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MacroModel User Manual

1. 122 substructure in CMBrACE eee 127 remote Calculations ooooonionnnnninninicnonacncnnicancnnnos 23 results checking and interpreting AAA ove ans sucsesaseesseens 95 AA IT 43 dihedral drives aiii icons 72 AYN AMNCS soii 106 Minimization 0c eee ete eects nancncanna crono 51 MINTA anidar 114 results dependence on task distribution 24 MacroModel 9 6 User Manual 185 Index 186 S Scan tabiri n 2100 Schr dinger contact information 00 176 Scripting with Python s src 173 SD minimization method wee AT Shells AEANMING sionista dista 35 simulation teMperatUlE occoncninnonnoninnocinnncnnnnnn 102 simulation time oooconconnnnncnccnnccocnnnnorcnnnnnncnncnncnos 103 SIZE imitations iii ai 15 solvation treatment descripta is 9 selec E e ees A E tas ts 26 SPM CO ucraniana nta 73 structures alignment Of 170 substructure A sdesesstaceeesieacies 29 33 filling out residues 10 eects 35 for freezing or fixing atoms 28 shell radius ooooooccnoncccoocccconacconancnnnccono 34 35 Mia 39 specifying for eMBrAc sses 127 substructure files ASUS Msi mead 34 format sessen 30 reading and writing 36 Substructure tab EEE o superposition rigid body s s s 159 MacroModel 9 6 User Manual Systematic Pseudo Monte Carlo search method coccooocncnncconoccnonncononcconnnononcconnn conca conn conos 13 T temperature dynamics calculati0MS
2. sssssssssssssssssssssssssssssssssessesssssssnsetsessessensssssensssseeseseeese 65 8 1 Performing a Coordinate Scan in Maestro ccccecccecceeseeeeeeeteeeeeeeteeeeeeens 65 8 2 Command File Examples 0 ccccccecceecceeeeeeeeeeeeeeeeeeeeeaeeecesaeeeseesaeeeseesaeeeseees 67 8 3 Plotting Scan Results in Maestro cccecceecceeeeeceeeeneeeceeeeeeeeeeaeeeeeeeaeeaeeeeas 68 8 3 1 1D and 2D Plot Panel General Features 8 3 2 The 1D Plot Panel cos rial eee 8 3 3 2D Plot Panel iia nriat ne 71 8 4 Checking and Interpreting Results 00 00 00 eceeeeesceeeeeeeceeeeeeceeeaeeeseeeaeeeeeens 72 Chapter 9 Conformational S arches sssssssssssssssssssssssssssssssssssssssssssssessssssstseess 73 9 1 Conformational Search Methods ccccceccceeceeeeeeceeeeeeeeeeeeseeeseeeaeeeeeeseeeteees 73 9 2 Performing Conformational Searches ccccecceeeseeeeeeeeeeeeeeeeeeeeesaeeeeee 74 9 2 1 Conformational Search Method avion aci 75 9 2 2 Automatic Setup of Conformational Search Variables oocoonoccccnnoccccnconannnno Tt 9 2 3 Global Search Restrictions 9 2 4 Low Mode Parade Siam SAAS 9 2 5 Setting Conformational Search Variables Manually oooionnnnninnnocnnocinocanananos 80 925 A scat tesctwtasasoceeecte cease ce uacterasaneceanaeeneraseiswteterscqsevaneaurs 81 9 2 5 2 TOPSIOM OTALONS eiiidh iaiia enaena S iaa AE E aE 82 9 2 5 3 Molecule Tran SRO s ant iaia 84 9 2 5 4 Comparison Atoms cairo a
3. 5 3 Command File Examples To run MacroModel calculations a molecular structure file and a command file are required The molecular structure file contains the structures to be used as input in the calculation The command file contains the name of the input structure file the name of the output structure file and an ordered list of operation codes opcodes for the calculations Once you set up a job in Maestro and click either Start or Write Maestro writes out a molecular structure file and a command file For many types of jobs command files written this way are complete and adequate but for some types of jobs you may need to adjust the Maestro gener ated command file The command files and the log files for the examples given in this section can be found in S SCHRODINGER macromodel vversion samples Examples Below is an example of a command file for an energy calculation with solvation A description of the opcodes and their arguments follows MacroModel 9 6 User Manual Chapter 5 Current Energy Calculations ecalc mae ecalc out mae MMOD 0 1 0 0 0 0000 0 0000 0 0000 0 0000 FFLD 10 1 0 1 1 0000 0 0000 0 0000 0 0000 EXNB 0 0 0 0 0 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 41 5692 99999 0000 0 0000 0 0000 SOLV 3 1 0 0 0 0000 0 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 ELST il 0 0 0 0 0000 0 0000 0 0000 0 0000 MMOD Creates and updates an intermediate structure file so that structures can be displayed in
4. COPY Saves a copy of the current structure in internal reference arrays for later use BGIN END Loop over the remaining structures in the file ALGN Aligns each structure with the reference structure by the center of mass and moments of inertia arg1 3 arg2 1 All four equivalent alignment are generated arg3 5 18 6 autoref Restrained Minimizations A script is available for performing restrained minimizations The primary application is for the minimization of protein ligand structures just after hydrogen atoms have been added In this procedure the heavy atoms in the system are restrained using a harmonic potential while the hydrogen atoms do not have restraining potentials applied Before you use autoref you must convert the structure file from Maestro format mae to MacroModel format dat using the structure conversion utility maemmod as shown below SSCHRODINGER utilities maemmod basename mae basename dat The syntax of the autoref command is as follows SSCHRODINGER utilities autoref options basename dat The output file is named basename_ref dat The command options are as follows k Keep output structure files from intermediate stages 1 rmsd Specify maximum RMS deviation from the initial structure default is 0 3 m Use the MMFFs force field instead of the default OPLS_2005 0 Use the OPLS_2001 force field instead of the default OPLS_2005 y Print version number and exit MacroModel 9 6 U
5. 0 0 Maximum allowed value degrees 180 0 Define torsions to check FF Pick Atoms s E Show markers Delete Delete All Close Help Figure 9 8 The Torsion Check panel MacroModel 9 6 User Manual Chapter 9 Conformational Searches Torsion checks can be added by picking atoms in the Workspace To define a torsion for checking choose either Atom or Bond from the Pick menu then pick four atoms or three bonds in the Workspace A new entry is added to the list at the top of the Torsion Check panel and the torsion check is marked with a solid red line and a check mark The currently selected torsion check is marked by solid lines on either side of the red line For each torsion check the minimum and maximum torsional angle must be defined Any search structures in which the checked torsional angle is not between the minimum and maximum angle is rejected and not included in search results 9 2 5 8 Ligand Bonds Conformational searches of inorganic complexes produce structures in which ligand positions vary with respect to the metal center Maestro permits the specific definition of the ligand bonds around which the reorientation takes place To use this feature choose Atom or Bond from the Pick menu and click on the desired bonds or atom pairs that define these bonds in the Workspace A new entry appears in the list at the top of the panel and Maestro marks the bond with a purple dotted line and a scissor
6. 14 2 Conformational Searches With eMBrAcE eMBrAcE can perform conformational searches in addition to minimizations Energy differ ence mode is the only mode supported for conformational searches with eMBrAcE Searches are conducted on the receptor each ligand and each ligand receptor complex The energies used in the energy difference equation AE E E complex receptor ca a for the receptor and the ligand are the values from the lowest energy conformations found for those systems However multiple complex conformations may be retained and a separate E plex 18 used in the energy difference equation for each one MCOP arg6 specifies the number of such conformations to keep MacroModel 9 6 User Manual 123 Chapter 14 eMBrAcE 124 _ eMBrAcE Conformational Search IET Potential Substructure Mini eMBrAcE Csearch Method Torsional sampling MCMM Number of steps 100 Number of input conformations available to seed each search 1 Number of structures to save for each search 1 Energy window for saving structures 500 0 kJ mol Probability of a torsion rotation molecule translation 0 50 Minimum distance for low mode move 3 000 Maximum distance for low mode move 6 000 Eliminate redundant conformers using 4 Maximum atom deviation Cutoft 0 25 A o so A v RMSD Start Write Close Help Figure 14 2 The eMBrAcE Conformationa
7. or reverse standard deviation values and not the average As mentioned above only the total free energies are strictly meaningful the components are only estimates In addition to examining the final free energy summary it is useful to plot the progress of the perturbation There should be a continuous smooth change in free energy from window to window with no large jumps or sudden increases in the standard deviation If discontinuities are observed then the simulation should probably be run with more sampling per window and possibly more windows 15 3 Criteria for a Successful Simulation The answers to the following questions will help you perform successful simulations 1 Do the input structures have the same numbering with dummy atoms used for atoms which are present in one structure and not in another One useful way to check the input file is to set up a simple command file as follows MacroModel 9 6 User Manual Chapter 15 Free Energy Simulations fep diala mae fep diala out mae EXNB 0 0 0 0 0 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 0 0000 0 0000 0 0000 0 0000 FFLD 3 0 0 0 0 0000 0 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 FEIA 0 0 0 0 0 0000 0 0000 0 0000 0 0000 FEAV 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MINI a 0 1000 0 0 0000 0 0000 0 0000 0 0000 FEAV 0 0 0 0 1 0000 0 0000 0 0000 0 0000 MINI 1 0 1000 0 0 0000 0 0000 0 0000 0 0000 This command file performs a min
8. 0000 0000 D alanine dipeptide Figure 15 1 Numbering system for the alanine dipeptide 0000 0000 0000 0000 0000 0000 300 0000 0000 0000 0000 0000 0000 0000 300 0000 0 0000 300 0000 0 0000 0 0000 Ooo oa a G G MacroModel 9 6 User Manual SS O OG G oo So cco ee oS SS oa O amp 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 FEIA Reads the second structure the perturbation endpoint from the mae file and sets up 145 Chapter 15 Free Energy Simulations 146 MCNV Specifies that between 1 and 2 of the torsions specified by TORS commands will be varied at each MC step MCSD In this example we use mixed mode Monte Carlo Stochastic Dynamics to perform the simulation Because a successful FEP simulation requires a thorough sampling of the confor mation space at each window we strongly recommend using the mixed mode simulation method during free energy calculations TORS Defines the torsion angles used in the Monte Carlo part of the MCSD calculation In this case it is the and y angles of the dipeptide BGIN Free energy perturbation calculations are usually performed in a BGIN END loop which completes all the windows from A 0 to A 1 FEAV Generates the interactions corresponding to the value of A given in arg5 The interpreta tion of this command can lead to some confusion The first time it i
9. 2 4 3 Bond Dipole Cutoffs BDCO Since a system of atoms can be described as consisting of bond dipoles and atom centered delocalized formal charges the energetics of the charges can be considered as due to charge charge charge dipole and dipole dipole interactions This conceptualization is at the heart of the Bond Dipole Cutoff BDCO method By applying different cutoff distance criteria to these three different types of interactions based on how they scale with distance energetic accuracy is preserved while retaining the benefits of having a short non bonded pair list The implemen tation of BDCO does not involve any change in the functional form of a molecular mechanics force field Coulomb s law in its familiar form is preserved Rather the BDCO algorithm applies different successively shorter cutoff distances to charge charge charge dipole and dipole dipole interactions where the charges are delocalized formal charges and the dipoles are bond dipoles The resultant list of interactions is then used to generate charge products for pairs of atoms the charge product is defined as the numerator in Coulomb s law The charge product for a given pair of atoms is used directly in Coulomb s law to give the electrostatic energy and associated force for that pair 2 4 4 BDCO and Molecular Modeling The reason BDCO works is that although long cutoffs are used for charge dipole and charge charge interactions there are relatively few
10. In addition when working with enzymes you may want to examine how the structure of the loop changes as you change the sequence in the loop The MacroModel LOOP tool is a conformational search method for protein loops It generates a variety of structures that are both diverse and geometrically appropriate for the protein loop and minimizes the energy of these structures LOOP functions in much the same manner as MCMM and is used in conjunction with the MINI MCOP MSYM and LPOP opcodes LOOP is best used in conjunction with other methods like LLMOD to sample the loop structures more thoroughly For more information on LOOP see the MacroModel Reference Manual 13 1 Performing LOOP Calculations When performing a LOOP calculation you can indicate the loop sequence you want to examine in one of two ways e Indicate that you want to use the loop sequence is that in the original protein e Create an auxiliary filename 1sq file which lists the desired loop sequence 13 1 1 Input Restrictions For the current implementation of LOOP input must meet the following criteria e Only one loop can be examined at a time although successive calculations may focus on different loops e The protein loop and the residues it is immediately attached to must consist of amino acids containing the backbone atoms Np Ca Cp where Np and Cp are nitrogen and car bon atoms involved in peptide bonds MacroModel 9 6 User Manual 115 Chapter 13 Protein
11. torted sp systems MacroModel 9 6 User Manual Chapter 2 Basic Molecular Modeling Handling of conjugation MM2 uses specific V1 V3 torsional terms for various conju gated systems whereas MM2 uses an SCF Tr calculation in uncommon systems MM3 AIll force field equations are identical to those of authentic MM3 from Allinger 2 except for those differences listed above for MM2 AMBER AII force field equations are identical to those of authentic AMBER from Kollman The MacroModel default for hydrogen bonding uses Kollman s recent 6 12 Lennard Jones treatment 3 and an improved peptide backbone parameter set 4 OPLS All force field equations are identical to those of OPLS AMBER from Jorgensen 5 OPLS_2001 Also referred to as OPLSAA this force field developed by Professor W Jorgensen of Yale University is probably the best available for condensed phase simulations of peptides All force field equations are identical to those of authentic OPLSAA 6 Macro Model s implementation has been validated by comparison to BOSS OPLSAA calculations for a wide variety of organic systems Comparisons to ab initio calculations and experiment show that OPLS_2001 reproduces conformational energies well for systems for which it has been specifically parameterized Especially good results can be expected for proteins With the exception of improved charge van der Waals and torsion parameters for sulfur in thiols and thiol
12. 101 102 101 101 101 101 93 46 101 02 kJ mol MacroModel 9 6 User Manual 0 335E 01 LT 0 500E 01 Ave deg K 295 260 265 272 269 267 265 266 268 268 T 4 1 5 9 1 2 1 0 3 6 Ave H 300 kJ mol 39 77 kJ mol Chapter 15 Free Energy Simulations Acceptance Ratio for Mixed Mode Simulation 0 02744863 Average kinetic energy 43 55 kJ mol Av temperature Average total energy 57 47 kJ mol Std dev Tila Average potential energy lt H gt scaled to 300 0 deg K 95 Av stretch 12 Av bend 15 Av torsion 253 Av van der Waals Lay Av electrostatic 162 Av solvation 1 0 Av solvation 2 0 BatchMin V8 5 Stochastic Dynamics Simulation MC SD Mixed Mode Free energy perturbation calculation Averaged interaction array lambda 0 400000 FEP Window 9 Time Total E 13 92 72 59 90 57 70 00 00 268 6 deg K kJ mol kJ mol kJ mol kJ mol kJ mol kJ mol kJ mol kJ mol kJ mol 0 5ps T Average T lt G gt 0 35 0 40 lt G gt 0 45 0 40 ps kJ mol deg K deg K kJ mol kJ mol 10 000 35 5 306 2 284 0 1 11 0 89 20 001 46 5 294 7 304 7 1 16 0 98 30 000 19 9 292 4 302 6 1 04 0 82 40 000 24 2 366 7 301 7 0 98 0 77 50 001 57 1 282 4 300 0 0 95 0 72 60 000 24 3 317 0 299 3 0 94 0 70 70 001 24 6 265 0 302 7 0 96 0 72 80 001 31 0 310 1 301 0 0 94 0 71 90 002 31 1 287 6 300 3 0 95 0 71 100 001 59 1 277 9 298 9 0 97 0 74 Fin
13. 69 Chapter 8 Coordinate Scans 70 Decimal places Specify the number of decimal places to be displayed for the values on the x and y axes PostScript Opens the 1D Plot PostScript panel or 2D Plot PostScript panel which allow you to save a Post Script image of the plot area When you have entered the file name and selected a paper size and orientation click Write to write the file 8 3 2 The 1D Plot Panel After a scan calculation with a single geometric parameter has been successfully completed the resulting grd file can be displayed graphically using this panel To open a grd file click the Open button navigate to the file select it and click Open The data from the grd file is displayed in the plot area The corresponding structures are read into Maestro as a scratch entry and one of the structures is displayed in the Workspace The appearance of a displayed plot can be changed using the controls on the left side of the panel and the controls in the 1D Data panel which is opened using the Data Sets button e The ranges of the axes can be changed by entering values in the Minimum Coordinate Maximum Coordinate Minimum Energy and Maximum Energy text boxes e The symbol shape and color and the curve style color and width are all controlled from the 1D Data panel To change these attributes select the data set in the list at the top of the panel then choose the attributes from the option menus
14. 7 Redundant Conformer Elimination 0 Xx Use structures from File m File name Browse Comparison atoms atleast 3 must be defined 12 Delete Delete All Heavy Atoms O H S H Heavy Atoms Eliminate redundant conformers using 4 Maximum atom deviation Cutoff 0 50 A v RMSD Culot 0 50 A _ Compare structures in place no superposition W Retain mirror image conformations Source of energy OPLS_2005 s Energy window for saving structures 21 00 kJ mol 5 02 kcal mol Start Write Close Help Figure 17 1 The Redundant Conformer Elimination panel MacroModel 9 6 User Manual Chapter 17 Redundant Conformer Elimination Compare structures in place no superposition If you select this option the conformers are not superimposed translated and rotated to obtain the closest alignment of atoms in the process of comparing the structures but the comparison is made with the structures in their given locations By default the structures are superim posed This option could be used for example for Glide poses where the position of the ligands with respect to the receptor is important Retain mirror image conformations By default both a structure and its mirror image are considered when comparing with the other structures If one of the two matches the structure is eliminated To ensure that both the struc ture and its mirror image are kept select th
15. AMBER urraca casados 6 compatible H treatment snl AMBER OA icons cita R 6 angles COOrdinate SCAN oe saisi ete te ete eeeeeeeeee 67 monitored in dynamics calculations 100 arguments opcode cooooocccoconoconocananonancnoninncnnnonno 21 ASL use in substructure files onnnon 31 atom positions CONSTA E csi tae 31 fixing and freezing 27 atom sets interaction energies between 167 automatic setup in CSearch calculations 0 0 0 ieee 78 in MC SD calculations eee eee 107 B bond dipole cutoffs BDCO ceeeeee 10 12 Cc charges using from structure files 27 chiral atoms selecting for CSearch o 86 command leen 19 embedded in shell script o ooooncnionc nic 22 Mita ia 20 command file examples alignment of structures s s s 170 ASE T vecina andadas 167 coordinate scans 107 CSearch 00 s 90 current energy ce 40 dynamics ni n nai 104 CMBLACE is sscssnsencestsverstevicntercsendsseoteovesstsees 128 eMBrAcE conformational search 134 eMBrAcE distributed oononnnccccnnnnnccns 141 free energy perturbation eee 145 geometry calculations 0 cere 167 LOOP eiras AaS 117 MC SD calculations eects 109 Oo A toes 48 MINTA ciencias reaa 113 multiple minimization eee 59 partition coefficient estimation 0 62 redundant conformer elimination 166 rewinding output f
16. Chapter 9 Conformational Searches 9 4 Checking and Interpreting Results Like other methods that involve minimizations it is important to check that all of the minimi zations for the conformers generated are converged If some of the results are not converged they can be minimized further using multiple minimization see Chapter 7 for details You can also use Jaguar for further refinement of the conformers After you have optimized the structures with Jaguar you should perform a redundant conformer elimination using the Jaguar energy as the source of energy because some conformers that are considered separate by MacroModel might optimize to the same minimum in Jaguar See Chapter 4 of the Jaguar User Manual for more information on Jaguar optimizations and Chapter 17 of this manual for information on redundant conformer elimination A procedure for a combined MacroModel Jaguar conformational search is described in Section 6 6 of the Jaguar User Manual Often conformational searches yield large numbers of conformers Clustering the conformers into families of similar structures can lead to useful insights XCluster is an excellent tool for performing clustering analysis on collections of conformers obtained from conformational searches See Chapter 16 and the MacroModel XCluster Manual for more information MacroModel 9 6 User Manual 95 96 MacroModel 9 6 User Manual Chapter 10 Dynamics Calculations Molecular dynamics sim
17. If no file is entered the structural input is taken from the source indicated by the Use structures from menu choice at the top of the panel There are three choices of minimization mode Minimization of non conformers Minimization of conformers and LogP estimation If you choose the first of these the setup is complete and you can proceed to write the job files or start the job Estimation of partition coefficients is described in the next section The remaining controls in this tab are for the second choice Mini mization of conformers and are described below 7 Multiple Minimization ETE Use structures from Workspace included entries Potential Constraints Substructure Mini Mutt Input file Browse Minimization mode wv Minimization of non conformers 4 Minimization of conformers Comparison Atoms defined Eliminate redundant conformers using 4 Maximum atom deviation Cutoft 0 50 A y RMSD Cutoft 0 50 A E Retain mirror image conformations Energy window for saving structures 21 0 kJ mol 5 02 kcal mol Maximum number of structures to save 100 wv LogP estimation Start Write Close Help Figure 7 1 The Mult tab of the Multiple Minimization panel MacroModel 9 6 User Manual Chapter 7 Multiple Minimizations _ Comparison Atoms 24 AY 27 Heavy Atoms O H 5 H Heavy Atoms Define comparison atoms W
