Constraints 0 Substructure Mini
66. om the Pick to option menu choose Clear labels The Label atoms section is renamed Clear labels to reflect the new action Click the Atom Selection button and choose Select g The Atom Selection dialog box opens MacroModel 9 9 Quick Start Guide 11 Chapter 2 Using Maestro 12 3 In the Atom tab select Element from the list on the left then select O from the Element list in the center 4 Click Add then click OK to remove the labels for all oxygen atoms 5 In the Atom Labels panel click Clear All Labels to remove all atom labels 6 Close the Atom Labels panel 2 6 Adjusting Bond Orders Atom Types and Formal Charges Most PDB structures derived from X ray crystallography data do not have hydrogen atoms formal charges or bond orders When the structure is imported into Maestro the conversion utility uses templates for assigning multiple bonds in standard residues but cannot do so for ligands Thus you need to explicitly add multiple bonds and formal charges to the ligands if necessary In this exercise you will learn how to perform these structural corrections manually however the Protein Preparation Wizard see the Protein Preparation Guide is designed to automate many of these routine tasks The tools for these tasks are found in the Build panel or on the Build toolbar The lerr ligand Raloxifene needs multiple bonds assigned and the piper idine nitrogen adjusted to be a four coordinate positively charged
67. residues that have atoms within a specified distance of the currently displayed atoms This is useful for displaying the part of a protein that is close to a ligand 1 Choose Molecules from the Display Sel button menu R 2 Click on an atom in the ligand to display only the ligand Schr dinger Suite 2012 Update 2 Chapter 2 Using Maestro 3 4 Choose 6 A from the Within button menu ae a For more complicated atom selections you can use the Display Undisplay Atoms panel choose Workspace Display Undisplay Atoms Redisplay all atoms by choosing All from the Also display button menu 2 5 Applying and Removing Atom Labels You can apply labels to any atoms in the Workspace You can also specify the label content label placement and label appearance In the exercise in Section 2 2 on page 7 you labeled atoms with their PDB residue names This exercise demonstrates how to apply and remove various types of atom labels To apply atom labels 1 4 J Choose Composition from the Pick to Label button menu i The Atom Labels panel opens Click Remove All to remove the current properties from the Fields list Click Add select Atom number Atom type MacroModel and Formal charge in the Atom Properties tab and click OK In the Label atoms section choose Molecules from the Pick menu In the Workspace click on an atom in the ligand to label its atoms To remove atom labels 1 2 Fr
68. s panel 13 Choose Workspace Surface gt Undisplay All 2 8 4 Creating a Map of the Binding Site Maestro can be used to create maps of receptors The map shows hydrophobic and hydro philic regions and is a tremendous asset when manually docking or adjusting ligands in a receptor For this exercise use the structure that was given the hydrogen treatment and map the region near the ligand The atoms in the ligand do not need to be mapped so they are excluded from the structure to map but the ligand makes a logical center to place the bounding box 1 Open the Project Table panel Table button Project gt Show Table or press CTRL T 2 Click the In box of the 1err_htreat entry to display it in the Workspace 3 Choose Workspace Surface Hydrophobic philic The Hydrophobic philic Surfaces panel opens Hydrophobic philic Surfaces Part of structure to map amp Pick Entries v Markers e Bounding box pick Entries v Markers ome Box margin 6 0 Grid spacing Standard v Start write close Figure 2 11 The Hydrophobic philic Surfaces panel MacroModel 9 9 Quick Start Guide 19 Chapter 2 Using Maestro 20 4 Oo N A 12 13 14 15 16 17 18 In the Part of structure to map section click the Atom Selection button then click Select a The Atom Selection dialog box opens