18. L Yuh Y H Lii J H Molecular Mechanics The MM3 Force Field for Hydrocarbons J Am Chem Soc 1989 111 8551 Ferguson D M Kollman P A Can the Lennard Jones 6 12 function replace the 10 12 form in molecular mechanics calculations J Comput Chem 1991 12 620 McDonald D Q Still W C AMBER torsional parameters for the peptide backbone Tetrahedron Lett 1992 33 7743 Jorgensen W L Tirado Rives J The OPLS Potential Functions for Proteins Energy Minimization for Crystals of Cyclic Peptides and Crambin J Am Chem Soc 1988 110 1657 Jorgensen W L Maxwell D S Tirado Rives J Development and Testing of the OPLS All Atom Force Field on Conformational Energetics and Properties of Organic Liquids J Am Chem Soc 1996 118 11225 11235 Kaminski G A Friesner R A Tirado Rives J Jorgensen W L Evaluation and Reparametrization of the OPLS AA Force Field for Proteins via Comparison with Accurate Quantum Chemical Calculations on Peptides J Phys Chem B 2001 105 6474 6487 Cornell W D Cieplak P Bayly C I Gould I R Merz K M Ferguson D M Spellmeyer D C Fox T Caldwell J W Kollman P A A second generation force field for the simulation of proteins nucleic acids and organic molecules J Am Chem Soc 1995 117 5179 Halgren T A Merck Molecular Force Field I Basis Form Scope Parameterization and Performance of MMFF94 J Comput Chem 1996 17
19. Maestro the graphical user interface GUI for MacroModel see the Maestro online help the Maestro Overview or the Maestro User Manual Chapter 1 provides a brief introduction to MacroModel and describes how it interacts with Maestro A good general background to force field based molecular modeling particularly as it is implemented in MacroModel is given in Chapter 2 Running MacroModel from the command line without Maestro is described in Chapter 3 Chapters 4 17 provide more infor mation on how to run particular classes of calculations Chapter 18 describes additional features geometry queries and interaction energy calculations Information on how to get addi tional help for performing MacroModel calculations is given at the back of this manual 1 2 MacroModel MacroModel is a general purpose force field based molecular modeling program with appli cability to a wide range of chemical systems MacroModel provides researchers with multiple advanced methods to aid the understanding of chemical structure energetics and dynamics A large selection of force fields is available in MacroModel including the latest technical advances introduced into OPLS_2005 a force field that Schr dinger is actively developing Numerous minimization methods are available enabling geometry optimizations for a broad selection of structural classes A wide range of methods is available for conformational searching allowing efficient sampling of the potentia
20. READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 AUTO 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MINI 1 0 2000 0 0 0000 0 0000 0 0000 0 0000 MCMM 50 0 0 0 0 0000 0 0000 0 0000 0 0000 AUTO 0 0 0 0 0 0000 1 0000 0 0000 0 0000 BGIN 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MCOP 1 0 10000 0 0 0000 2 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MINI 1 0 2000 0 0 0000 0 0000 0 0000 0 0000 END 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MBAE I 0 0 0 0 0000 0 0000 0 0000 0 0000 FFLD Use OPLS_2001 with constant dielectric electrostatics which is appropriate if GB SA solvation is being used SOLV The GB SA effective water model is being used EXNB Extended non bonded cut offs should be used with GB SA solvation BDCO Use the Bond Dipole CutOff BDCO method for truncating electrostatic interactions Arg5 and arg6 specify the cutoffs used for charge dipole and charge charge interactions respectively MSYM Invokes the numbering symmetry library mmsym which automatically and more gener ally identifies a suitable numbering order for using in comparing conformations MBAE Turn on eMBrAcE argl 1 Using Energy Difference mode arg2 1 Conformation searches will be performed in eMBrAcE calculations arg3 0 The lowest energy structures of the ligand receptor complex are written to the output structure file MCMM Use Monte Carlo Multiple Minimum searching Arg1 defines the number of steps to use for the search of the receptor MCNV
21. Thus only a proper receptor substructure needs to be indi cated to prepare the appropriate MCMM parameters Examples can be found in Section 14 3 on page 127 In addition only the substructure facility can be used to indicate fixed or frozen atoms in an eMBrAcE calculation and ligand atoms cannot be fixed or frozen Other than by adjusting the substructure it is not possible to adjust the AUTO parameters for individual complexes in an eMBrAcE automated calculation Conformational searches on protein ligand complexes are computationally intensive and the use of substructures is strongly recommended to reduce the CPU time and memory required Even with fairly small substructures and very short searches such searches require hours or days for each ligand processed To perform an eMBrAcE conformational search first configure the general job settings in the upper portion of the eMBrAcE Minimization panel and the Potential and Substructure tabs Then configure the eMBrAcE settings in the eMBrAcE tab and the conformational search settings in the CSearch tab which are described below Method There are only three methods available for performing an eMBrAcE conformational search Torsional sampling MCMM Low mode sampling and Mixed torsional Low mode sampling Large scale low mode LMC2 searches are not supported at this time Low mode calculations are limited to a few hundred atoms and should be used for systems with smaller ligand substructu
22. cc ccceseesseseeeeeeeeeseeeeseeeenseeseeeaeseeteeseeneeeets 143 15 2 Setting Up FEP Calculations ccccceeeeeeceeeeeseeeceeeaeeesaesaseeeeetaeeaeees 144 15 21 The StU HAs TRING zaio E E E E IEA 144 15 22 The Command PIS ox ascatinnsgamstdansida edda lts 145 15 2 3 Other Possible Command Files ics ooo didas 147 15 2 4 The Output File sisi 148 MacroModel 9 6 User Manual Contents 15 3 Criteria for a Successful Simulation 0 0 000 eee eee trees 150 15 4 Other Types of Free Energy Calculations 0 0 ccccceeeeeeeeseeeeeeeeeeeees 152 15 4 1 Hydrogen Bonding Preference of a Glycyl Lactam in Organic Solution 152 15 4 2 Conformational Free Energies for a Diamide in Solution 00 ee 153 A cs scelizers lence cadence tagsiadesec asa odes SEa a E eet laa kali 154 Chapter 16 Molecular Clustering with XClusSter cccccccccimmmanss 157 16 1 The XCluster Panel iii iaa 157 16 1 1 Selecting the Structure SOUCO viviana 157 16 1 2 Selecting the Clustering Criterion o oonncnnnnncnnnnnncnoncnncnnarnnnrn nara rnrnrnrnrnnnnn 158 16 1 3 Defining the Comparison Atoms Or TOrSiONS oooonocccincnncnnncnnonnnarananncancnannnn 159 16 2 Command File Examples asnriinsaniu nner 160 16 3 XClUSter QUU iia lied pli mes R al 161 Chapter 17 Redundant Conformer Elimination 163 17 1 Eliminating Redundant Conformers Using Maestro ccceeeeees 163 17 2 Command File Examples 0 cccceccceeee
23. 0 0 0 0000 0 0000 0 0000 0 0000 MCOP 1 0 0 0 0 0000 0 0000 0 0000 0 0000 CONV 2 1 0 0 0 0000 0 0000 0 0000 0 0000 MINI 9 0 2000 0 0 0000 0 0000 0 0000 0 0000 SOLV The GB SA effective water model is being used FFLD This example uses OPLS_2001 with constant dielectric electrostatics which is appro priate if GB SA solvation is being used EXNB Extended non bonded cut offs should be used with GB SA solvation SUBS Read in a substructure from an sbc file Currently best results are obtained if all the non loop atoms in the system are frozen A shell containing complete residues for all atoms within 6 A is usually sufficient MacroModel 9 6 User Manual 117 Chapter 13 Protein Loop Construction 118 READ Read in the protein structure LOOP Turn on LOOP argl N terminus atom number for the loop This is the atom number for the peptide Nitrogen atom that joins the loop to the protein at the N terminus of the loop Atom 423 for this example arg2 C terminus atom number for the loop This is the atom number for the peptide Car bon atom that joins the loop to the protein at the C terminus of the loop Atom 467 for this example arg3 0 Use the sequence for the loop from the protein structure supplied arg4 4 Generate four candidate loop structures Typically you would want to generate many more than this arg5 0 0 Save up to the default number of structures 10 000 arg6 0 26 If a given pair of
24. 0 0000 0 0000 CRMS 0 0 0 0 0 0000 0 2400 0 0000 0 0000 DEMX 0 0 0 0 51 0000 0 0000 0 0000 0 0000 BGIN 0 0 0 0 0 0000 0 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 CONV 2 0 0 0 0 0100 0 0000 0 0000 0 0000 MSYM 0 0 0 0 0 0000 0 0000 0 0000 0 0000 COMP 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MINI 1 0 5000 0 0 0000 0 0000 0 0000 0 0000 END 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MacroModel 9 6 User Manual 61 Chapter 7 Multiple Minimizations 62 COMP Argl1 0 specifies that all heavy atoms are to be used as the comparison atoms when redundant conformer elimination is performed 7 6 3 Multiple Minimization with Substructures Defined by ASL The following example illustrates the use of ASL in a multiple minimization calculation that constrains heavy atoms of the molecules The file asl_test mae file consists of two mole cules cyclopentane and cyclohexane asl_test mae asl_test out mae FFLD 14 1 0 0 1 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 41 5692 99999 0000 0 0000 0 0000 BGIN 0 0 0 0 0 0000 0 0000 0 0000 0 0000 SUBS 0 0 0 0 0 0000 0 0000 0 0000 0 0000 READ 1 0 0 0 0 0000 0 0000 0 0000 0 0000 CRMS 0 0 0 0 0 0000 0 2500 0 0000 0 0000 CONV 2 0 0 0 0 0500 0 0000 0 0000 0 0000 MINI Hl 0 500 0 0 0000 0 0000 0 0000 0 0000 END 0 0 0 0 0 0000 0 0000 0 0000 0 0000 READ Arg is set to 1 to clear all molecular information for the previously read molecules The substructure file used for this example is as follows AS
25. 0000 0000 0000 0000 0000 0000 0000 0000 0000 Using the distributed MacroModel procedure to perform a free energy calculation For more information about distributed MacroModel see Section 3 3 on page 23 The NPRC command can be used to distribute the free energy calculation over a number of hosts in a manner similar to that described for Monte Carlo conformational searching In this case the smallest job that can be distributed on any host is one complete FEP window so the opportuni ties for load balancing are limited 15 2 4 The Output File Similar output for each window of the perturbation will be obtained in the 1log file The output obtained when the command file described above was run appears below This output is for the value of A middle 0 4 FEP averaged force field lambda Loading FEP coordinates 1 Starting conjugate gradient minimization Minimization converged gradient Iterations Conf 1 E BatchMin V8 5 Time ps 000 3004 UNA b 000 001 000 001 001 000 001 001 000 000 120 138 502 out of 1000 0 034 0 400000 kJ mol Stochastic Dynamics Simulation MC SD Mixed Mode Total kJ mol E 8 2 2 25 70 4 9 8 0 4 3 0 5ps T deg K 297 1 172 3 263 5 308 8 ei 6 7 4 2 5 252 272 276 271 266 261 Final potential and kinetic energy CPU Time Average potential energy 1 2 sec Ave kJ mol 103 102 101
26. 1 but an increment of 10 is usually sufficient 5 Optional Repeat the picking operations to define a second coordinate MacroModel 9 6 User Manual Chapter 8 Coordinate Scans To change the initial and final values and the increment for the scan calculation select a coor dinate entry from the list at the top of the tab then enter values in the Initial Final and Incre ment text boxes To delete a defined coordinate select it in the list of coordinates and click Delete To delete all defined coordinates click Delete All 8 2 Command File Examples To run MacroModel calculations a molecular structure file and a command file are required The molecular structure file contains the structures to be used as input in the calculation The command file contains the name of the input structure file the name of the output structure file and an ordered list of operation codes opcodes for the calculations Once you set up a job in Maestro and click either Start or Write Maestro writes out a molecular structure file and a command file For many types of jobs command files written this way are complete and adequate but for some types of jobs you may need to adjust the Maestro gener ated command file The command files and the log files for the examples given in this section can be found in SCHRODINGER macromodel vversion samples Examples Below is an example command file for a dihedral scan calculation and explanat
27. 445 466 470 0 0000 0 0000 0 0000 0 0000 COMP 473 476 482 487 0 0000 0 0000 0 0000 0 0000 COMP 1291 1296 1299 1303 0 0000 0 0000 0 0000 0 0000 COMP 1307 1309 1313 1318 0 0000 0 0000 0 0000 0 0000 COMP 1326 1362 1366 1370 0 0000 0 0000 0 0000 0 0000 COMP 1372 2105 2109 2115 0 0000 0 0000 0 0000 0 0000 COMP 2120 2155 2159 2164 0 0000 0 0000 0 0000 0 0000 COMP 2172 2323 2327 2331 0 0000 0 0000 0 0000 0 0000 MacroModel 9 6 User Manual 93 Chapter 9 Conformational Searches 94 COMP 2333 4599 4600 4601 0 0000 0 0000 0 0000 0 0000 COMP 4602 4603 4604 4605 0 0000 0 0000 0 0000 0 0000 COMP 4606 4607 4608 4609 0 0000 0 0000 0 0000 0 0000 COMP 4610 4611 4612 4613 0 0000 0 0000 0 0000 0 0000 COMP 4614 4615 4616 0 0 0000 0 0000 0 0000 0 0000 MSYM 0 0 0 0 0 0000 0 0000 0 0000 0 0000 CHIG L17 119 165 167 0 0000 0 0000 0 0000 0 0000 CHIG 223 439 468 1291 0 0000 0 0000 0 0000 0 0000 CHIG 1311 1364 2107 2157 0 0000 0 0000 0 0000 0 0000 CHIG 2325 0 0 0 0 0000 0 0000 0 0000 0 0000 TORS 4600 4610 0 0 0 0000 180 0000 0 0000 0 0000 TORS 4604 4605 0 0 0 0000 180 0000 0 0000 0 0000 TORS 4605 4606 0 0 0 0000 180 0000 0 0000 0 0000 TORS 4606 4611 0 0 0 0000 180 0000 0 0000 0 0000 MOLS 4633 0 0 0 0 0000 180 0000 0 0000 1 0000 TORC 135 134 132 133 90 0000 180 0000 0 0000 0 0000 TORC 164 163 161 162 90 0000 180 0000 0 0000 0 0000 TORC 1310 1309 1307 1308 90 0000 180 0000 0 0000 0 0000 TORC 2118 2117 2115 2116 90 0000 180 0000 0 0000 0 0000 CO
28. Applications menu in the main menu bar The controls in the MINTA tab are described below Input File Use the first part of the panel to enter the name of the input file This must be a Maestro formatted file that contains one or more valid conformations These structures are usually the results of a previous conformational search The Open button opens a file selector for locating the desired input file If no file is entered the structural input is taken from the source indicated under Use structures from Number of MINTA iterations The MINTA numerical integrals are calculated in statistical blocks to achieve better conver gence The number of blocks used is referred to as the number of MINTA iterations The default value is 5 and the minimum value is 1 MacroModel 9 6 User Manual 111 Chapter 12 Minta Calculations Use structures from Project Table selected entries Potential Substructure Mini MINTA Input file Browse Number of MINTA iterations 5 Number of energy evaluations per MINTA iteration 2000 Temperature K 300 0 Hard limit for sampling along normal modes ji o Soft limit for sampling along normal modes st dev 3 Start Write Close Help Figure 12 1 The MINTA tab of the MINTA panel Number of energy evaluations per MINTA iteration MINTA integration is based on single point energy evaluations The default number of energy
29. At the same time atom number 9 which begins as a united atom methyl in the starting structure is extinguished to a dummy atom in the structure at the end of the simulation Numbering of the structures must be checked very carefully before a free energy simulation is attempted MacroModel 9 6 User Manual Chapter 15 Free Energy Simulations 15 2 2 The Command File The command file used to perform the perturbation of the L to the D form is shown below fep mae L alanine dipeptide fep out mae EXNB BDCO FFLD READ FEIA MCNV MCSD TORS TORS BGIN FEAV MINI MDIT MDYN FESA MDYN END FESU EXNB Extended non bonded cutoffs should be used in free energy calculations FFLD This example used the AMBER force field with the default distance dependent dielec tric treatment for electrostatics We also recommend the use of the GB SA solvation model in a real application oo0Oo0O0O0Oo0oPOOQqUurPpPROOoONyOoOO o0o0O0O0O00O000o0 _73J0A4NNyNOOOOO 100 oo AS A SAO AA O O O A O ES O0OoO0O0O0OOOOOoOoOoOoOoOoOoOo oOoOoOo Oo Ww O OO So CO OC 6 o Ww o o O O 0 Aa the arrays for averaging of the interactions 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 5000 0000 5000 0000 0000 READ Required to read the first structure in the mae file 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0500 0000
30. Basic Molecular Modeling 2 3 MacroModel Solvation Treatment While many molecular modeling studies are carried out without including the effect of solvent the omission is largely one of expedience Most experimental studies are carried out in solvent and the solvent medium can have a major effect on molecular structures and energies For some molecular types such as a small organic molecule with only one polar functional group solvation does not appear to be a major determinant of conformational energies However for molecules having several polar functional groups the effect of solvent can be dramatic since the electrostatically least stable structures are often the most heavily solvated stabilized in a polar solvent Using an explicit solvent model is one approach however it has its own disadvantages In particular explicit solvation calculations run much more slowly because there are so many particles when hundreds of explicit solvent molecules are included Furthermore convergence is a problem in that longer simulations or different solvent starting configurations often give different final energies Consequently simple energy minimization is not useful in an explicit solvent MacroModel uses an alternative solution model which treats the solvent as a fully equilibrated analytical continuum starting near the van der Waals surface of the solute The model is termed the GB SA model and is described in the literature 16 Macro
31. Conjugate Gradient This is a conjugate gradient minimization scheme that uses the Polak Ribiere first deriva tive method with restarts every 3N iterations 17 This is the best general method for energy minimization but it should not be used to find transition states e TNCG Truncated Newton Conjugate Gradient TNCG uses second derivatives and line searching and is highly efficient for producing very low gradient structures It generally converges in one tenth the number of iterations necessary for a PRCG but each iteration takes more time Often FMNR re minimization of TNCG structures gives the lowest final gradients 18 MacroModel 9 6 User Manual Chapter 6 Minimizations e OSVM Oren Spedicato Variable Metric This is a variable metric minimization that uses the Oren Spedicato modification 19 of the Fletcher Powell quasi Newton method Convergence to saddle points is possible Typical convergence occurs in 3N 6N iterations but note that iteration speed is rela tively slow OSVM is not recommended for structures with poor starting geometries e SD Steepest Descent This is a steepest descent minimization method The SD should not be used to find sad dle points and convergence is poor towards the end of minimization This is a good method for starting geometries that are far from the minimum but switching to another method is recommended when derivatives fall below 10 kJ mol or so It is generally not opt
32. D 01 D 03 D 02 D 01 D 02 D 00 D 03 Energetic Interactions Between Atom Sets Atom sets 1 and 2 1999662 1473 506894 30 an OF H e O H on FF Ae mOwoworF oon o bh oy o oo 121 hb Elect Hbnd vdW Part of nonbonded Part of nonbonded Elect Hbnd vdW with no of interactions Use these for eMBrAcE interaction energies for ligand 4erk Total Energy kJ mol Stretch Proper Torsion Out of Plane Electrostatic Van der Waals Solvation GB Non bonded 0 0 0 0 0 0 0 0 2295194 0000000 0000000 0000000 9417975 1651001 2976043 2592798 14 4 1 2 Energy Difference Mode D 03 D 00 D 00 D 00 D 02 D 03 D 02 D 03 212457 0 0 0 65023 9236 138198 74259 Part of nonbonded Part of nonbonded Elect Hbnd vdW Energy difference mode first applies the type of calculation selected currently only minimiza tion is supported to the receptor by itself For each ligand in turn it then applies the calcula tion to the ligand by itself and the complex of the ligand with the receptor and reports the energy difference Below is an example command file for an eMBrAcE job run in energy difference mode A description of the opcodes used in the file follows MBAE_eDiff mae MBAE_eDiff out mae SOLV 3 FFLD EXNB BDCO MBAE SUBS READ MI
33. Help Figure 4 3 The Substructure tab MacroModel 9 6 User Manual Chapter 4 General Settings To ensure that the substructure consists of only complete residues select Complete residues The defined substructures then include all the atoms in the residues to which the defined atoms belong Interactions between constrained atoms both fixed and frozen are normally not calculated which saves time but excludes these interactions from the final energy You can include these interactions in the calculation by selecting Calculate constrained atom mutual interactions 4 5 2 Creating a Shell of Atoms Defined substructures indicate which atoms may freely move during the energy calculations Often subsequent sets of atoms surrounding the substructure are intended to be fixed and or frozen during the computation This is accomplished by defining shells around the substructure in the Shells constrained and frozen atoms portion of the Substructure tab To create a shell around a defined substructure click New in the Substructure tab of the relevant MacroModel panel under the Shells list If Show markers is selected the shell atoms are indicated in the Workspace by colored markers orange purple yellow green and so on Once you have created one or more shells you can define and modify their contents in the following ways by selecting a shell from the Shells list and using the controls in the Selecte
34. LEM POLAT seriinin aiene 102 MA E 103 Dynamics panel Dynamics tab iii did E ECalc tab ninas 39 electrostatic interaction truncation 10 electrostatic treatments 16 eMBrAcE calculations ooonnciccncnnccnonccnccncnncn 121 association energy mode 123 command file examples 0 0 0 128 A 122 sample OUtpUt ooocnicnicnnnnnoninnnninninncninacinos 130 enantiomers comparison of in XCluster 159 entry for receptor in CMBrACcE eee 122 environment variables SCHRODINGER peores ice repens SCHRODINGER_TMPDIR MacroModel 9 6 User Manual equilibration time eee eeeeeeeeeeeeeeeeeees 103 F FEP calculations cccccccssscesseceeseeessseeeeees 143 hints for SUCCESS ooooccocccconnnononccoonnconnnnonnnos 150 literature references fOT cccococonccccocncincnnoos 154 preparing 144 sample output 148 structure file 144 file conversion coooccnocccononcnoncconnnaconnnccanacconancnnns 16 files LOWLY PO italia force field A S EA EEES FMNR minimization method force feldgrau ea E ES 5 A R EAN 5 SEIS CUT naaa ie 26 free energy perturbation calculations see FEP calculations H H bonds monitored in dynamics calculations 100 hydrogen treatment cee eeeeeeeeeneeeeeeeeeeeees 17 l interaction energies using ASET ooonniciinnninnns 167 iteration limit minimization calculations 48 J job submission command iN
35. Maestro as the job progresses FFLD Force field selection Arg denotes the actual force field used in the calculation in this case MMFF94 Arg2 defines the electrostatic treatment for the calculation Default arg 0 is to use the dielectric treatment encoded in the force field however in this case a constant dielectric is used due to the use of solvation model 3 see SOLV below Arg4 is MMFF94 specific Arg4 1 defines the MMFF94s version of the force field which ensures planarity around delocalized sp2 nitrogens EXNB Extended non bonded interaction cut off This is set by default when solvation is used in a calculation The default values for extended cut off are 8 A vdW arg5 20 A charge charge electrostatic arg6 4 A hydrogen bonding arg7 BDCO Use the Bond Dipole CutOff BDCO method for truncating electrostatic interactions Arg5 and arg6 are used to specify the cutoffs used for charge dipole and charge charge interac tions respectively SOLV Specify the implicit solvation treatment to be used in the calculation Arg defines the type of solvation model to be used Argl 3 means that the GB SA solvation model will be used Arg2 defines what type of solvent is used Arg2 1 selects water as the solvent READ Directs MacroModel to read the input file ELST Calculates the single point energy of the input structure s Argl determines the extent of output listing and to which files the output will be written Argl 1 gives
36. Manual Chapter 9 Conformational Searches e Intermediate Sample the torsions of amide or ester linkages of non standard groups like anhydrides carbamates hydrazones and so on Normal ester and amide linkages are not sampled nor are azo and imido linkages Sets AUTO arg8 1 e Enhanced Sample all amide like and ester like linkages including standard amides and esters Azo and imido linkages are not sampled Sets AUTO arg8 2 e Extended Sample rotations around C N and N N bonds in addition to all amide and ester derivatives Sets AUTO arg8 3 9 2 3 Global Search Restrictions In the Customize the search section you can set restrictions on the scope of the search and its output In addition you can specify the criterion for equivalent structures in the lower portion of the panel Retain mirror image conformations By default the search algorithm compares each trial structure and its mirror image with the list of unique structures to determine if the trial structure is unique If you select this option mirror images are considered to be separate structures and both structures are retained Maximum number of steps For each search method specify the number of steps to be performed in the Maximum number of Steps text box When the number of generated trial structures matches the value in field the conformational search is terminated Use N steps per rotatable bond Use this text box to specify the number of unique
37. across 89 MAKETS 250s bets soevestssess aa A 81 Number of StEPS cccisceseroeisssssdessseseoseseoeee 79 number of steps per rotatable bond 79 resetting variables 78 81 torsion Check inicias 88 translations and rotations eee 84 variables ovni ida a il 77 CSearch methods AAA hice AN 73 MCMM esti iia ait feta 73 MCMMILMCS ennccconnonncnnononannonanannnonannennonan 74 SAn a tAE E E 75 MacroModel 9 6 User Manual 183 Index 184 SSPMG imita T current energy calculations cece 39 Current Energy panel cece eeeeeteeeteeees 39 D dielectric constant modifying eee 27 directory installation Maestro working distances atomic RMS for XCluster ee 159 checked in CSearch constraining COOLdinate SCAN c ss scesscssseccenssecescentenavassaeser monitored in dynamics calculations 99 distributed calculations oooooccncoccconaccnonnns 23 36 dynamics calculations eee eeeeeeeeeeeeees 97 command file examples 0 0 0 0 cee 104 equilibration time eee eeeeeeeeeee 103 Method usina ias 102 monitored angles oooocnioninnonnnnnnnnnncncnnnno 100 monitored dihedralS oooocononcincnc iom 100 Monitored distances eseseseeseeeeeeeeeeees 99 monitored H bonds c eeceeseeeeseereeeees 100 monitored surface areas 99 SHAKE acond 102 Simulation time 0 0 eeeeeeeeeeeeeeeeeeeeeeeeeeee 103
38. an AGN ATOMS ciales 17 2 11 2 Hydrogen Treatment in the AMBER Force Fi eld ooonnoncnnnnnnnnniccncnnnccnccnan 17 Chapter 3 Running MacroModel From the Command Line 19 3 1 Preparing for MacroModel Calculations oooococcnionnninnnnicinnnnicnoncccrnonnccnn 19 3 1 1 Environment Variable siii 19 3 1 2 The Command File unsisna a panas peana 19 3 1 3 The MacroModel Command File Format oooonccnnnnnnccnncnnncnnacncnnnonncononorncrnnnano 20 3 2 Submitting Jobs From the Command Line ooocconiccncniccninncicnnnncnccncanacaninnn 21 3 2 1 Using an Executable Command File tsississiscscsescdseisesscorsidsassviscosssteabesszeascanacsead 22 3 3 Running Remote and Distributed Calculations ooonoininninnininnnnnnicninnncno 23 3 4 Interacting With a Running MacroModel Job 24 Chapter 4 General Settings ccsssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssessssssssssess 25 4 1 General MacroModel Calculation Setup ooocoicninninininnicinnnnicnciccancicn 25 4 1 1 Specifying Job Input Source ooooonconncnnncnnncnnnnnncnnccnnrncarnnnrn raro rnncnarnrr cnn 25 4 2 The Pot ntial Tab voii n nn REA 26 4 3 Fixing and Freezing Atoms in Large SySteMS ooonicnioninicnnnnnicnnnncccnnoninacicnn 27 4 3 1 Methods for Freezing and Fixing Atoms oooonoconcnncconnnorncannononnnrncnanonrn ran noncnos 28 4 3 2 Freezing and Fixing Individual Atoms cc eeesseeeseseeeeareeeeesseeeeeeseees
39. an explanation of the controls in this tab see Section 6 1 on page 45 The Mult tab which includes access to the Comparison Atoms panel is unique to the Multiple Minimization panel and is described in the next section To open the Multiple Minimization panel choose Multiple Minimization from the MacroModel submenu of the Applications menu on the main menu bar 7 2 Setting Up Multiple Minimization Calculations In the Multiple Minimization panel set the options in the upper portion of the panel and in the Potential Constraints and Substructure tabs See Section 4 1 through Section 4 5 for a detailed discussion of these settings Then set the options in the Mini tab as described in Section 6 2 on page 45 With these portions of the job setup complete set the parameters of the multiple minimization calculation in the Mult tab MacroModel 9 6 User Manual 53 Chapter 7 Multiple Minimizations 54 If you want to use structures from a file rather than from the project you can use the Input file text box and associated Browse button to select a file Either enter the name of the input struc ture file in the text box or click Browse to display a file selector that can be used to browse the file system for the desired input file The file must be in either Maestro or MacroModel format and contain one or more valid structures Often these structures are the results from a previous conformational search which are to be reminimized
40. and how many structures are saved for the searches of the ligand receptor complexes argl 1 Print information for every search step to the log file arg3 10000 Use a large number here to avoid spurious lines in the eMBrAcE summary table at the end of the run arg6 2 0 Save only the two lowest energy conformations from the complexes for each ligand READ Sequentially read the ligand structures MINI Minimize the energy of each conformation generated in the search of each ligand and each ligand receptor complex using the PRCG minimization technique arg1 1 for up to arg3 2000 iterations END End the loop for the ligands MBAE Turn off eMBrAcE and summarize the results arg 1 14 4 2 2 Low Mode Conformational Search This example performs a low mode conformational search The input file is similar to that of the MCMM search example above A copy of this file is available at SSCHRODINGER macromodel vversion samples Examples MBAE_LMCS com The example is followed by descriptions of the opcodes Opcode descriptions that are omitted may be read from the corresponding opcodes in the MCMM conformational search example given above in Section 14 4 2 1 on page 134 SEARCH_LMCS mae SEARCH_LMCS out mae FFLD LY 1 0 0 1 0000 0 0000 0 0000 0 0000 SOLV 3 1 0 0 0 0000 0 0000 0 0000 0 0000 EXNB 0 0 0 0 0 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 89 4427 99999 0000 0 0000 0 0000 MSYM 0 0 0 0 0 0000 0 0000 0 0
41. at the top of the Torsion Rotations panel MacroModel 9 6 User Manual Chapter 9 Conformational Searches Torsion Rotations Minimum rotation 0 0 Maximum rotation 180 0 Define torsions to rotate Pick Atoms s E Show markers Delete Delete All Close Help Figure 9 3 The Torsion Rotations panel If Show markers is selected the bonds defined as torsion rotations are indicated in the Work space by a purple line and an icon a purple horizontal line encircled by an arrow The functions of the Torsion Rotations panel are described below Minimum rotation The minimum acceptable rotation of a torsion must be specified Each time that a torsion must be rotated an increment for rotation larger than this value is selected The default minimum rotation is 0 If a torsion rotation is added for a double or amide bond i e to search both E and Z isomers around these bonds the minimum value for rotations should be set to 90 This maximizes the probability that interconversion between the two isomers will occur Maximum rotation This text field allows you to specify a value for the maximum acceptable torsion rotation incre ment Each time that a torsion must be rotated an increment for rotation smaller than this value is selected The default maximum rotation is 180 Define torsions to rotate To define torsion rotations manually choose Atom or Bond from the Pick menu and
42. carried out The default value is 300 0 K MacroModel 9 6 User Manual Chapter 10 Dynamics Calculations Time step fs Determines the time step used in the integration of the equations of motion during the simula tion Smaller values lead to more accurate but computationally intensive simulations for a given amount of time simulated The default value is 1 5 fs Equilibration time ps Determines the length of the settling down period at the start of the simulation The equili bration period is needed to allow initial velocities to stabilize before any monitoring data or sampled structures are written to output files Simulation time ps The total time allowed for a given simulation The default is 10 ps However if you want converged results specify a much longer time even for small to medium sized systems Use structures from Project Table selected entry Potential Constraints Substructure Mini Monitor Dynamics Method Stochastic dynamics SHAKE Nothing Simulation temperature K 300 0 Time step fs 1 500 Equilibration time ps 1 0 Simulation time ps 10 0 Start Write Close Help Figure 10 6 The Dynamics tab of the Dynamics panel MacroModel 9 6 User Manual 103 Chapter 10 Dynamics Calculations 104 10 3 Command File Examples To run MacroModel calculations a molecular structure file and a command file are required T
43. evaluations per MINTA iteration is 2000 and the minimum value is 1 Temperature K The value entered in this text box sets the temperature for the MINTA calculations The default value is 300 K and the minimum value is O K Hard limit for sampling along normal modes A This value determines a distance to which sampling is limited from the equilibrium geometry of the structure along any of the normal mode directions in 3N 6 5 dimensional normal mode space where N is the number of atoms The default value is 1 0 A the minimum value is 0 0 A and the maximum value is 3 0 A MacroModel 9 6 User Manual Chapter 12 Minta Calculations Soft limit for sampling along normal modes st dev This value determines the units of standard deviation for sampling along normal modes Sampling is limited to different distances from the equilibrium geometry along different normal mode directions For a particular mode i sampling is limited to a particular distance equal to this value times the standard deviation of the multidimensional Gaussian function along the particular normal mode direction i 12 2 Command File Examples To run MacroModel calculations a molecular structure file and a command file are required The molecular structure file contains the structures to be used as input in the calculation The command file contains the name of the input structure file the name of the output structure file and an ordered list of operation code
44. find in the Monitor panel This command archives job information as well as the machine and system information and includes input and output files but not structure files If you have sensitive data in the job launch directory you should move those files to another location first The archive is named jobid archive tar gz and should be sent to help schrodinger com instead More information on the postmortem command can be found in Appendix A of the Job Control Guide MacroModel 9 6 User Manual Getting Help On Windows machine and system information is stored on your desktop in the file schrodinger_machid txt If you have installed software versions for more than one release there will be multiple copies of this file named schrodinger_machid N txt where N is a number In this case you should check that you send the correct version of the file which will usually be the latest version If Maestro fails you can copy the information from the DOS window from which Maestro was launched To do so use the window manager menu in the top left corner of the window point to Edit then Select All and press ENTER The text is now in the buffer and can be pasted into a message MacroModel 9 6 User Manual 177 178 MacroModel 9 6 User Manual References 10 11 12 Allinger N L Conformational Analysis 130 MM2 A Hydrocarbon Force Field Utilizing V1 and V2 Torsional Terms J Am Chem Soc 1977 99 8127 Allinger N
45. fixed or frozen atoms The substructure must be specified in a substructure file and read in with a SUBS 0 command and cannot be specified in the command file Likewise fixed or frozen atoms must be specified in the substructure and cannot be speci fied independently Finally if only automatic comparison atom setup is required for a multi conformer multiple minimization with redundant conformer elimination then COMP arg1 0 may also be used in the command file Examples are given in Section 7 6 2 on page 61 MacroModel 9 6 User Manual 57 Chapter 7 Multiple Minimizations 58 AUTO is not currently compatible with LOOP and must be used carefully with eMBrAcE For more information on the parameters that AUTO is assembling use DEBG 520 or 521 7 5 Preparation of Multi Ligand Structure Files With premin MacroModel s multiple minimization capabilities are used in a script named premin which is designed to prepare multi ligand structure files for use in Glide and other applications Data base files sometimes contain problematic ligand structures that are either chemically incorrect or have species that are not covered by the force field parameters This script culls out such problematic structures and minimizes the energy of all other structures The problematic struc tures and the minimized structures are saved in separate files You can also filter out problem atic structures without doing a preminimization The preminim
46. icon The selected bond is distinguished by purple lines on either side of the dotted line After the bonds have been selected click Perform Automatic Setup in the Conformational Search panel Maestro generates molecular rotation and translation commands for each frag ment created by the defined ligand bonds In addition it produces torsion rotations torsion checks and chiral atom definitions To view or edit the automatically generated settings open the Torsion Rotations Torsion Check or Chiral Atoms panels Ligand Bonds Define ligand bonds FF Pick Bonds s W Show markers Delete Delete All Close Help Figure 9 9 The Ligand Bonds panel MacroModel 9 6 User Manual 89 Chapter 9 Conformational Searches 90 9 3 Command File Examples To run MacroModel calculations a molecular structure file and a command file are required The molecular structure file contains the structures to be used as input in the calculation The command file contains the name of the input structure file the name of the output structure file and an ordered list of operation codes opcodes for the calculations Once you set up a job in Maestro and click either Start or Write Maestro writes out a molecular structure file and a command file For many types of jobs command files written this way are complete and adequate but for some types of jobs you may need to adjust the Maestro gener ated command file T
47. is 2 7 kcal mol lower in energy than the most stable non hydrogen bonded energy minimum When molecular dynamics simulations were performed at 300 K 31 and the hydrogen bond popula tion was monitored during the simulation we found that only 56 of the conformations could be considered hydrogen bonding at this temperature Thus the hydrogen bonded populations reflect the experimentally observed populations because the simulation is exploring the free energy surface of the molecule The minima obtained from the conformational search are the lowest points on very broad energy wells which include many states lacking well defined hydrogen bonds So even using a high quality force field and solvation model was not sufficient to reproduce experiment without the use of the appropriate simulation methodology MacroModel 9 6 User Manual Chapter 15 Free Energy Simulations Cy NS O Figure 15 2 The glycyl lactam structure 15 4 2 Conformational Free Energies for a Diamide in Solution This compound was one of a series studied by Gellman et al 32 using variable temperature IR and NMR in organic solvent If we consider that there are two states of the molecule hydrogen bound and non hydrogen bound each representing many possible conformations we can perform a series of simulations at different temperatures in the range 200 300 Kand perform a van t Hoff analysis on the results which is directly comparable to that reported from t
48. molecular potential energy are computed may be controlled using the Cutoff option menu Default cutoff distances are 4 for hydrogen bonding 7 for van der Waals and 12 for electrostatics The van der Waals and electrostatic cutoff distances are the center of a soft cutoff that starts at 1 smaller than the specified distance and ends at 1 larger than the specified distance 4 3 Fixing and Freezing Atoms in Large Systems Two important reasons for imposing constraints on molecular systems are to force the modelled system to meet desired geometric conditions and to reduce the cost of the calcula tion by eliminating interactions that are expected to have little influence on the results When modeling molecular systems you might want to constrain some of the degrees of freedom such as atom positions or distances angles and dihedral angles Constraints are useful in the following situations e When it is inherently hard to get the system to adopt the desired geometries in the absence of constraints e When the potential functions are inadequate for the system e When parts of the system that would normally lead to the appropriate geometries are not represented MacroModel 9 6 User Manual 27 Chapter 4 General Settings 28 When modelling a large system it is often desirable to focus calculations on important regions and ignore any large portions of the system from which no significant influence is expected For exampl
49. not an exact correction inclusion of this contribution in this manner does help significantly The correction is enabled by default MacroModel 9 6 User Manual Chapter 2 Basic Molecular Modeling 10 see the description for debug flags 830 and 832 under the DEBG opcode description in the MacroModel Reference Manual for information on disabling the correction In calculations using continuum solvation MacroModel uses an approximate solvent acces sible surface area function for derivatives and then computes final energies with a more exact area function at the end of the calculation Consequently the intermediate energies which are listed during energy minimization iterations will differ from the final energies See the MacroModel Technical Manual for a discussion on the performance of the GB SA model with different sources of partial atomic charge 2 4 Truncation of Electrostatic Interactions For large systems interactions between non bonded pairs separated by more than a given distance need to be ignored in order to make simulations tractable Such treatment for van der Waals interactions is less necessary since the interaction dies off as 1 r where r is the inter atomic distance Electrostatic interactions on the other hand die off as 1 r and pose a greater challenge because of their long range nature MacroModel versions prior to 8 1 used residue based cutoffs for systems that had residue information in their coordin
50. of the system interact and move normally Using substructures Uses Maestro s substructure facility to define within a molecular system flexible substructures and fixed and frozen shells You can also directly modify a command file to create or modify substructures Atoms that are not in the substructure or specified as fixed or frozen are ignored To constrain only a few atoms the first method using FXAT commands is best and is also easily achieved through point and click operations in Maestro To constrain a larger number of atoms you will find it is much more efficient to use substructures Note Constraints can be violated if you use automatic setup see Section 9 2 2 on page 77 If so MacroModel will fail With either method a positive force constant can be specified for the restraining harmonic potential for fixed atoms Free movement of the atoms within a specified range can be facili tated with the use of flat bottomed potentials in which the two halves of the harmonic potential are separated by a specified distance within which the potential is zero MacroModel 9 6 User Manual Chapter 4 General Settings 4 3 2 Freezing and Fixing Individual Atoms Individual atoms can be constrained either by picking the desired atoms using the tools in the Constraints tab of the MacroModel panels within Maestro or by using the FXAT command in a jobname com file Atoms are fixed or frozen in their original position by using to