69. t All in both the Constrain section and the Freeze section In the Substructure tab clear any previously defined substructures and shells In the CSearch tab select Large scale low mode sampling from the Method option menu Enter 100 in the Maximum number of steps text box In the Mini tab enter 1 00 in the Convergence threshold text box Click Start to open the Start dialog box Choose Append new entries as a new group from the Incorporate option menu Enter LLMOD in the Name text box After the job finishes Maestro incorporates the structures into the Project Table Depending on the size of the structure the computation may take some time to complete Schr dinger Suite 2012 Update 2 Chapter 5 Other Calculations MacroModel has a range of other capabilities than those already encountered This chapter provides exercises to illustrate some of these capabilities 5 1 Embrace ligand binding to a receptor Molecular dynamics Energy profiles as a function of dihedral angles Free energy calculations using MINTA Partition coefficients between two solvents Cluster analysis of structures Ligand Binding using Embrace Embrace is an automated routine that uses a collection of individual ligands each pre posi tioned with respect to a given receptor Embrace automatically performs energetic calculations on each complex formed from the receptor and the individual ligands Embrace can work in two modes interaction mode and
70. ter 4 Conformational Searches 8 In the CSearch tab choose Torsional sampling MCMM from the Method menu 9 Ensure that Multi ligand is not selected 10 Do one of the following e Select Perform Automatic Setup during calculation to assign MCMM parameters for the freely moving substructure region automatically during the calculation e Deselect Perform Automatic Setup during calculation click Reset All Variables then click Perform Automatic Setup to assign MCMM parameters to the entire freely moving region Enter the following command in the command input area of the main window to assign MCMM parameters to the ligand only autosetup mol n 4 11 For a shorter computation change the value in the Number of steps text box to 200 To enter the job information and start the job 1 Click Start 2 In the Start dialog box choose Append new entries as a new group from the Incorporate option menu 3 Enter SubsAuto in the Name text box 4 Click Start to launch the job The sample files included in the distribution have conformational search variables defined only for the ligand 4 6 Large Scale Low Mode Conformational Search The large scale low mode LLMOD conformational searching routine is a unique method for generating candidate conformations of very large structures including full proteins Combina tions of low frequency vibrational modes are used to produce candidate structures These modes represent simultaneous
71. the label Maestro also provides a tool for automatic assignment of bond orders To use it choose Tools Assign Bond Orders Automatic assignments should always be checked because the rules that are used for the assignments cannot cover every possibility MacroModel 9 9 Quick Start Guide 13 Chapter 2 Using Maestro 14 2 7 Adding Hydrogens to a United Atom Structure Modern force fields use all atom structures and Maestro contains a facility to rationally add the appropriate number of hydrogens to carbon atoms with approximately the correct geom etry This exercise demonstrates how to use the tools in the Add Hydrogens Advanced panel to add hydrogens to the structure in the Workspace 1 Choose Edit gt Add Hydrogens Advanced 2 Choose All atom with No Lp from the Treatments option menu see Figure 2 6 3 Under Modify hydrogen treatment click All to add a full complement of hydrogens to the original structure 4 Close the Add Hydrogens Advanced panel You can also add hydrogen atoms with the Add H toolbar button This button applies the current hydrogen treatment to the selected atoms H Now save the modified structure as a new entry in the project 1 Click the Create Entry button on the Workspace toolbar r 2 Enter lerr_htreat in the Entry name text box and click Create to update the Project Table with the new entry Add Hydrogens Advanced Treatment All atom with No Lp X
72. toms for set click the Atom Selection button and choose Select 2 The Atom Selection dialog box opens In the Set tab select User defined from the list on the left then select Ligand from the User defined list in the center and click Add Click the Proximity button The Proximity dialog box opens Under Proximity select Within and Angstroms and enter 5 0 in the text box Under Fill select Residues Click OK in the Proximity dialog box and in the Atom Selection dialog box The 1ig 5A set is defined Set 4 Alpha carbons Create a set of all the alpha carbon atoms in the structure atoms with a PDB atom type C alpha 1 2 Create a new set named alphac Under Atoms for set click the Atom Selection button and choose Select er The Atom Selection dialog box opens In the Atom tab select PDB type from the list on the left then select CA from the PDB type list in the center Click Add then click OK to define the alphac set 2 9 3 Defining Atom Sets With Boolean Operations New sets can be created from existing sets using Boolean operations If you do not already have the Sets panel displayed open it from the Tools menu MacroModel 9 9 Quick Start Guide 23 Chapter 2 Using Maestro 24 Set 5 NOT the ligand and NOT within 5 A Create a new set that contains all atoms that are neither in the ligand molecule nor within 5 A of the ligand 1 2 4 5 Create a