51. ooconononinc mm 102 MC SD calculations ess LOT MINTA calculations sa 112 TNCG minimization method ccccccee 46 torsions checked in CSearch oooocncocnnoccccooncconncononacono for comparison in XCluster constraining s s s in MC SD calculations oooococcncccnconnnnnnnos monitored in dynamics calculations 100 sampling amide ester azo and imido 78 translations and rotations in MC SD calculations nica 107 V variable torsions in MC SD calculations 108 vibrational modes visualizing 0 0 cee 169 X XCluster calculationS oooonnocnnoonnnincnconnacinnoss 157 120 West 45th Street 101 SW Main Street 3655 Nobel Drive Dynamostrafe 13 QuatroHouse Frimley Road 29th Floor Suite 1300 Suite 430 68165 Mannheim Camberley GU16 7ER New York NY 10036 Portland OR 97204 San Diego CA 92122 Germany United Kingdom SCHRODINGER
52. operational codes Examples of command files for various standard MacroModel 9 6 User Manual Chapter 1 MacroModel Overview modeling operations are provided at the end of relevant chapters in this manual Because all jobs are now handled by the Schr dinger Job Control facility MacroModel jobs can be moni tored from Maestro even when jobs are launched from the command line 1 5 Command Line Utilities MacroModel is distributed with the following command line utilities which are stored in the utilities directory of the software installation autoref Performs a restrained minimization of a protein ligand structure using MacroModel See Section 18 6 on page 171 para_bmin Provides an easy to use method of distributing serial MacroModel searches across multiple processors See Section 3 3 on page 23 premin Robustly minimizes ligand structures in a multistructure Maestro file using MacroModel Problematic structures are separated out for exami nation See Section 7 5 on page 58 serial_split Splits the output structure file from a serial search into separate structure files for each individual search performed See Section 18 7 on page 172 The following command line utilities which are installed with the software may be useful in conjunction with MacroModel calculations applyhtreat Adds or removes hydrogen atoms dummy atoms and lone pairs to structures in a MacroModel or Maestro file and produces a new Maestro file ma
53. panels This tab contains tools for specifying a force field a solvent treatment and an electrostatic treatment for the calculation The Potential tab is displayed by default when the energetic panel is opened Selecting a Force Field To specify a force field for a MacroModel calculation select the desired force field from the Force field option menu The default force field is OPLS_2005 For information about MacroModel implementation of the supported force fields see Section 2 1 on page 5 Selecting a Solvation Treatment MacroModel calculations are carried out with water as solvent by default but you may carry out the calculation in the gas phase or with another solvent MacroModel provides the GB SA continuum solvation treatment and water octanol or chloroform may be chosen To change the solvent select the name of the desired solvent from the Solvent option menu 7 Current Energy ETE Use structures from Workspace included entry Potential Constraints Substructure ECalc Force field OPLS_2005 s Solvent Water 41 Electrostatic treatment Constant dielectric 4 Dielectric constant 1 0 Charges from Force field 1 Cutoff User defined Yan der Waals 8 0 Electrostatic 20 0 H bond 4 0 Read Settings From Command File Start Write Close Help Figure 4 1 The Potential tab MacroModel 9 6 User Manual Chapter 4 General Settings Selec
54. separate file so that they can be used in subsequent calculations To write a substructure file click Write sbc File specify the desired file name and click OK Include the sbc suffix in the name You can choose to include the ASL expressions in the substructure file by selecting Write ASL formatted sbc file For more information on use of ASL in substructure files see page 66 of the MacroModel Reference Manual The atom coordinates written to the substructure file can be absolute coordinates or relative coordinates If you select Write absolute atom coordinates writes the absolute atom coordi nates from the current structure are written to the substructure file and these coordinates will be used whenever you use this substructure file If you want to define the substructure for use with more than one structure leave this option unselected In this case zeroes are written to the substructure file for the coordinates These zeroes are interpreted as relative coordinates that is the coordinates are taken from whichever structure the constraints in the substructure file are applied to To read an existing substructure file click Read sbc File navigate to the desired file and select it then click OK If you want you can then edit the substructure to create a new substructure using the controls in the Substructure tab 4 6 Setting Up Running And Monitoring Jobs When you have finished with all the settings for the calculation click
55. sisseseade 21 remote and distributed oooooconcnnnncnnnnnnno 23 jobs general SOtUp cine 25 input source MOMICOTING ococccccccnncononnnoncnononcnnnannnnnonnnns L LBFGS minimization method 47 Index ligand bonds checked in CSearch calculations 89 EMOS iria ai 73 LOOP calculations ooooccccninicnononncononancnnnicancnos 115 command file examples c eceeeeeees 117 example output oo cece ee eee eens 119 input restrictions oooononnnncninnonacncnnnccnncnnno 115 structure handling ooooocnicninnnnicnonccncnnncinnnos 116 low mode conformational search methods 73 low mode settings 0oooooncinnnnncnonncncnconanccnnacancnnns 80 Lsa file example srancocancisrati ncirs ri 116 M Maestro starting ninian niia 4 MBAE OpCOdE csccscsscssssesssereoseeseeees 129 132 MCY SD calculations ooooocinnnioninanncnnonccncnnncancnos 107 automatic SCLUP oo eee eeeeeeeeeeeeeeeeetees 107 command file examples ceeeeeee 109 MC to SD ratio woe eee eee eseeeeteeeeeeees 108 MC SD panel insciis ria 107 MCEMM ist ass T3 MCMMILMCS sisiniinanaiia iaa 74 minimization calculations ooonncniinnnnon m 45 command file examples cee 48 CONVErgence parameters 47 minimization MethodS ooocccnnniinnnnnnnmmmnm 46 PMN Ricos aid 47 ILBEGS iieaoe tardaba aes 47 OSV Misi n ina eh ties wees 47 PROG iee IO 46 SD 47 TNGG iiics 46 Minimization panel wee AS MINTA calculation
56. structures to save per rotatable bond The total number of structures is still limited by the Maximum number of steps setting This option is useful for serial searches where the structures might have different numbers of rotatable bonds The default is 100 Number of structures to save for each search Use this text box to specify the number of unique structures to save when the search is complete counting from the structure that is lowest in energy If the value is zero all unique structures are saved Energy window for saving structures The default value is set to 21 kJ mol The value in this text box is used to compare trial struc tures Any new structures generated and minimized are saved as results of the search only if MacroModel 9 6 User Manual 79 Chapter 9 Conformational Searches 80 they are within the energy window value above the current global minimum Lowering this value results in the search saving fewer structures Eliminate redundant conformers using If comparison atoms are chosen or Perform automatic setup during calculation is selected structures produced during a conformational search are compared to see if they are unique Two options are available for the conditions for structures to be considered different e Maximum atom deviation consider structures to be different if the maximum atom devi ation for any atom exceeds the threshold given in the Cutoff text box e RMSD consider structures t
57. such interactions in proportion to the number of dipole dipole interactions in systems commonly modeled using molecular mechanics For example of the 20 types of amino acids seen in proteins only 5 usually have charged Lys Arg His Glu Asp side chains For a uniform distribution of amino acid types 1 4 of the amino acids in a sequence will be charged Assuming approximately 15 atoms per amino acid the delocalized formal charge for a charged amino acid will on average reside on 2 of the 15 atoms 1 4 2 15 1 30 so only 1 of every 30 atoms in an average protein is expected to have delocalized formal charge The number of dipoles in the system is approximately equal to the total number of atoms Since delocalized formal charges occur on 1 30 of the atoms the proportion of charge charge interactions is 1 30 1 30 1 900 of the total number of charge charge charge dipole and dipole dipole interactions Likewise the proportion of charge dipole interactions is 1 30 1 1 30 The number of charge charge and charge dipole interac tions in such a system is very small compared to the number of dipole dipole interactions and assigning long cutoffs to the former two types of interactions will not impact the size of the non bonded list However use of long cutoffs for such interactions will positively impact the accuracy of the calculation due to the long range nature of these interactions Refer to the BDCO opcode in the MacroModel Reference Ma
58. supported see Section 4 3 of the Job Control Guide Additional diagnostic options which do not run the job but provide information are also given in the section mentioned In particular you should note the syntax of the HOST option which is used to specify the list of hosts used for the job Launching a MacroModel job using the bmin script creates the output structure file and the jobname log file The 1log file contains MacroModel job information such as job number and C shell timings and any system errors as well as output from the job 3 2 1 Using an Executable Command File If you have a command file that must be run repeatedly such as the MacroModel test scripts you can embed the contents of the command file in an executable shell script Below is an example though we generally recommend using shell scripts as described in the previous section MacroModel 9 6 User Manual Chapter 3 Running MacroModel From the Command Line bin csh f cat lt lt EOC gt a_run com jobname mae jobname out mae FFLD READ ELST 2 EOC SSCHRODINGER bmin a_run If the above contents were contained in an executable file called mm2 ELST you could run the included commands by entering the file name on the command line mm2 ELST 3 3 Running Remote and Distributed Calculations Remote MacroModel jobs run on a different host from the one on which the command is entered to start the job Distributed MacroModel allows cert
59. to be used in the search of each isolated ligand and each ligand receptor complex Arg1 defines the number of steps to use for each search This need not match that used in the search of the receptor MCOP Monte Carlo options that determine what and how often data is written to the log file and how many structures are saved for the searches of the ligand receptor complexes argl 1 Print information for every search step to the log file arg3 10000 Use a large number to avoid spurious lines in the eMBrAcE summary table at the end of the run arg4 1 Indicates that the searches are considered to be part of a serial calculation arg6 2 0 Saves only the two lowest energy conformations from the complexes for each ligand 14 4 2 3 MCMM Conformation Search With COPY ALGN eMBrAcE conformational searches may also be used with COPY and ALGN to position ligands using a crystal structure of a complex of a closely related ligand While this combination of commands may be useful the positioning is crude and the searching of conformational space is slow and quite limited compared to that available in Schr dinger s docking program Glide Below is an example command file for COPY and ALGN in combination with MBAE for an MCMM conformational search Apart from the alignment step the input file is similar to that of the MCMM search example above A copy of the input file is available at SSCHRODINGER macromodel vversion samples Examples MBA
60. to such other third party software or linked sites do not constitute an endorsement by Schr dinger LLC Use of such other third party software and linked sites may be subject to third party license agreements and fees Schr dinger LLC and its affiliates have no responsibility or liability directly or indirectly for such other third party software and linked sites or for damage resulting from the use thereof Any warranties that we make regarding Schr dinger products and services do not apply to such other third party software or linked sites or to the interaction between or interoperability of Schr dinger products and services and such other third party software Revision A September 2008 Contents Document Conventions sand ao xi Chapter 1 MacroModel OVervView sssssssssssssssssssssssssssssssssssssssssssssessteeseseeeeseesesses 1 1 1 MacroModel User Manual ooococonncnnonncnicncnnnnnnconrnocnnnno cnn rra 1 1 2 MacroModeL ai does 1 1 3 MacroModel and Maestro Interaction oo oononninioncinninncnnnnonnccncnncncnnrnnnno 2 1 4 Calculation Preparation and Submission oooccccninicnonnniononconncnccnccnannccannnnn 2 1 5 Command Line Utilities ccc cee ceeeeeeceeeeeeesaeeeceesaeeecaesaseeseetaeeeseetaees 3 1 6 Running Schrodinger Software 0 cccccccccceeeeeeeeeceeseeeceeeseeeseeaseeseeeaeeeseeeaees 4 1 7 Citing MacroModel in Publications 00 00 0000 cece ceee eee eeceeeeeeeeeeseeseeeaeee
61. trial structures Any new structures generated and minimized are kept only if their energy is less than this value above the current global minimum Lowering this value results in fewer structures saved The default value is set to 500 kJ mol Probability of a torsion rotation molecule translation Minimum distance for low mode move Maximum distance for low mode move These three text boxes are relevant only to the low mode searches and are active only when a method involving low mode conformational searching is selected The first text box is used only with the Mixed torsional Low mode sampling method and allows the setting of a probability that any defined torsion rotations and molecule translations are made at each step during the search This should be a number from 0 0 to 1 0 The other two text boxes are used for setting the minimum and maximum distance for a low mode move During a search the fastest moving atom is moved randomly generated distances that are between these two limits Eliminate redundant conformers using If comparison atoms are chosen or Perform automatic setup during calculation is selected structures produced during a conformational search are compared to see if they are unique Two options are available for the conditions for structures to be considered different Maximum atom deviation consider structures to be different if the maximum atom devi ation for any atom exceeds the threshold given in the Cutoff tex
62. type is provided in this section From Maestro Separate panels for current energy energy minimization dihedral driving conformational search ligand torsion search multiple minimization dynamics MC SD and MINTA are avail able in Maestro To set up a calculation display the relevant panel and adjust the settings as desired then click Start to set up and launch the job Alternatively you can choose to write out the structure and command files that you will need to launch the job later from the command line by clicking Write From the Command Line Some types of MacroModel calculations cannot be prepared or submitted from Maestro For these jobs you must manually create the necessary command file which provides Macro Model with the instructions it needs to perform the related calculation For this task you might find it easiest to use a Maestro generated command file as a template Once you set up a job in Maestro and click either Start or Write Maestro writes out a molecular structure file and a command file These files are required to run MacroModel calculations The molecular structure file contains the structures to be used as input in the calculation The command file contains the name of the input structure file the name of the output structure file and an ordered list of operation codes opcodes for the calculations The MacroModel Reference Manual contains detailed information about all of the Macro Model commands and
63. variables before performing an automatic setup click Reset All Variables Perform automatic setup during calculation Perform automatic setup during calculation performs the same tasks as Perform Automatic Setup but it permits you to set up parameters for all the structures that are processed when the search is performed This option disables the controls used with Perform Automatic Setup You can use this option with any of the conformational search methods but you must use it with serial MCMM searches By default it is selected This option inserts AUTO opcodes into the command file See Section 7 4 on page 57 and the MacroModel Reference Manual for more information on AUTO Note Automatic setup is not intended for use with constraints If you set constraints and use automatic setup MacroModel can fail because the automatic setup can request move ment of atoms that have constraints Torsion sampling options You can use the options on this menu in the Customize the search section to determine which of the torsions around amide and ester linkages and other planar groups azo and imido groups are selected for sampling during Automatic Setup The options are as follows e Restricted Do not sample amide and ester derivatives or other planar groups Torsional constraints are applied to ensure that the relative conformation of these groups is main tained during the MCMM and minimization process Sets AUTO arg8 0 MacroModel 9 6 User
64. will be constrained The angle is kept in place through a force constant defined in arg5 kJ mol Arg6 lists the desired value for the fixed torsion and arg7 gives the half width of the flat bottom potential used 1 e the flexibility of the constrained angle CONV Defines convergence criteria Argl 2 signifies derivative convergence if no CONV command is present default criterion is 0 05 kJ mol A this value is set in arg5 MINI Starts the minimization Argl defines the type of minimization algorithm to be used Arg1 9 means that Truncated Newton Raphson Conjugate Gradient will be used In arg3 the number of minimization steps is defined Arg3 can be set to a large number since the calcula tion stops automatically as soon as the convergence criterion has been reached MacroModel 9 6 User Manual 49 Chapter 6 Minimizations 6 3 2 Multiple Method MWRT Minimizations MWRT minimizations enable multiple minimizer methods to be applied to a structure during the minimization stage This can enhance the performance of the minimization process The first example below demonstrates the efficient minimization of a small protein domain mwrt_mini mae mwrt_mini out mae FFLD 14 1 0 0 1 0000 0 0000 0 0000 0 0000 SOLV 3 1 EXNB 0 0 0 0 0 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 89 4427 99999 0000 0 0000 0 0000 READ CON 2 0 0 0 0 0020 0 0000 0 0000 0 0000 MWRT 0 MINI 0 1 100 0 0 0000 0 0000 0 0000 10 0000 MINI 1 1 30
65. 0 0 0 0 0000 AUTO 1 0 0 0 0 0000 ADDC 1 0 0 0 0 0000 END 0 0 0 0 0 0000 DEMX Arg5 sets the energy window to 10 kJ mol BGIN Begin the loop over conformers READ Read the next conformer this set for the remaining conformers ADDC Check the current conformer Arg redundant conformers MacroModel 9 6 User Manual co Oo gt 2 2 2 G 0000 0000 0000 0000 0000 0000 0000 SoS 60 05 00 a 0000 0000 0000 0000 0000 0000 0000 OO0OO0OoooOo 0000 0000 0000 0000 0000 0000 0000 AUTO Automatically set up comparisons Argl 1 sets up comparisons only once and uses 1 indicates that Jaguar energies should be present in the input structure file and that these energies are to be used in the process that eliminates Chapter 18 Additional Features MacroModel has some additional features that are not available from the Maestro interface Command file examples of some of these types of calculations are provided in this chapter Note that some of these command files do not have the first MMOD line as seen in command files generated from the interface The MMOD monitoring command is not necessary because these files cannot currently be monitored from Maestro 18 1 Geometry Calculations Geometric properties such as atom positions distances angles and dihedrals can be measured using the GEOM opcode Below is an example of the command file for a geometry calculation and explanation
66. 0 0 0 0000 0 0000 0 0000 10 0000 MINI 9 I 50 0 0 0000 0 0000 0 0000 10 0000 MWRT 1 MINI 4 1 30 0 0 0000 0 0000 0 0000 10 0000 MWRT argl value of zero stores the MINI minimization parameter data MINT In order the MINI commands request 100 SD iterations 300 PRCG iterations 50 TN iterations and 30 FMNR iterations The last MINI command is after the second MWRT command and actually initiates the minimization MWRT arg1 value of 1 instructs computaton to run sequential minimizations after the next MINI command The second example performs MWRT minimization on multiple drug candidate structures mwrt_multmin mae mwrt_multmin out mae FFLD 14 1 0 0 1 0000 0 0000 0 0000 0 0000 SOLV 3 1 EXNB 0 0 0 0 0 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 89 4427 99999 0000 0 0000 0 0000 BGIN READ CONV 2 0 0 0 0 0020 0 0000 0 0000 0 0000 MWRT 0 MINI 0 1 100 0 0 0000 0 0000 0 0000 10 0000 MINI al 1 300 0 0 0000 0 0000 0 0000 10 0000 MINI 9 1 50 0 0 0000 0 0000 0 0000 10 0000 MWRT 1 MINI 4 1 30 0 0 0000 0 0000 0 0000 10 0000 END MacroModel 9 6 User Manual Chapter 6 Minimizations BGIN END Defines the start end of a loop over the input structures All commands between the BGIN and END lines are performed for each structure in the input file 6 4 Checking and Interpreting Results Any individual minimization is intended to minimize the structure in the local minimum which may not be the global minimum of the s
67. 00 0000 WRIT Record the receptor structure in the output structure file READ The second READ reads in the first reference ligand COPY Copy the current structure to the reference storage area for use in aligning the ligands BGIN Loop over all remaining ligands in the input structure file READ Read in the next ligand structure 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 o0o0O0O0o sO0OOOOOOOOOOO0OO0O0O0o0o0o0o0oooooooo Oo MacroModel 9 6 User Manual coo oOo 8 OS oF Oo O Oo OG G OG OC O OS So Se O 00 0 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 139 Chapter 14 eMBrAcE 140 ALGN Align the current structure with the reference structure by center of mass and moments of inertia argl 3 weighting atom positions by mass arg2 1 and write all 4 such align ments to the output structure file arg3 5 END End of loop for aligning the ligands RWND Rewind the output structure file and use it as the input structure file for the remainder of the calculation DEMX arg5 1000 0 means retain only the conformations within 1000 kJ mol of the minimum en
68. 000 0 0000 MBAE 1 1 0 0 0 0000 0 0000 0 0000 0 0000 LMCS 50 0 0 0 0 0000 0 0000 3 0000 6 0000 MCSS 2 0 0 0 500 0000 0 0000 0 0000 0 0000 MCOP 1 0 1000 0 0 0000 1 0000 0 0000 0 0000 DEMX 0 0 0 0 500 0000 0 0000 0 0000 0 0000 SUBS 0 0 0 0 0 0000 0 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 AUTO 0 0 0 0 1 0000 0 0000 0 0000 0 0000 CONV 2 0 0 0 0 0500 0 0000 0 0000 0 0000 MINI 1 0 2000 0 0 0000 0 0000 0 0000 0 0000 MacroModel 9 6 User Manual 137 Chapter 14 eMBrAcE 138 LMCS 50 0 0 0 0 0000 0 0000 0 0000 0 0000 BGIN 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MCOP 1 0 10000 1 0 0000 2 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MINI 1 0 2000 0 0 0000 0 0000 0 0000 0 0000 END 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MBAE 0 0 0 0 0000 0 0000 0 0000 0 0000 LMCS Use the low mode conformational search method Argl defines the number of steps to use for the search of the receptor AUTO Set up comparison atom lists torsional constraints and chirality checks for all the LMCS searches in this calculation Arg5 should be set to 1 so that torsional moves TORS are not identified and arg6 should be 0 0 or absent as the serial aspects of the searches are controlled by the next MCOP MINI Minimize the energy of each conformation generated in the search of the receptor using the PRCG minimization technique arg1 1 for up to arg3 2000 iterations LMCS The second LMCS causes low mode conformational searching
69. 000 100 0000 0 0000 0 0000 MSYM 0 0 0 0 0 0000 0 0000 0 0000 0 0000 COMP 0 0 0 0 0 0000 0 0000 0 0000 0 0000 CONV 2 0 0 0 0 0500 0 0000 0 0000 0 0000 MINI 11 0 500 0 0 0000 0 0000 0 0000 0 0000 LMCS Use the Low Mode Conformational Search method Arg1 100 means that 100 Monte Carlo steps will be carried out before the calculation stops MCSS Select starting geometries for Monte Carlo search steps Arg1 2 tells MacroModel to use as starting geometries structures whose energies are allowed by arg2 and arg5 and are used the fewest times as starting structures MCOP Argl 1 prints search results every step Arg4 1 signifies that this is a low mode serial search A separate conformational search will be performed on all molecules in the input file MacroModel 9 6 User Manual Chapter 9 Conformational Searches Arg5 0 implies a pure low mode conformational search rather than a mixed mode as in a previous example COMP Setting arg1 0 allows for all heavy atoms to be compared for each structure in the input file This removes the need to use atom numbers for the individual structures 9 3 3 Mixed MCMM Low Mode Search Using a Substructure File This example uses the CDK2 structure lelv with the co crystallized ligand cmg Alternate binding modes of the ligand are sampled using a mixture of torsional moves low mode moves and rotation and translation of the ligand in a conformational search This example was prepared with Maestro A su
70. 0000 CONV 2 0 0 0 0 0200 0 0000 0 0000 0 0000 MINI 1 0 1300 0 0 0000 0 0000 0 0000 0 0000 END 0 0 0 0 0 0000 0 0000 0 0000 0 0000 All opcodes above the RWND command are necessary for a standard low mode search The COMP command indicates that all heavy atoms are to be used for the redundant conformer comparison The minimizations after conformation generation are continued only until a gradient of 0 05 is reached as seen in arg5 of the CONV command Argl of the RWND command indicates that the output file of the low mode search is to be used as the input of the subsequent multiple minimization The second argument indicates that the intermediate conformation search output structure file is to be discarded and only the final results of the minimization are retained Below the RWND command are the opcodes necessary for the subsequent multiple minimiza tion Another CONV is included which indicates with the fifth argument a tighter convergence than was used in the conformation search 18 4 Visualizing Vibrational Modes Vibrational modes from MacroModel calculations can be visualized in Maestro using the ePlayer Two opcodes VIBR and VBR2 generate structures for a set of selected vibrational modes VIBR is used for small molecules whereas VBR2 is used for larger molecules of the order of seven residues or larger VBR2 utilizes the same techniques as a large scale low mode conformation search which include using ARPACK routines to solve the
71. 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 COPY 0 0 0 0 0 0000 0 0000 0 0000 0 0000 BGIN 0 0 0 0 0 0000 0 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 ALGN 3 1 5 0 0 0000 0 0000 0 0000 0 0000 END 0 0 0 0 0 0000 0 0000 0 0000 0 0000 READ The first READ reads in the receptor WRIT Record the receptor structure in the output structure file READ The second READ reads in the first reference ligand COPY Copy the current structure to the reference storage area for use in aligning the ligands BGIN Loop over all remaining ligands in the input structure file READ Read in the next ligand structure ALGN Align the current structure with the reference structure by center of mass and moments of inertia argl 3 weighting atom positions by mass arg2 1 and write all 4 such align ments to the output structure file arg3 5 END End of loop for aligning the ligands MacroModel 9 6 User Manual 141 Chapter 14 eMBrAcE An example command file is given below for a distributed eMBrAcE conformational search that uses the output of the separate COPY ALGN job above The file is available at SSCHRODINGER macromodel vversion samples Examples dist_ALGNed_MBAE_MCMM com The descriptions of most of the opcodes may be read from the corresponding opcodes in the MCMM conformational search example given above in Section 14 4 2 1 on page 134 COPY_ALGN out mae MBAE_CSEARCH
72. 1 0 0000 0 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 ELST i 0 0 0 0 0000 0 0000 0 0000 0 0000 DEBG Different debugging flags can be set In this example arg1 1 tells MacroModel to write out the set relationships to the log file ASET Defines atom sets Argl arg4 lists atom numbers of atoms that participate in a set The set number is defined in arg5 Arg6 allows for numerous alternatives of defining sets using argl arg4 For instance a range of atoms can be added to a set by using argl and arg2 first and last atom number of atoms to be included in the set only with arg6 2 as in this example Arg7 and arg8 control ASET properties written to the output structure file For details on the ASET opcode see Section 4 5 of the MacroModel Reference Manual ASNT Turn on off set interactions Argl and arg2 give the set numbers as defined in ASET Arg3 1 turns force field interactions on and arg4 1 turns constraint interactions on READ Read in the structure ELST Calculate the interaction energies between the specified sets and record only limited information on the interactions in the system to the log file 18 3 Rewinding the Output File for Additional Minimization The RWND opcode when included in a MacroModel command file uses the input or output file again for a second computation Currently this is supported only for a conformation search followed by a multiple minimization of the resulting
73. 24 AY 27 Heavy Atoms O H 5 H Heavy Atoms Define comparison atoms W Pick Atoms 1 All Selection Previous Select W Show markers Delete Delete All Close Help Figure 9 5 The Comparison Atoms panel e Click Heavy Atoms This adds only the non hydrogen atoms to the list of comparison atoms e Pick atoms in the Workspace Choose an object from the Pick menu and click atoms in the Workspace to add the atoms to the list of comparison atoms e Select atoms using the Atom Selection dialog box For more complex combinations of comparison atoms click Select to select atoms using the Atom Selection dialog box e Select all atoms Click All to add all atoms to the list of comparison atoms _ Comparison atoms are marked in light green in the Workspace with an icon beside them The currently selected comparison atom is marked in aquamarine 9 2 5 5 Chiral Atoms Because Monte Carlo conformational searches can generate and then minimize highly strained structures chiral atoms in a molecule might be inverted To prevent structures with inverted centers from appearing on the final list of optimized structures you must identify a molecule s chiral atoms before beginning a search Once defined the chirality of each center is compared against that in the starting structure If inversion has occurred the search result is rejected The simplest way to define chiral atoms
74. 490 519 Halgren T A Merck Molecular Force Field II MMFF94 van der Waals and Electro static Parameters for Intermolecular Interactions J Comput Chem 1996 17 520 552 Halgren T A Merck Molecular Force Field III Molecular Geometrics and Vibrational Frequencies for MMFF94 J Comput Chem 1996 17 553 586 Halgren T A Nachbar R B Merck Molecular Force Field IV Conformational Ener gies and Geometries J Comput Chem 1996 17 587 615 MacroModel 9 6 User Manual 179 References 180 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Halgren T A Merck Molecular Force Field V Extension of MMFF94 using Experi mental Data Additional Computational Data and Empirical Rules J Comput Chem 1996 17 616 641 Halgren T A MMFF VI MMFF94s Option for Energy Minimization Studies J Comput Chem 1999 20 720 729 Halgren T A MMFF VII Characterization of MMFF94 MMFF94s and Other Widely Available Force Fields for Conformational Energies and for Intermolecular Interaction Energies and Geometries J Comput Chem 1999 20 730 748 Still W C Tempezyk A Hawlely R C Hendrickson T A General Treatment of Solvation for Molecular Mechanics J Am Chem Soc 1990 112 6127 Polak E Ribiere G Note sur la Convergence de M thodes de Directions Conjugu es Revenue Francaise Informat Recherche Operationelle Serie Rouge 1969 16 35 P
75. 99999 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 CONV 2 0 0 0 0 0500 0 0000 0 0000 0 0000 MINI 1 0 500 0 0 0000 0 0000 0 0000 0 0000 MCNV 1 3 0 0 0 0000 0 0000 0 0000 0 0000 TORS 1 14 0 0 0 0000 180 0000 0 0000 0 0000 TORS 6 26 0 0 0 0000 180 0000 0 0000 0 0000 TORS 14 15 0 0 0 0000 180 0000 0 0000 0 0000 TORS 15 16 0 0 0 0000 180 0000 0 0000 0 0000 TORS 16 17 0 0 0 0000 180 0000 0 0000 0 0000 TORS 17 18 0 0 0 0000 180 0000 0 0000 0 0000 TORS 26 27 0 0 0 0000 180 0000 0 0000 0 0000 MCSD 1 0 0 0 0 0000 0 0000 300 0000 0 0000 MDIT 0 0 0 0 300 0000 0 0000 0 0000 0 0000 MDYN 0 0 1 0 1 5000 1 0000 300 0000 0 0000 MDSA 20 0 0 0 0 0000 0 0000 1 0000 0 0000 MDYN 1 0 T 0 1 5000 10 0000 300 0000 0 0000 WRIT 0 0 0 0 0 0000 0 0000 0 0000 0 0000 Several opcodes have been discussed in previous chapters Only the opcodes relevant to the MC SD procedure are described below MINI Minimize the structure before the dynamics simulation MCNV The number of torsion angles to vary during the MC portion of the simulation Here between one and three torsion variations are specified MacroModel 9 6 User Manual 109 Chapter 11 MC SD Calculations 110 TORS Specify the torsion angles to vary by atom number MCSD Specify MC SD sampling at 300 K with an MC to SD step ratio of 1 1 MDIT Specify dynamics simulation at a temperature of 300 K MDYN Perform equilibration dynamics run for 1 ps MDSA Sample 20 structures during the f
76. AcE job may be distributed across a number of processors To distribute an eMBrAcE job add an NPRC line early in the com file such as immediately above the FFLD line See the description of the NPRC opcode in the MacroModel Reference Manual for more information For example NPRC 2 16 0 0 0 0000 0 0000 0 0000 0 0000 MacroModel 9 6 User Manual Chapter 14 eMBrAcE would run the job on two processors with 16 ligands processed in each subjob For energy difference eMBrAcE calculations the receptor is processed first within the parent process prior to starting up any child processes There are two restrictions on distributed eMBrAcE jobs First the output structure mode which is controlled by arg3 of the MBAE opcode must be either O complexes only or 1 ligands only and not 2 receptor ligands and complexes Second distributed eMBrAcE runs may not contain COPY and ALGN commands to pre position the ligands Instead the pre posi tioning of the ligands must be accomplished in a separate non distributed calculation The output from that calculation is then used as input for the distributed eMBrAcE conformational search calculation An example command file to align ligands prior to an eMBrAcE conformational search calcu lation is given below This file is available at SSCHRODINGER macromodel vversion samples Examples ALGN_pv com COPY_ALGN mae COPY_ALGN out mae READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 WRIT 0 0 0 0 0 0000 0
77. All ligand atoms are automatically added to the SUBS list at this stage ASET This series of ASET opcodes places the substrate atoms in set 1 and all other atoms in set 2 If the ligand structure has multiple molecules in it then this case would place all of the molecules for that structure in set 2 The first ASET line removes all of the atoms from the existing set by placing them in set 0 which is a dummy set The second ASET line places all atoms in set 2 The third and fourth ASET commands remove the receptor atoms numbered from 1 to 4729 from set 2 and place them in set 1 Other ASET combinations may be useful depending on the system e g you could leave out particular molecules such as water mole cules from the substrate CT Note that while the interaction energies from all sets are recorded in the 1og file only those for sets 1 and 2 are recorded in the output structure file for eventual inclusion in Maestro s Project Table MINT Minimize the energy of the structure using the PRCG minimizer ELST Invokes the ASET mechanism for calculating interaction energies Argl 1 causes limited information to be stored in the 1log file only Other values may produce very large mmo files END End the loop over ligands MBAE When arg 1 MBAE is turned off This command is not needed in this example Below is the data generated by eMBrAcE for one ligand The complete output file contains one s
78. C searching method is most efficient for smaller mole cules See Reference 22 for more information Low Mode Conformational Search Methods If you have little or no prior knowledge of the system to be searched the Low Mode Confor mational Search LMCS 23 based on the principles behind saddle point searching allows MacroModel 9 6 User Manual 73 Chapter 9 Conformational Searches 74 for automatic searching without the need to define parameters to be varied during the search One important consequence of this is that LMCS allows for a serial search of multiple different molecules without user intervention A related method Large Scale Low Mode LLMOD 24 25 has been developed for large scale conformational searching such as protein loop optimization homology model refine ment and fully flexible docking for induced fit modeling LLMOD is similar to LMOD but computes low mode eigenvectors of a Hessian matrix that is referenced only implicitly through its product with a series of vectors LLMOD is the first conformational search method that can be applied to fully flexible unconstrained protein structures Serial LLMOD calcula tions are not currently supported Mixed MCMM Low Mode Conformational Search Methods A pure LMCS search is local in scope but performs exceptionally well in global searches through hybridization with MCMM 26 By defining key torsions to be varied through MCMM steps the mixed MCMM LMCS se
79. E calculations For a thorough descrip tion of the distributed MacroModel calculations including the specific types of calculations supported see the MacroModel Reference Manual Below are a two simple examples that illustrate how to perform these calculations To run these examples first ensure that the hosts and accounts have been prepared and an appropriate schrodinger hosts file is available MacroModel 9 6 User Manual 23 Chapter 3 Running MacroModel From the Command Line 24 For distributing calculations focused on a single input structure internal distributed calcula tions are used For example to distribute a conformational search of a protein ligand complex across two processors add the line NPRC 2 20 10 1 0 0000 0 0000 0 0000 0 0000 just after the MMOD command in the example com file given in Section 9 3 3 on page 93 The job can then be started just like any other MacroModel job SCHRODINGER bmin jobname Another type of job that can be distributed is MCMM serial searches in which each input struc ture is subjected to a separate search see Section 9 3 2 on page 92 You can do this with the para_bmin command which can be run directly on the unmodified non distributed files SSCHRODINGER utilities para_bmin NJOBS 5 HOST comp1 1 comp2 2 serial lmcs This command divides the job into five tasks all of which are run on computers comp1 or comp2 These computers must be described in the schrodinger
80. END 0 0 0 0 0000 0 0000 0 0000 0 0000 MBAE 1 0 0 0 0 0000 0 0000 0 0000 0 0000 SOLV The GB SA effective water model is being used FFLD Use OPLS_2001 with constant dielectric electrostatics which is appropriate if GB SA solvation is being used EXNB Extended non bonded cut offs should be used with GB SA solvation BDCO Use the Bond Dipole CutOff BDCO method for truncating electrostatic interactions Arg5 and arg6 are used to specify the cutoffs used for charge dipole and charge charge interac tions respectively MBAE Turn on eMBrAcE argl 0 Using Interaction energy mode arg2 0 MINI calculations being performed arg3 0 Minimized complex structures are written out If arg3 were 1 only the ligand structures extracted from the minimized complex structure would be recorded READ The first READ command obtains the structure of the receptor SUBS Substructures may be used All opcodes related to the substructure SUBS FXAT FXDI FXBA and FXTA should be defined in an sbc file The sbc file should contain only lines referring to the receptor with the receptor atoms numbered starting from 1 BGIN Start the loop that processes each substructure in turn MacroModel 9 6 User Manual 129 Chapter 14 eMBrAcE 130 READ Read in a ligand This also produces a combined structure consisting of the receptor and the ligand with the receptor atoms being numbered lower than the ligand atoms
81. E_ALGN com MacroModel 9 6 User Manual Chapter 14 eMBrAcE The example is followed by descriptions of the opcodes Opcode descriptions that are omitted may be read from the corresponding opcodes in the MCMM conformational search example given above in Section 14 4 2 1 on page 134 ALGN_SEARCH_MCMM mae ALGN_SEARCH_MCMM out mae FFLD SOLV EXNB BDCO READ WRIT READ COPY BGIN READ ALGN END RWND MSYM MBAE MCMM MCNV MCSS MCOP DEMX SUBS READ AUTO MINI MCMM AUTO BGIN MCOP READ MINI END MBAE al 5 5 1 PROOOUWwWOOOOOOOOoOQ0U OPOOOGOPNPO O YA Ao 1 oo 0000000 O FO 0 0 ff OF co Co Oo fF co Co CO Cc Oo Cc Oo Oo FF oo O OOO CO Oe OO mo ao oS oS 100 DOD OCOCOrGCOOGOGGOGOGOOCGCOCOOGOOGOOOGOOCGOCOCOCOOGOOOGOGOGOGOOGOOGOOGOCGOOO O O oo oo fo co 6 68 Oo oc co oe O GOG Ha o OO Oo Oo OC OOo Oo oo OGO READ The first READ reads in the receptor 0000 0000 0000 4427 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 500 0000 1000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 9999 SO oo Oo Nr ao oS oo ocr oo oOo fo fb oOo coo Oo vw oOo 2 S amp 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 00
82. L1 1 all FXAT 0 0 0 0 0 0000 0 0000 0 0000 0 0000 FXAT 0 0 0 0 1 0000 0 0000 0 0000 0 0000 ASL1 0 atom ele H ASL2 200 0 not atom ele H The first three lines clear all free fixed atom and frozen atom definitions respectively The fourth line adds all hydrogens to the substructure The fifth line constrains all heavy atoms to their starting positions with a constraining force constant of 200 kJ mol A 7 6 4 Partition Coefficient Estimation Below is an example of a command file for conducting log Poctanol water Calculations on a series of molecules It is very similar to that used for multiple minimization of non conformers logP mae logP out mae FFLD 1 1 0 1 1 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 41 5692 99999 0000 0 0000 0 0000 SOLV 3 9 0 0 0 0000 0 0000 0 0000 0 0000 LOGP 1 I 1 0 0 0000 0 0000 0 0000 0 0000 BGIN 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MacroModel 9 6 User Manual Chapter 7 Multiple Minimizations READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 AUTO 0 1 0 0 0 0000 1 0000 0 0000 0 0000 CONV 2 0 0 0 0 0500 0 0000 0 0000 0 0000 MINI 1 0 5000 0 0 0000 0 0000 0 0000 0 0000 END 0 0 0 0 0 0000 0 0000 0 0000 0 0000 SOLV Specifies the first or primary solvent Arg2 9 corresponds to octanol LOGP Turns on partition coefficient estimation and specifies the second solvent Arg2 1 corresponds to water AUTO Necessary for the proper processing of LOGP calculations Arg2 1 instructs AUTO not to make a lis
83. Loop Construction 116 An all atom representation of the protein must be used e No disulfide bonds are permitted within the loop or between the loop and the rest of the protein No atoms in the loop can be frozen e LOOP will not work from a collection of input protein structures It will work only from one such structure 13 1 2 Structure Handling Considerations When using LOOP you should be aware of the following e Rings such as the one in proline are treated as rigid e If comparison atoms COMP are specified explicitly or implicitly see arg3 then MSYM must be used All LOOP runs renumber the atoms within the structure such that the loop atoms become the highest numbered atoms in the structure During a run MacroModel tracks the shifted atoms numbers for the atoms in the system LOOP automatically produces a substructure file filename out sbc containing the shifted atom numbers for use in follow up stud ies 13 2 Example lsq Input File Consider the following contents of an example auxiliary file filename 1sq E ER Based on the file contents LOOP creates a new loop with the seven specified amino acids starting with GLY at the N terminus end of the loop The format and contents of the file meet the following criteria e Only alpha amino acids are used e The amino acids used all appear in the Maestro fragment tables found in the Maestro Build panel MacroModel 9 6 User Manual Cha
84. MacroModel 9 6 User Manual O Schr dinger Press MacroModel User Manual Copyright O 2008 Schr dinger LLC All rights reserved While care has been taken in the preparation of this publication Schr dinger assumes no responsibility for errors or omissions or for damages resulting from the use of the information contained herein Canvas CombiGlide ConfGen Epik Glide Impact Jaguar Liaison LigPrep Maestro Phase Prime PrimeX QikProp QikFit QikSim QSite SiteMap Strike and WaterMap are trademarks of Schr dinger LLC Schr dinger and MacroModel are registered trademarks of Schr dinger LLC MCPRO is a trademark of William L Jorgensen Desmond is a trademark of D E Shaw Research Desmond is used with the permission of D E Shaw Research All rights reserved This publication may contain the trademarks of other companies Schr dinger software includes software and libraries provided by third parties For details of the copyrights and terms and conditions associated with such included third party software see the Legal Notices for Third Party Software in your product installation at SSCHRODINGER docs html third_party_legal html Linux OS or SCHRODINGER docs html third_party_legal htm Windows OS This publication may refer to other third party software not included in or with Schr dinger software such other third party software and provide links to third party Web sites linked sites References