73. tructure file MCMM out mae contains all structures found within the specified energetic window The output log file MCMM 1og includes a convenient listing of the molec ular mechanics potential energy of all the output structures 4 2 Serial MCMM Conformational Search Serial MCMM conformational searches perform an MCMM conformation search on each input structure with MCMM parameters that are set up automatically by means of an AUTO opcode in the command file 1 Import Serial mae from your working directory 2 In the Project Table select the three imported entries 3 Choose Applications gt MacroModel gt Conformational Search Schr dinger Suite 2012 Update 2 Chapter 4 Conformational Searches 4 Choose Project Table selected entries from the Use structures from option menu 5 In the CSearch tab choose Torsional sampling MCMM from the Method option menu 6 Select Multi ligand Perform automatic setup during calculation at the top of the panel is automatically selected and dimmed because it is mandatory for this type of calculation 7 Enter 100 in the Number of steps text box 8 Click Start to open the Start dialog box 9 Choose Append new entries as a new group from the Incorporate option menu 10 Enter SerialMCMM in the Name text box 11 Click Start to launch the job The output structures are incorporated into the Project Table when the conformational search is finished as a group named Serial MCM
74. ures from Workspace included entries hd Potential Constraints 0 Substructure ECalc Force field MMFFs Solvent None Electrostatic treatment Constant dielectric Sitnie br Fe Dielectric constant 1 0 Charges from Force field Cutoff Normal gt l Van der Waals 7 0 Electrostatic 12 0 H bond 4 0 Debugging Options Read Potential Settings From Command File Write Close Help Figure 3 2 The Current Energy panel showing the Potential tab 8 Click Start to launch the job The energetic settings you selected instruct the Maestro job control facility to use the contents of the Workspace as input to perform a current energy calculation and to replace the entry that is in the Workspace with the structural results of the calculation The settings also instruct Maestro to use the MMFFs force field not to use a solution model since this is a gas phase calculation and to generate a complete listing of the molecular mechanics energy terms The job finishes quickly and the results are incorporated into the project Since you selected Replace existing entries no new entries are added to the Project Table Job files for this calcu lation are placed in your working directory or the directory you chose for output files The detailed energy listing is written to a separate file Ecalc out mmo Schr dinger Suite 2012 Update 2 Ch
75. visualization tasks as well as for preparing MacroModel calculations The Sets panel allows you to create and manipulate sets using the full range of atom selection tools Once created sets can be used in the Atom Selec tion dialog box or from relevant Pick menus Sets are saved within a Maestro project To use defined sets in another project you can write them to a file using the Write button then read them into the new project using the Read button These exercises use the all atom protein ligand complex in lerr mae 1 Choose New from the Project menu and name the project lerrsets 2 Import the structure from lerr_htreat mae 2 9 1 Defining an Atom Set by Selecting Atoms With the contents of lerr_htreat mae displayed in the Workspace make a set that includes all atoms in the ligand Set 1 Ligand 1 Choose Tools Sets The Sets panel opens 2 Click New in the lower portion of the panel Name ligand Atoms for set mol num 4 VDA x Pick Atoms v Markers Xx Apply marker offset New Delete Read Write Workspace selection Replace Add Subtract Close Figure 2 12 The Sets panel MacroModel 9 9 Quick Start Guide 21 Chapter 2 Using Maestro 22 Enter ligand in the Set name text box and click OK A new set is created named ligand In the Sets panel under Atoms for set select Markers see Figure 2 12 Choose Molecules fro

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