85. Model 9 6 User Manual 31 Chapter 4 General Settings 32 Current Energy a Use structures from Workspace included entry Potential Constraints Substructure ECalc Constrain Atoms Distances Angles Torsions Reset All Freeze Atoms Reset All Start Write Close Help Figure 4 2 The Constraints tab Specifying atoms to be constrained To constrain an atom distance angle or torsion display the appropriate constraining panel by clicking on the corresponding button in the Constraints tab Atoms Distances Angles or Torsions Choose a structural unit from the Pick menu and click on the desired atom s in the Workspace The picked atoms appear in the list in the upper portion of the panel To constrain many atoms simultaneously you can use an ASL expression ASL expressions can be built using the Atom Selection dialog box which you open using the Select button For more information on ASL see the online help or the Maestro Command Reference Manual Specifying the force constant and atom flexibility By default the constrained structural elements have harmonic potentials with a force constant of 100 kJ mol with the current value of the element used for the potential minimum The force constant can be modified For fixed distances angles and torsional angles the position of the potential minimum can be adjusted A flat bottom potential essentially
86. Model is provided with param eter files for water water s1v octanol octanol slv and chloroform chc13 s1v Using the GB SA model slows calculations by a factor of approximately three relative to the gas phase However because of the increased accuracy of modeling in solvent it is suggested that the GB SA continuum solvation model be used in all calculations for molecules for aqueous solutions Solvation is controlled by the Solvent option menu located in the Potential tab of the MacroModel panels within Maestro or by the SOLV command in MacroModel command files The calculation of Born radii in the GB part of the GB SA model is performed by doing a volume integral Stretch bend and non bonded pairs including 1 4 interactions contribute to this integral For large systems such as proteins in which non bonded cutoffs typically are used and not all non bonded pairs are included on the non bonded pair list in order to expedite calculation Born radii are subject to systematic error This is because the volume integration is performed by using pairs on the stretch bend and non bonded pair lists and the latter excludes longer range interactions when non bonded cutoffs are in use To correct for this error MacroModel calculates the contribution from such longer range non bonded pairs every time a non bonded pair list update is done This contribution is taken to be a fixed value and is used in energetic and derivative calculations Although
87. NI BGIN READ hb pb q EN gt E a a e a S q e TE E o E e ER DE o DA o E e A 200 A D 10 00 50 1020 po CS JU cero JUE az JU gt JUDE lt gt BS to OE zo JE too E o SO 1000 01 0 0 0 0 0 0 4427 0 0 0 000 000 000 000 000 000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 0000 9999 D 0 00 50 0 0 0000 0 0000 0 0000 0 0000 0 0000 0 0000 0 0000 0 0000 0 0000 0 0000 0 0000 0 0000 0 0000 0 0000 0 0000 0 0000 0 0000 0 0000 0 0000 0 0000 MacroModel 9 6 User Manual 131 Chapter 14 eMBrAcE 132 MINI 1 0 2000 0 0 0000 0 0000 0 0000 0 0000 END 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MBAE 4 0 0 0 0 0000 0 0000 0 0000 0 0000 SOLV The GB SA effective water model is being used FFLD This example uses OPLS_2001 with constant dielectric electrostatics which is appro priate if GB SA solvation is being used EXNB Extended non bonded cut offs should be used with GB SA solvation MBAE Turn on eMBrAcE argl 1 Using Energy Difference mode arg2 0 MINI calculations being performed arg3 1 Ligand structures extracted from the minimized complex are written to the out put structure file If arg3 were set to 0 the minimized complex structure would be recorded SUBS Substructures may be used All opcodes related to the substructure should be defined in an sbc file The sbc file should contain only lines referring to t
88. NV 2 0 0 0 0 1000 0 0000 0 0000 0 0000 MINI 9 0 1000 0 0 0000 0 0000 0 0000 0 0000 SUBS With arg1 0 look for an sbc file that contains information on how the substructure is set up in the system MCOP Arg1 1 print search results every step Arg5 0 5 specifies that this mixed Monte Carlo Low Mode search will attempt Monte Carlo torsional and or molecular translation moves half the time The rest of the attempted moves will be generated using low mode moves MOLS Arg1 4 sepecifies one atom from each molecule to be moved using molecular transla tion rotation moves Arg5 and arg6 specify the minimum and maximum rotation angles while arg7 and arg8 specify the minimum and maximum translation distances 9 3 4 Conformational Searches Using Multiple Minimization Methods MWRT MWRT minimizations enable multiple minimizer methods to be applied to a structure during the minimization stage which can enhance the performance of the minimization process This method can be used in a conformational search Examples are given in the examples directory SSCHRODINGER macromodel vversion samples Examples The example mwrt_csearch demonstrates an efficient small molecule conformational search using MWRT The example mwrt_serialsearch is a multi structure example In this second example AUTO arg6 1 indicates a multi structure conformation search More information about MWRT is available in Section 6 2 3 on page 48 MacroModel 9 6 User Manual
89. ONV MINI The VIBR opcode selects the first five non trivial modes for anima tion with five frames per quarter vibration cycle 18 5 Alignment of Structures The combination of the COPY and ALGN opcodes permits very rapid approximate alignment of ligands with a reference ligand using center of mass and moments of inertia These commands may be used to preposition ligands crudely prior to an eMBrAcE conformational search calcu lation based upon the position of a reference ligand already positioned in the active site While this combination of commands may be useful the positioning is crude and searching confor mational space is slow and quite limited compared to that available in Schr dinger s docking program Glide Note that COPY ALGN may require the purchase of a separate license Below is an example command file for a COPY ALGN run to align structures in the input struc ture file algn mae Opcode descriptions follow MacroModel 9 6 User Manual Chapter 18 Additional Features algn mae algn_all out mae READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 COPY 0 0 0 0 0 0000 0 0000 0 0000 0 0000 BGIN 0 0 0 0 0 0000 0 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 ALGN 3 1 5 0 0 0000 0 0000 0 0000 0 0000 END 0 0 0 0 0 0000 0 0000 0 0000 0 0000 READ The first READ command reads in the first structure which is the reference structure The remaining structures are read in a BGIN END loop with another READ command
90. Pick Atoms 1 All Selection Previous Select W Show markers Delete Delete All Close Help Figure 7 2 The Comparison Atoms panel Comparison Atoms During multiple minimizations of conformers redundant structures are eliminated if compar ison atoms are specified The structures are compared against other low energy structures that have already been minimized The comparison is performed by rigid superposition comparing only those atoms specified as comparison atoms in the setup taking into account the topo logical symmetry of the molecule To define comparison atoms click the Comparison Atoms button and use one or more of the following options e Click Heavy Atoms O H S H This adds all the non hydrogen atoms and the hydrogen atoms attached to oxygen and sulfur to the list of comparison atoms e Click Heavy Atom This adds only the non hydrogen atoms to the list of comparison atoms e Pick atoms in the Workspace Choose a structural unit from the Pick menu in the Define comparison atoms section and pick atoms in the Workspace to add the atoms in the structural unit to the list of compari son atoms e Select atoms using the Atom Selection dialog box For more complex combinations of comparison atoms you can select atoms using the Atom Selection dialog box to build an Atom Specification Language ASL expression for the required atoms See Section 5 3 of the Maestro User Manual for more infor
91. Results ooociocioiininninicninnionnnonnonconnncnccnccnanncnns 106 Chapter 11 MC SD Calculations ssssssssssssssssssssssssssssssssssssssssssssssssssssssssessssees 107 111 The MC SD Pa ol ccoo tota tai ad nde in as 107 11 2 Setting Up MC SD CalculationS ooonoininninninninininnicninnnnnononnconncccnrcnanncnns 107 11 3 File Examples iia 109 11 4 Checking and Interpreting Results ooocionioiininninicninnionnnonnoconncnccnccnanncnns 110 Chapter 12 Minta CalculationS acnccacaronioncrnoncinoniandinoncinancandniancininaenininesisiacinicnussand 111 12 1 The MINTA Panels uommssnsransnniao data 111 12 2 Command File Examples c cccccccccceccseseeeeeeeceeeeceesaeeecesaseesaesaseaneetateasaes 113 12 3 Checking and Interpreting Results 000 000 eee ceeeeeceeeeceeeeeeeeeaeeeeeeeateeeees 114 Chapter 13 Protein Loop Construction scssassessssessssissssssssanssassestsvsanassseststansitiisns 115 13 1 Performing LOOP Calculations ooononniinininninininnicnninn nono 115 MacroModel 9 6 User Manual vii Contents viii 134 1 Input REStHICHONS ninia 115 13 1 2 Structure Handling Considerations is mini aia 116 13 2 Example Isq Input File sessio a 116 13 3 Command File Examples ccccccccececceeeeeeeeeceeeeeeeaeeeceesaseecaesaseaneetaseaeaes 117 13 3 1 LOOP Job Using the Input Structure Sequence cooccconccconoccccccccconcncnnncnonnnnns 117 13 3 2 LOOP Job Using the Sequence F
92. Sets the number of degrees of freedom to be varied at each MC step With different arg1 and arg2 values the search varies a random number of degrees of freedom between the numbers defined in argl and arg2 For eMBrAcE calculations we recommend setting argl to a small number and arg2 to no more than 10 MacroModel 9 6 User Manual 135 Chapter 14 eMBrAcE 136 MCSS MC structure selection allows for the setting of selection of starting structure for the search steps Argl 2 defines use directed selection of starting structures where the least used structures will be used as starting geometries as long as they are low enough in energy as defined in arg5 This is more efficient in exploring new areas of the potential energy surface than for instance a random walk starting geometry scheme Arg5 gives the energy window for selecting a new starting structure which must be within arg5 kJ mol of the lowest energy conformer found in the search MCOP Monte Carlo options that determine what and how often data is written to the log file and how many structures are saved argl 1 Print information for every search step to the log file arg3 10000 Use a large number here to avoid spurious lines in the eMBrAcE summary table at the end of the run arg6 1 0 Save only the lowest energy conformation of the receptor this value must be specified as 1 0 y EMX arg5 500 0 means retain only the conformations within 500 kJ mol of t
93. Start to open the Start dialog box and choose options for how and where the job is run The Start dialog box provides a standard interface to the Job Control facility which manages all jobs submitted from Maestro This dialog box has a standard set of controls but is configured to include applica tion specific or task specific controls when needed For example for distributed jobs the Host menu is replaced by a table that allows maximum flexibility in selecting hosts and processors For more information on this dialog box see Section 4 2 of the Job Control Guide Distributed MacroModel calculations can be started from Maestro for the following job types e Multiple minimization of non conformers e Redundant conformer elimination e Ligand torsional search e Serial conformational searches using MCMM LMOD or MCMM LMOD You may want to set up a MacroModel calculation and save the generated input files without actually submitting the job This may be the case for example if you want to use MacroModel from the command line To create the structure file and the command com file needed to MacroModel 9 6 User Manual Chapter 4 General Settings launch the job at a later time specify the desired values using the settings on the desired MacroModel panel and then click the Write button located in the lower right corner of the panel After you click the Start button in the Start dialog box the Monitor panel is displayed and the cont
94. The Monitored Torsions panel For example in a typical N H to O C hydrogen bond the picking order should be N H O then C After the fourth atom has been selected a new entry appears in list at the top of the panel The H bond is marked with solid yellow lines between X and H and between Y and Z and a dotted yellow line between H and Y The currently selected H bond has solid lines on either side of the dotted line You can specify the monitoring criteria for the selected list entry by entering a maximum H Y distance a minimum X H Y angle and a minimum H Y Z angle in the appropriate text boxes If you do not specify values the default values are used The default value for the H Y distance is 2 5 A the minimum X H Y angle has a default value of 120 and the minimum H Y Z angle is 90 If the distance is greater than the maximum or either of the angles is smaller than the minimum the H bond is not counted in the current population survey Monitored H Bonds Define monitored H bonds FF Pick Atoms E Show markers Maximum H Y distance 2 500 Minimum H Y angle 120 0 Minimum H Y Z angle 90 0 Delete Delete All Close Help Figure 10 5 The Monitored H Bonds panel MacroModel 9 6 User Manual 101 Chapter 10 Dynamics Calculations 102 10 2 1 6 Monitoring Output The values associated with the monitored output of structures energie
95. To select the atoms choose a structural unit from the Pick menu and pick an atom in the Workspace You can constrain many atoms simultaneously using an ASL expres sion in the Atom Selection dialog box which you open with the Select button To remove constraints from an atom select its name from the list and click Delete To remove constraints from all currently frozen atoms click Delete All 4 5 The Substructure Tab The Substructure tab is used to set the definition of a substructure and any shells of constrained or frozen atoms that surround it If any substructure or shell atoms are specified an input substructure file jobname sbc is created and used All instructions relating to the fixed and frozen atoms are entered in the input substructure file and read from this file when the calculation is launched 4 5 1 Defining a Substructure You can select the atoms you want to include in a substructure definition by picking the desired atoms chains residues molecules or entries from the Workspace structure To do this select the structural unit you want to use from the Pick menu in the Freely moving atoms substruc MacroModel 9 6 User Manual 33 Chapter 4 General Settings 34 ture section and then pick atoms in the Workspace If Show markers is selected the atoms in the substructure are marked with white markers In addition to defining substructure atoms by picking them from the structure you can specify many a
96. a harmonic potential with the two halves sepa rated by a region of zero potential can be requested by specifying the half width for the flat region in the text box MacroModel 9 6 User Manual Chapter 4 General Settings Specifying a nondefault force constant and half width prior to selecting atoms If atom centered constraints are being applied constraint parameters can be set up beforehand with the Maestro command constrainedset For example to set the force constant to 50 and the width to 0 8 enter the following command in the Command Input Area of the main window constrainedset constant 50 width 0 8 Constrained atoms that are subsequently selected use these constraint parameters Removing constraints To remove one constraint select it from the list at the top of the specific constraints panel and click Delete To remove all constraints of a particular type click Delete All in the corresponding constraints panel To remove all constraints of all types click Reset All in the Constraints tab 4 4 2 Freezing Atoms Frozen atoms have no forces acting on them and do not move from their initial position in the structure Frozen atoms do influence other non frozen atoms in the structure mostly through nonbonded interactions Frozen atoms differ from constrained atoms in that constrained atoms may move slightly To freeze atoms click Atoms in the Freeze section of the energy panel The Frozen Atoms panel is displayed
97. a listing of the total molecular mechanics energy to the log file and a complete listing with all internal coordi nates to the mmo file Arg2 allows for switching between kJ mol and kcal mol units for the energies listed MacroModel 9 6 User Manual 41 Chapter 5 Current Energy Calculations 42 5 4 The Force Field Viewer If you want to view details of the force field used in a MacroModel calculation you can use the Force Field Viewer panel in Maestro You first ensure that Complete is selected from the Energy Listing option menu before you run the job The data displayed by the Force Field Viewer is located in mmo files which are created when energy operations are performed using Complete energy listings To read an mmo file click Browse and navigate to the desired file The Force Field Viewer panel has a number of buttons that represent the various types of inter actions that can be present in a calculation stretch bond angle etc After an mmo file has been read buttons that correspond to types of interactions present in that particular file become active Each button when selected displays a corresponding panel In each panel the interac tions are listed and selection of an interaction in the list marks the interaction in the displayed structure with a magnifying glass icon and a line or an asterisk By default the first item in the list is selected These panels are described in detail in the online help The Wils
98. abular Data A dialog box opens in which you can enter a file name for the file The data for all available plots is written to this file 8 3 3 2D Plot Panel After a 2D scan calculation has been successfully completed the resulting grd file can be displayed as a contour plot using this panel To open a gra file click the Browse button navi gate to the file select it and click Open The data from the grd file is displayed in the plot area as a contour map The corresponding structures are read into Maestro as a scratch entry and one of the structures is displayed in the Workspace Only one grd file can be displayed at any given time Reading in a second file clears the data from the first The appearance of a displayed plot can be changed using the controls on the left side of the panel You can set the number of contour lines in the Number of Contours text box the line thickness in the Contour Width text box and use dashed lines for negative contour values by selecting Negative Dashed You cannot however change the range of coordinates displayed To determine the contour intervals Maestro divides the range of energy values specified in the Minimum Energy and Maximum Energy text boxes or the maximum and minimum values in the file by n 1 where n is the specified number of contour lines This means that the maximum and minimum energy values are not represented by contour lines The plot area itself is an interactive tool as well
99. ace The final way to select comparison atoms is with the Atom Selection dialog box which you open with the Select button With this tool complex atom sets can be easily and quickly selected If you selected Torsional RMS you can choose either Atom or Bond from the Pick menu in the Define comparison torsions section and define the torsions by picking The Delete and Delete All buttons can be used to edit or clear the comparison list MacroModel 9 6 User Manual 159 Chapter 16 Molecular Clustering with XCluster 160 16 2 Command File Examples A sample XCluster command file is given below for an Atomic RMS displacement calculation A subset of heavy atoms has been chosen to serve as the comparison atoms in the RMS calcu lation Five lead structures are written to the output structure file start sample command file Sfile cluster mae Mmsym Enant Arms Pp s 00 UU NI WA FR OUP Ps Hs Ww Ww ul N Cluster Writelead 5 cluster out mae all end sample command file Sfile Specifies the input structure file Mmsym The MMSYM symmetry library will be used in the RMS difference calculation MMSYM automatically recognizes local and global molecular symmetry Enant Enables consideration of enantiomers of each conformer Arms Atom numbers used when generating the distance matrix Cluster Builds clusters at all clustering levels and calculates simple statistics for the cluster ings Writelea
100. acro Model opcodes are described in detail in Chapter 4 of the MacroModel Reference Manual This section illustrates how to combine these opcodes and produce a sensible command file To do this we will use a simple example a calculation of the free energy difference between D and L forms of the alanine dipeptide this should give a free energy difference of zero in isolation Though this is not a very useful simulation it illustrates free energy perturbation calculations Note that most of the perturbations we have tested involve small perturbations with changes of up to only three atoms 15 2 1 The Structure File When you perform a free energy perturbation calculation in MacroModel the input structure file mae must contain two separate MacroModel structures These correspond to the start and end point for the calculation The numbering of the structures is critical all equivalent atoms must have the same number in each structure Dummy atoms MacroModel atom type 61 must be used as place holders for atoms created or destroyed during the perturbation The numbering of the structures used in our example is shown in Figure 15 1 Here we are performing a FEP calculation between the L and D enantiomers of the alanine dipeptide using the AMBER force field so we have no explicit hydrogen on the alpha carbon The perturbation involves changing dummy atom 13 in the starting L structure to a united atom methyl in the D structure
101. ae The remaining lines in the command file provide the instructions to MacroModel concerning the type and order of calculations to be performed The opcode lines must be of the following fixed format OPCD 123456 123456 123456 123456 FFFFF FFFF FFFFF FFFF FFFFF FFFF FFFFF FFFF Each opcode has four letters and is preceded by a blank space A specific opcode can be ignored commented out in a command file by placing a character other than blank space before the opcode The eight fields after the opcode are referred to as arguments and are often referred to simply as arg s Argl through arg4 are integer arguments Fortran I6 format while arg5 through arg8 are floating point arguments Fortran F10 4 format The opcodes indi cate individual energetic calculations or options and the arguments indicate additional options or quantify the parameters of the calculation Many arguments have default values which are indicated by a value of zero as the argument Thus is it unnecessary to indicate explicitly all arguments in the instruction file if the default values are sufficient The default values are included with the opcode descriptions in the MacroModel Reference Manual It is important to strictly adhere to the format of the command file We recommend using an existing command file as a template rather than to build one from scratch Tabs are not allowed in MacroModel instruction files 3 2 Submitting Jobs From the Command Line The bm
102. ain types of calculations to be run in a distributed fashion across a number of different hosts Remote MacroModel jobs can be run from Maestro but at present distributed MacroModel jobs can only be run from the command line Remote and distributed jobs can only be run on Unix hosts not on Windows Schr dinger s Job Control facility controls both remote and distributed MacroModel jobs The Job Control facility enables remote and distributed MacroModel jobs to run reliably on a wide range of computer platforms If you intend to run jobs on various hosts you must set up the hosts for remote access and provide information on the hosts to the Job Control facility through a file named schrodinger hosts How to provide this information is described in the Job Control Guide Brief instructions for setting up the required information on remote hosts and for configuring batch queues is given in the Installation Guide Any MacroModel job can be run remotely The normal Unix commands are used to run the job with additional information specifying which host from the hosts file to use SCHRODINGER bmin HOST remote_host_name jobname MacroModel can divide some types of calculations into tasks These tasks may be distrib uted over a number of processors to reduce the calculation time Calculations that can be distributed using MacroModel include many of the conformational searching methods as well as Free Energy Perturbation FEAV FESA and eMBrAc
103. al potential and kinetic energy 84 41 38 78 kJ mol CPU Time 12 5 sec Average potential energy 96 48 kJ mol Acceptance Ratio for Mixed Mode Simulation 0 03341983 Average kinetic energy 48 46 kJ mol Av temperature 298 9 deg K Average total energy 48 02 kJ mol Std dev 15 55 kJ mol Average potential energy lt H gt scaled to 300 0 deg K 96 29 kJ mol Av stretch 15 40 kJ mol Av bend 17 81 kJ mol Av torsion 27 36 kJ mol Av van der Waals 13 13 kJ mol Av electrostatic 169 99 kJ mol Av solvation 1 0 00 kJ mol Av solvation 2 0 00 kJ mol Free energy perturbation window 9 Lambda left center right 0 350 0 400 0 450 Number of samples in average 3921 Bonded Nonbonded Solvation Total G left center 0 094 0 867 0 000 0 967 0 134 kJ mol G right center 0 059 0 694 0 000 0 737 0 166 kJ mol Similar output was obtained for the other 20 windows of this simulation The first part of the output shows the result of the minimization at this value of A and the equilibration simulation Then the actual free energy sampling is performed and a free energy for the forward and MacroModel 9 6 User Manual 149 Chapter 15 Free Energy Simulations 150 reverse simulation is reported Notice that free energy reported should become stable to a few hundredths of a kJ mol near the end of the sampling period Note however that this is a necessary but insufficient indicator of convergence during the simulation as
104. and frozen atoms For more information see the MacroModel Reference Manual sections on of FXAT FXDI FXBA FXTA and SUBS Making selections in the Constraints tab adds the appropriate opcode entries into the Macro Model command file jobname com for the computation being prepared When you make selections in the Substructure tab however the constraints are added to a separate input substructure file usually named jobname sbc This mechanism allows large numbers of constraints to be shared between different energetic jobs for the same structural system Complementing this feature Maestro can read and write substructure files For more informa tion about the Substructure Facility see Section 4 3 on page 27 Structural constraints can be added in both the Constraints tab and the Substructure tab for a single computation Note Constraints can be violated if you use automatic setup see Section 9 2 2 on page 77 If so MacroModel will fail 4 4 1 Constraining Atoms Distances Angles and Torsions Individual atom positions bond distances bond angles and torsion angles can all be defined from the Constraints tab When you click the button corresponding to the structural element you want to constrain a panel is displayed which you can use to pick the desired elements and define the relevant settings The panels for defining constrained atoms distances angles and torsions are generally the same Exceptions are noted below Macro
105. and launch the job see Section 4 6 on page 36 or click Write to write the files for future use see Section 4 6 on page 36 4 1 1 Specifying Job Input Source For most MacroModel jobs run from the Maestro interface you can use as input either the structures included in the Workspace or the entries selected in the Project Table For these jobs if you have a file containing the structures of compounds you want to evaluate first import the structures into a project using the Import panel and then select the desired structures in the Project Table In addition there are some MacroModel calculations such as eMBrAcE Mini mization that allow you to use an input file directly without having to import the structures into the Project Table The default setting for MacroModel job input is Workspace included entries If you want to perform MacroModel calculations only on the structures currently appearing in the Work space you do not need to change the Use structures from setting However 1f you want to use Project Table entries as input change the Use structures from setting to Project Table selected entry or Project Table selected entries depending on which of these is present When using this setting make sure that you have selected the desired entries in the Project Table panel MacroModel 9 6 User Manual 25 Chapter 4 General Settings 26 4 2 The Potential Tab The Potential tab appears on all of the MacroModel energy
106. and rotated The controls for MC SD simulations are in the MCSD tab with the exception of the tempera ture setting which is in the Dynamics tab To define the torsions to be rotated and the molecule translation and rotation selections auto matically click the Perform Automatic Setup button To view and edit the automatically gener ated settings or to specify the settings manually open the Torsion Rotations and Molecule Trans Rot panels by clicking the corresponding buttons These panels are the same as for conformational searches For a more detailed description of these panels see Section 9 2 5 2 on page 82 and Section 9 2 5 3 on page 84 MacroModel 9 6 User Manual 107 Chapter 11 MC SD Calculations 108 Use structures from Project Table selected entry Potential Constraints Substructure Mini Monitor Dynamics McrSD Perform Automatic Setup Reset All Variables Ratio of SD ta MC steps 1 Minimum number of torsions to vary 1 Maximum number of torsions to vary 1 Torsion Rotations Molecule Trans Rot Start Write Close Help Figure 11 1 The MCSD tab of the MC SD panel The value entered in the Ratio of SD to MC steps text box determines how many Monte Carlo trials will be performed for each dynamics time step The default value is 1 but the number can be increased to give more dynamics steps per Monte Carlo step You can specify the minimum and ma
107. arch has proved faster and more efficient than any other searching algorithm for a variety of systems MCMM LMCS has successfully been applied to difficult tasks such as searching the conformational space of a ligand in the active site of a protein Mixed MCMM LMC72 searches are also supported 9 2 Performing Conformational Searches You can use the Conformational Search panel to set up and submit MacroModel conforma tional search calculations The panel has six parts five of which are common to other Macro Model panels For more information about the controls in the Mini tab see Section 6 1 on page 45 For information about the upper portion of the Conformational Search panel and the Potential Constraints and Substructure tabs see Section 4 1 on page 25 through Section 4 5 on page 33 The CSearch tab is unique to the Conformational Search panel Controls in this tab allow you to chose a search method define an energy window for saving structures set up torsion chiral center and distance checks and define other search parameters To open the panel select Conformational Search from the MacroModel menu in the main menu bar If the MacroModel menu is not in the main menu bar choose MacroModel from the Appli cations menu To set up a conformational search you must first select any entries that you want to use as input from the Project Table or display the structure you want to use in the Workspace In the Conformational Search panel
108. arg6 360 and step sizes arg7 30 CONV Defines convergence criteria Argl 2 signifies derivative convergence The default criterion if no CONV command is present is 0 05kJ mol A this value is set in arg5 MINI Starts the minimization Argl defines the type of minimization algorithm to be used Arg1 9 means that Truncated Newton Raphson Conjugate Gradient will be used In arg3 the number of minimization steps is defined Arg3 can be set to a large number since the calcula tion automatically stops as soon as the convergence criterion is reached 8 3 Plotting Scan Results in Maestro You can display the results of a coordinate scan in the 1DPlot panel or the 2DPlot panel in Maestro depending on how many parameters you chose These panels were designed for dihe dral scans but can be used for any kind of scan The panels and their use is described below Since there are many common features of these panels the general features are described first The information given below is also available in the online help To open the 1D Plot panel or the 2D Plot panel choose 1D Plot or 2D Plot from the Tools menu in the main window 8 3 1 1D and 2D Plot Panel General Features Each panel consists of a plot area on the right and a set of controls on the left The common controls are described below the controls specific to a given plot are described in later sections Minimum Energy Maximum Energy These text boxes allow you to set the e
109. as a display area If you middle click in the plot area the structure in the Workspace is updated to reflect the coordinate values that corre spond to the pointer position on the plot and the energy and coordinate values are displayed in the Energy and Coordinate text boxes MacroModel 9 6 User Manual 71 Chapter 8 Coordinate Scans 72 Open 37 9 44 3 50 7 thioether out PostScript 57 0 63 4 69 8 Minimum energy 18 8 hipo pacta 2 Maximum energy 88 9 Full Scale Number of contours 10 s Contour width 2 4 Negative dashed Energy units kJ mol w kcal mol Energy scale 4 Absolute w Relative 4 Constrain to square Coordinate 1 Coordinate 2 Energy Decimal places X Axis Y Axis 0 60 120 180 240 300 360 Coordinate 1 TEN Close Help Figure 8 4 The 2D Plot panel 8 4 Checking and Interpreting Results Coordinate scan calculations involve minimizations and you should check that minimizations for all coordinate values converge MacroModel 9 6 User Manual Chapter 9 Conformational Searches A frequent question in molecular modeling studies is What conformations are important in this system One way to address this question is to perform a conformational search in order to find a set of low energy conformers MacroModel excels at conformational searching with a number of state of the art conformational searching methods des
110. ate files and atom based cutoffs for systems with only one residue or without such information MacroModel versions from 8 1 on include a new method for the truncation of electrostatic interactions It is termed Bond Dipole Cutoffs BDCO and lever ages the physics of charge charge charge dipole and dipole dipole interactions to give very accurate absolute electrostatic and generalized Born energies An example is the benzamidine trypsin complex PDB code 3ptb which contains 3245 atoms in an all atom representation for which results are given in Table 2 1 In addition to a smaller error in energy by two orders of magnitude than that seen with residue based cutoffs the BDCO calculation uses fewer non bonded pairs Because of this the BDCO calculation runs slightly faster than the residue based cutoff calculation Similar results are seen for generalized Born solvation polarization energies Table 2 1 Use of different cutoffs in a calculation on the benzamdine trypsin complex Number of Non bonded Pairsin Total Electrostatic Error Method Energy Calculation Energy kJ mol kJ mol BDCO 2731027 28697 73 2 08 res 3628479 29179 45 479 64 all 5254184 28699 81 0 0 a Residue based cutoffs b All non bonded pairs included in calculation MacroModel 9 6 User Manual Chapter 2 Basic Molecular Modeling The following subsections provide an overview of the physical basis and implementation of this novel method for truncating e
111. ated by more than 0 25 A upon superposition are considered different TORS Defines the variable torsions in the molecule Arg and arg2 are the atom numbers of the two central atoms defining a variable torsion Arg5 and arg6 define the minimum and maximum dihedral angle variations in both directions CONV Defines convergence criteria Arg1 2 specifies derivative convergence default criterion is 0 05 kJ mol A and this value is set in arg5 MINI Starts the minimization Argl defines the type of minimization algorithm to be used Arg1 9 means that Truncated Newton Raphson Conjugate Gradient will be used In arg3 the number of minimization steps is defined Arg3 can be set to a large number since the calcula tion automatically stops as soon as the convergence criterion has been reached 9 3 2 Multi Structure Conformational Search Using LMOD An example command file appears below for a conformational search calculation using low mode conformational searching Descriptions of the opcodes in the file follow However opcodes that are also in the MCMM command file example are not repeated See the explana tions in Section 9 3 1 serial lmcs mae serial lmcs out mae FFLD 10 1 0 1 1 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 41 5692 99999 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 LMCS 100 0 0 0 0 0000 0 0000 3 0000 6 0000 MCSS 2 0 0 0 50 0000 0 0000 0 0000 0 0000 MCOP 1 0 0 1 0 0000 0 0000 0 0000 0 0000 DEMX 0 166 0 0 50 0
112. ated with more minimization steps At the end of the log file is a table summarizing the results for all the ligands Substructures can be specified using ASL The substructure file has to be created by hand An example of a substructure file that uses ASL is SSCHRODINGER macromodel vversion samples Examples MBAE_Input_asl sbc This file is used with the command file MBAE_Tnput_as1 com and is reproduced here ASL1 1 all FXAT 0 0 0 0 1 0000 0 0000 0 0000 0 0000 FXAT 0 0 0 0 0 0000 0 0000 0 0000 0 0000 ASL1 0 not mol num 2 and fillres within 2 50 mol num 2 ASL1 1 m 2 ASL2 100 0 not fillres within 2 5 m 2 and fillres within 3 0 fillres within 2 5 m 2 ASL2 1 0 not fillres within 3 0 fillres within 2 5 m 2 and fillres within 3 0 fillres within 3 0 fillres within 2 5 m 2 Substructure addition and removal are performed with the ASL1 command Fixed and frozen atom definitions are made with the ASL2 command See the MacroModel Reference Manual for information on the syntax of these commands In the above example The first three lines clear all free fixed atom and frozen atom definitions respectively Although this is not very useful in the context of eMBrAcE it is useful when a SUBS command is used within a BGIN END loop The fourth line adds the atoms defined by the ASL string to the substructure In this case mol num 2 molecule number 2 is the ligand Thus the binding site consi
113. atoms is closer than arg6 times the sum of their van der Waals radii after loop generation just prior to minimization then the structure is rejected and another loop structure is generated Default 0 25 arg7 0 0 Automatically add all heavy atoms in the loop to the comparison list used in identifying conformations that are identical COMP entries Also automatically add all chiral atoms in the loop to the list of chiral atoms that need to be checked CHIG entries before accepting a generated conformer oO EMX arg5 1000 0 Keep conformers that are up to 1000 kJ mol higher in energy than the lowest energy conformers Such a large value might be appropriate if a follow up study using a conformational search method like LLMOD were going to be conducted MSYM arg2 1 Use mmsym to compare conformers The comparison is done in place that is translations and rotations of the protein as a whole are not permitted when comparing struc tures MCOP Print messages to the log file concerning every conformation generated CONV Minimizations are converged when the RMS gradient is less than 0 1 kJ mol A MINT Minimize the structure using the TNCG minimizer This LOOP run also writes out COMP and CHIG command lines containing the shifted atom numbers to the log file for explicitly and implicitly specified COMP atoms and CHIG atoms in the system These lines could be inserted into the command files for subsequent studies MacroModel 9 6 User Man
114. bstructure is used in which the freely moving region includes the ligand and any residues with atoms within 3 0 of the ligand A fixed and frozen region was also set up in the Substructure tab The conformational search parameters were initially set by using the Perform Automatic Setup button in the CSearch tab The parameters were then modi fied using the individual parameter panels in the CSearch tab to arrive at the sample instruction file below Only torsions in the ligand are being explicitly sampled in this example Descriptions of the opcodes in the file follow However opcodes in the previous command files in the chapter are not repeated See the previous examples for those explanations subs mecmm 1mod mae subs memm 1mod out mae MMOD 0 il 0 0 0 0000 0 0000 0 0000 0 0000 FFLD 11 dl 0 0 1 0000 0 0000 0 0000 0 0000 EXNB 0 0 0 0 0 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 89 4427 99999 0000 0 0000 0 0000 SUBS 0 0 0 0 0 0000 0 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 CRMS 0 0 0 0 10 0000 0 5000 0 0000 0 0000 LMCS 10 0 0 0 0 0000 0 0000 3 0000 6 0000 MCNV 2 4 0 0 0 0000 0 0000 0 0000 0 0000 MCSS 2 0 0 0 50 0000 0 0000 0 0000 0 0000 MCOP 0 0 0 0 5000 0 0000 0 0000 0 0000 DEMX 0 666 0 0 50 0000 100 0000 0 0000 0 0000 COMP 117 121 128 133 0 0000 0 0000 0 0000 0 0000 COMP 136 140 158 162 0 0000 0 0000 0 0000 0 0000 COMP 165 169 174 176 0 0000 0 0000 0 0000 0 0000 COMP 223 225 231 236 0 0000 0 0000 0 0000 0 0000 COMP 439
115. calculation based on the energy difference between iterations With the Movement setting MacroModel 9 6 User Manual Chapter 6 Minimizations 48 MacroModel determines when to stop the calculation based on the maximum atomic move ment at each iteration When the Nothing option is selected the calculation runs for the maximum number of iterations as specified in the Max Iterations text field The value in the Maximum iterations text box determines when MacroModel should end the calculation if the specified convergence criterion hasn t been met The default value is 50 for SD and FMNR minimization methods and 500 for the remaining methods To specify a different number of iterations enter it into the Maximum iterations text box The value entered in the Convergence threshold text box determines the threshold applied to the Converge on method The default convergence setting is convergence on Gradient with a threshold of 0 05 These settings will suffice in most cases 6 2 3 Using Multiple Minimization Stages During a Minimization The MWRT feature of MacroModel enables multiple minimizer methods to be automatically applied during the minimization stage of a MacroModel computation Each phase of an MWRT minimization can use a different minimizer method For instance an initial steepest descent minimization could be followed by an all purpose method with the process concluded by a minimizer method expected to result in final converge
116. cconnonccncnconnononn nn conorcor canon nr rc rra ninia 48 6 3 1 Constrained Minimizar ance iexteraceesszceubereascceeisiarescisnanietusacgesezee 49 6 3 2 Multiple Method MWRT Minimizations oooooonncccnnnccnccccnnccnnnncccnoncncancnonancannnc 50 6 4 Checking and Interpreting Results oonocccninnininninoncnnnnnicnonnccnnnccnncrnananancnnn 51 Chapter 7 Multiple MinimMizations ssrnrinannaninnaniii 53 7 1 The Multiple Minimization Pan el o ooooconnonnoncnicnnncnicnnnoncnncnccnnnncanrncnrncnn 53 7 2 Setting Up Multiple Minimization CalculationS oooinininninnididinninnicnionnnnno 53 7 3 Partition Coefficient EStiMati0N o ooonnninnininlvnininninninnnnonnnnnnccnnnnenccrnananancn 56 7 4 Automatic Setup AUTO ooccccionicioncnocicnnciococonnccncccnnnanononn no caronno rca roca nnn 57 7 5 Preparation of Multi Ligand Structure Files With premin 58 7 6 Command File Examples cccccccccceecceeeeeeeeeeeeeeeeeeeesaeeeseecaeeeseeeaseeseesaeeeseees 59 7 6 1 Energy Minimization of Multiple Non Conformets c cece teeeeeteeeee 59 7 6 2 Multiple Conformer Minimization With Automatic Redundant Conformer EllminatON z22 Sick Kee eee RR ee hike eat Re ee 61 7 6 3 Multiple Minimization with Substructures Defined by ASL 0 eee 62 MacroModel 9 6 User Manual Contents vi 7 6 4 Partition Coefficient Estima hacen eadineneeaeei cies 62 Chapter 8 Coordinate SCAIG
117. ceeeeeeeeeeceeeeceeseeeeceeeaeeesaesaseeseeeateaeaes 165 Chapter 18 Additional Features ssssssssssssssssssssssssssssssssssssssssssssssssssssssssssesseses 167 18 1 Geometry Calculations i omnia 167 18 2 Calculating Interaction Energies Using ASET uooccnioniciinnoniniononnicnoncccnns 167 18 3 Rewinding the Output File for Additional Minimization 168 18 4 Visualizing Vibrational Modes 00 00 cece ene ceeeeeeeeeeeeeaeeaeeaeteeeeeseeeeaes 169 18 5 Alignment of Structures ccc cee ceeeeeeeeeeeeeeceesaeeecsetaeeessetaseesseeateeeees 170 18 6 autoref Restrained Minimizations oo eeen 171 18 7 serial_split Split Serial Search Output Structure Files 172 18 8 PIRON SOPIS ireen cala pida 172 GUIA Hel osado S 175 MacroModel 9 6 User Manual Contents MacroModel 9 6 User Manual 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 and screen output Italic filename Text that the user must replace with a value Sans serif CTRL H Keyboard keys uppercase Links to other locations in the current document or to other PDF
118. ch3och3_drive out ch3sch3_drive out Symbol Hollow Circle Symbol color Red zs Symbol size 3 Curve Solid Curve color Red al Curve width 1 Delete Close Help Figure 8 3 The 1D Data panel MacroModel 9 6 User Manual Chapter 8 Coordinate Scans You can display multiple plots from grd files in the 1D Plot window Each plot is added by clicking the Open button and selecting the grd file The data sets are listed in the 1D Data panel You can delete a plot by selecting it in the list and clicking Delete The plot area itself is an interactive tool as well as a display area If you middle click in the plot area the structure in the Workspace is updated to reflect the coordinate values that corre spond to the pointer position on the plot and the energy and coordinate values are displayed in the Energy and Coordinate text boxes You can drag horizontally with the middle mouse button and the structure changes as you move the mouse Note that the displayed structure s movement is rigid rotor The original calculations used to obtain the data for the plot however are performed with all other degrees of freedom minimized Even so the molecule s move ment should give some idea of the geometry at various points on the plot If you have more than one plot in the plot area only the last structure added is displayed and updated To create a tab separated file that can be read by a spreadsheet click T
119. command files written this way are complete and adequate For some types of jobs however you may need to adjust the Maestro generated command file Redundant conformer elimination is performed in MacroModel by the ADDC opcode Each time ADDC is executed it tries to add the current structure to the collection of output MacroModel 9 6 User Manual 165 Chapter 17 Redundant Conformer Elimination 166 conformers The same checks for redundancy and transformations such as net translation and rotation of the current structure are performed as in a multiple minimization of conformers see COMP but no minimization or energy estimation is conducted Energies from earlier MacroModel or Jaguar calculations may be used as part of the comparison process see in the MacroModel Reference Manual 1f MacroModel energies are to be used then a FFLD line with the same force field used to calculate the energies must precede the ADDC line See the MacroModel Reference Manual for information on ADDC DEMX ADDC should be used much like MINT in a multiple minimization calculation The command file below reads in conformers from the file addc mae orders them by increasing Jaguar energy superimposes the structures on the lowest Jaguar energy structure eliminates redundant conformers and writes out the resulting structures to addc out mae addc mae addc out mae DEMX 0 0 0 0 10 0000 MSYM T 0 0 0 0 0000 BGIN 0 0 0 0 0 0000 READ 0
120. conformers This enables a conformation search to be performed with a higher minimization gradient specified for generated conformers followed by minimization to a lower gradient with duplicate elimination all in a single MacroModel computation This workflow can be more efficient than minimizing all generated structures during the conformation search itself The same potential settings should be used for both segments of the calculation The command file below combines a low mode conformation search with a subsequent multiple minimization of the generated conformers to efficiently produce a set of low energy conformers with a small convergence gradient MacroModel 9 6 User Manual Chapter 18 Additional Features rwnd mae rwnd out mae MMOD 0 Y 0 0 0 0000 0 0000 0 0000 0 0000 FFLD 11 q 0 0 1 0000 0 0000 0 0000 0 0000 SOLV 3 Al 0 0 0 0000 0 0000 0 0000 0 0000 EXNB 0 0 0 0 0 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 89 4427 99999 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 LMCS 1000 0 0 0 0 0000 0 0000 3 0000 6 0000 MCSS 2 0 0 0 50 0000 0 0000 0 0000 0 0000 MCOP 1 0 0 0 0 0000 0 0000 0 0000 0 0000 DEMX 0 1666 0 0 50 0000 100 0000 0 0000 0 0000 COMP 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MSYM 0 0 0 0 0 0000 0 0000 0 0000 0 0000 CONV 2 0 0 0 0 0500 0 0000 0 0000 0 0000 MINI 1 0 5000 0 0 0000 0 0000 0 0000 0 0000 RWND 0 0 0 0 0 0000 0 0000 0 0000 0 0000 BGIN 0 0 0 0 0 0000 0 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0
121. consist of four atoms that define the bond to be broken and then re closed during an MCMM or SPMC step The simplest way to create ring closures is to use the Perform Automatic Setup button Macro Model makes reasonable decisions about where a ring should be opened The list of atoms in the ring that will be opened appears in the text box at the top of the Ring Closures panel Each ring closure is defined by four atoms The opening is made between the second and third atoms If Show markers is selected the ring closure is marked by a light green line which is broken between the second and third atoms A lightning bolt is also placed between the second and third atoms to show where the opening will be made The functions of the Ring Closures panel are described below Minimum distance You must specify the minimum acceptable distance between the second and third ring closure atoms If the distance between the ring closure atoms is less than this minimum distance then the ring is reopened and a different set of random variations is performed The default value for this is 0 5 A This value should suffice for most searches MacroModel 9 6 User Manual 81 Chapter 9 Conformational Searches 82 _ Ring Closures Minimum distance 0 500 Maximum distance 2 500 Define ring closures F Pick Atoms E Show markers Delete Delete All Close Help Figure 9 2 The Ring Closures panel Maxi
122. cribed in the sections below Conformational searches typically cycle through the process of generating a new structure minimizing it and then determining if the structure should be retained Structure retention can be based upon energy relative to that of the lowest energy conformer found so far in the search and redundancy with other generated structures 9 1 Conformational Search Methods A variety of conformational search methods is available The methods available in Macro Model are described below Monte Carlo Multiple Minimum MCMM The Monte Carlo method MCMM implemented in MacroModel is highly efficient in performing global searching exploring close as well as distant areas of the potential energy surface PES Random changes are made in torsion angles during the search Although there is no limit to the number of variable torsions allowed in the search more than about 10 or 15 flexible torsions greatly increases the complexity of the search You should therefore expect increased searching times and possibly also non convergence of the search See References 20 and 21 for more information Systematic Pseudo Monte Carlo SPMC If the task is to locate all possible conformational minima on the surface MacroModel s systematic method SPMC ensures the exploration of unusual torsional values SPMC allows for high efficiency throughout the search even at the end where other methods tend to revisit already found conformers The SPM
123. croModel 9 6 User Manual 65 Chapter 8 Coordinate Scans Coordinate Scan EE Use structures from Workspace included entry 4 Potential Constraints Substructure Mini Scan Delete Delete All Initial 0 0 Final 360 0 Increment 30 0 Define coodinate to scan Coordinate Type Dihedral F Pick Atoms s Select M Show markers Start Write Close Help Figure 8 1 The Scan tab of the Coordinate Scan panel You should pick two atoms or one bond for a distance three atoms or two bonds for an angle and four atoms or three bonds for a dihedral The picked atoms are marked with purple cubes until the last pick is made The cubes are then replaced with a line that marks the coordinate and a symbol for the scan type Distances are marked in purple angles in green and dihedrals in aquamarine You can also click the Select button to select protein dihedrals by their standard names psi phi omega etc 4 Enter values for the range and step size in the Initial Final and Increment text boxes An increment can be negative but only if the initial value is larger than the final value For distances the default values are 1 0 and 10 0 angstroms for the initial and final val ues and 1 0 angstroms for the increment For angles and dihedrals the default initial and final values are 0 and 360 and the default increment is 30 The minimum angle or dihedral increment is
124. ction 85 9 255 Chiral AMS ista 86 9 2 5 6 DistanGe Cheek antie a a aaiae 87 9 257 TORSION CHECK N it 88 9 2 5 8 Ligand BONdS rica a eraai tidenes 89 9 3 Command File Examples S ssaki iiae 90 9 3 1 Conformational Search Using MCMM 0 sscseseseeeseeeeereeereeeeeeeeeeeesnereneees 90 9 3 2 Multi Structure Conformational Search Using LMOD ee eee eee g2 9 3 3 Mixed MCMM Low Mode Search Using a Substructure File o cio nno 93 9 3 4 Conformational Searches Using Multiple Minimization Methods MWRT 94 MacroModel 9 6 User Manual Contents 9 4 Checking and Interpreting Results oooooconinnincnnnnncninnicnnnccnnncrnncnnanananinnn 95 Chapter 10 Dynamics Calculations vsiscicnicni lili 97 10 1 The Dynamics Panel 3 4 c c ccseacsscsscrscneatnanesceatnenseaeaconadaacssanaccestaansnanscesotaceananssess 97 10 2 Performing a Dynamics Calculation oouonoininininininnnionnonnnionncccncnanncncnnns 97 A A ladeisars 97 AS o AAA oiai oaa aiai 99 10 2 1 2 IDISIANCOS isena E EASE ANAE AE EE 99 A iaaa da a Ai aiia 100 10 2 1 4 TOrSiONS isc iris rn RRA 100 10 2 1 5 H BOMS iciciicininccnnar circa 100 10 2 1 6 Monitorning QUIPUE pcia 102 10 22 The D pamics Mac 102 10 3 Command File Examples ooocoionionicicnnnninnononnconnnnccncanancranrrcnnrrn ronca 104 10 3 1 Stochastic Dynamics sects aso iia a laa 104 10 3 2 Simulated Annealing iii a 105 10 4 Checking and Interpreting
125. cture The new starting structure must be within arg5 kJ mol of the lowest energy conformer found in the search MCOP Monte Carlo options determine what and how often data is written to the log file Arg1 1 ensures printing to the log file at every search step DEMX This command is used to prevent saving of high energy conformers during the search Arg5 defines the allowed energy window above the currently found global minimum New conformers that are not within arg5 kJ mol will be discarded Additionally a preliminary energy test can be performed during the energy minimization to ensure that a reasonable struc ture has been found Arg2 sets the number of energy iterations to be performed before the preliminary test a good value is approximately 1 3 of the total number of energy iterations while arg6 defines the energy above which conformers will be discarded a value of about 1 5 2 times arg5 is recommended MSYM Invokes the numbering symmetry library mmsym which automatically and more gener ally identifies a suitable numbering order for use in comparing molecular conformations COMP Argl arg4 list the atom numbers of atoms to be used in structural comparison with all previously found conformers A maximum of 200 atoms can be used in the comparisons For MacroModel 9 6 User Manual 91 Chapter 9 Conformational Searches 92 arg1 0 all heavy atoms are compared By default structures that have equivalent atoms sepa r
126. d Writes the lead structures for each of five clusters to the output structure file For more information on these commands see Chapter 4 and Chapter 8 of the MacroModel XCluster Manual MacroModel 9 6 User Manual Chapter 16 Molecular Clustering with XCluster 16 3 XCluster Output XCluster analysis is mainly carried out using the visualization tools in the XCluster interface after the cluster calculation is finished In addition structural output can be generated from the Write panel which you can open from the File menu or from the visualization panels A log file is generated after a successful XCluster computation as jobname c1g MacroModel 9 6 User Manual 161 162 MacroModel 9 6 User Manual Chapter 17 Redundant Conformer Elimination Collections of conformers can contain structures that are essentially the same based upon energetic or geometric considerations The redundant conformer elimination facility allows you to use MacroModel to remove the extra conformers rapidly without reminimizing or re evaluating the energy One important use for this facility is in the complementary use of MacroModel and Jaguar to conduct a very high quality conformational search In this approach MacroModel is used to perform the initial conformational search typically using GB SA solvation To increase the accuracy of the geometries and energies of the structures produced Jaguar is used to remini mize the collection of conformers S
127. d shell section Specifying a Shell Radius You can assign a radius by entering a value into the Radius text box The shell includes all atoms within the given radius of the previous shell or the substruc ture if it is the first shell Picking Additional Shell Atoms To add individual atoms to a shell select a structural unit from the Pick menu and pick Workspace atoms You can also add shell atoms by entering an ASL expression in the Additional atoms for shell section or by constructing an ASL expression in the Atom Selection dialog box which you open with the Select button Atoms may be added even if a substructure has not been defined Setting the Force Constant for a Shell Shell atoms that are to be constrained rather than frozen are allowed to move a finite distance based on the force constant value you supply Enter the desired force constant in the Force constant text box Freezing Atoms in a Shell To freeze atoms in a shell so that the atoms cannot move at all select Freeze atoms Filling Out Residues in a Shell You can include in the shell all atoms in residues having any members in the original shell definition by selecting Complete residues Deleting a Shell To delete an existing shell select the shell number in the Shells list and click Delete MacroModel 9 6 User Manual 35 Chapter 4 General Settings 36 4 5 3 Reading and Writing Substructures You may want to write your substructure definitions to a
128. del 9 6 User Manual 43 Chapter 5 Current Energy Calculations 44 You should also bear in mind the points raised in Section 2 2 on page 7 Detailed energy listings can be useful particularly in conjunction with Maestro s Force Field Viewer tool for the following reasons To gain insight into what interactions are key within the system To understand how important parameters of limited quality are for a particular calculation e To examine problematic structures MacroModel 9 6 User Manual Chapter 6 Minimizations Energy minimization is a key type of calculation in molecular modeling in part because it gives a distinct structure that is often related to a subset of conformers found under thermal conditions It also plays an important role in many compound calculations such as conforma tional searching and thus this chapter is a useful one to review carefully MacroModel provides a number of well tested and efficient minimization methods 6 1 The Minimization Panel The MacroModel Minimization panel is used to set up and submit minimization calculations from within Maestro The Minimization panel consists of five parts The first part the upper portion of the panel contains controls for general aspects of job set up such as job name and job source This portion of the panel also appears on the other MacroModel energy panels The Minimization panel contains four tabs the first three of which also appear in the
129. del 9 6 User Manual Chapter 14 eMBrAcE Association energy mode The eMBrAcE calculation can function in two modes The first mode is Energy difference mode In this mode the calculation is performed first on the receptor then on the ligand and finally on the complex The energy difference is then calculated using the equation AE Ptos Biar The full effects of relaxation and solvation are included in this mode The second is Interaction energy mode In this mode the atoms in the ligand and the receptor are separated into two sets and the interaction energy between the two sets is calculated Inter action energy mode deals with terms that can be considered pair wise additive so the surface energy term in the solvation energies is not included in the interaction energy Interaction energy mode does not include the relaxation or the change in solvation of the ligand on binding To specify a preference for calculation of the association energy select either Energy Differ ence Mode or Interaction Energy Mode Structures saved The three options for how output structures are written to the output structure file are Complexes only minimized complexes Ligands only ligand structures extracted from mini mized complexes and Receptor ligands and complexes in which the receptor minimized without a ligand and ligands minimized without the receptor are written For interaction mode the last option is equivalent to Complexes only
130. documents are colored like this Document Conventions In descriptions of command syntax the following UNIX conventions are used braces enclose a choice of required items square brackets enclose optional items and the bar symbol separates items in a list from which one item must be chosen Lines of command syntax that wrap should be interpreted as a single command File name path and environment variable syntax is generally given with the UNIX conven tions To obtain the Windows conventions replace the forward slash with the backslash in path or directory names and replace the at the beginning of an environment variable with a at each end For example SCHRODINGER maestro becomes 3SCHRODINGER maestro In this document to type text means to type the required text in the specified location and to enter text means to type the required text then press the ENTER key References to literature sources are given in square brackets like this 10 MacroModel 9 6 User Manual xii MacroModel 9 6 User Manual Chapter 1 MacroModel Overview 1 1 MacroModel User Manual This manual contains an introduction to the MacroModel molecular mechanics program For detailed information about command line MacroModel and MacroModel operation codes see the MacroModel Reference Manual For tutorial exercises that demonstrate Maestro and MacroModel functionality see the MacroModel Quick Start Guide For information on using
131. e Manual An alternative simplified input file is available for certain kinds of calculations Jobs using this simplified input file can be run with the SCHRODINGER macromodel command For details see Chapter 3 of the MacroModel Reference Manual 3 13 The MacroModel Command File Format To run MacroModel calculations a molecular structure file and a command file are required The molecular structure file contains the structures to be used as input in the calculation The command file contains the name of the input structure file the name of the output structure file and an ordered list of operation codes or opcodes for the calculations A generalized form of a MacroModel command file is given below jobname mae jobname out mae MMOD 0 1 0 0 0 0000 0 0000 0 0000 0 0000 FFLD 10 1 0 1 1 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 20 0000 99999 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 CONV 2 0 0 0 0 0500 0 0000 0 0000 0 0000 MINI Al 0 500 0 0 0000 0 0000 0 0000 0 0000 This file must have a name in the form of jobname com where jobname is replaced with the actual name of the job Thus a job that was actually named jobname could be submitted from the command prompt with a command such as SSCHRODINGER bmin jobname Maestro uses a similar command for computations prepared with the interface The first line of the instruction file above is the name of the input structure file The input structure file can be na
132. e in the minimization of a protein ligand complex the region of interest is the ligand and the area surrounding the ligand The large outer regions of the protein may not significantly influence the structure of the minimized ligand or its vicinity and these regions may therefore be excluded from the calculation Fixing or freezing remote portions of the system can help further reduce computational time and provide buffer zones between fully moving and ignored regions Frozen atoms cannot move while fixed atoms are restrained to lie close to the requested posi tions Moving atoms interact with all other moving fixed and frozen atoms in the usual way However among the fixed or frozen atoms only stretch interactions involving fixed atoms are considered Eliminating most of the interactions among the fixed or frozen atoms can save a great deal of computer time and is a useful approximation provided that the potentials restraining the fixed atoms are strong enough to prevent dramatic distortions of the molecular structures 4 3 1 Methods for Freezing and Fixing Atoms In MacroModel there are two ways of constraining parts of a molecular system Using constraints Manually fixes atoms and also distances angles or torsions through the use of FXAT or FXDI FXBA or FXTA commands either using the Constraints panel in Maestro or by directly modifying a command file Only the geometry of the items explicitly specified is affected All other parts
133. each structure in the input structure file and is enabled by selecting Multi ligand next to the Method option menu For this procedure Perform automatic setup during calculation is selected and cannot be deselected Mixed torsional Low mode sampling This method uses a combination of the random changes in torsion angles and or molecular position from the MCMM method together with the low mode steps from the LMOD method used in pure low mode See page 74 and the MCMM and LMCS opcode descriptions in the MacroModel Reference Manual for a detailed description of this method MacroModel 9 6 User Manual Chapter 9 Conformational Searches You can use ths method to perform a separate search on each structure in the input structure file by selecting Multi ligand next to the Method option menu For this procedure Perform auto matic setup during calculation is selected and cannot be deselected Large scale low mode sampling Large Scale Low Mode LLMOD is similar to Low Mode LMOD except that it uses tech niques to reduce the memory requirements so that it can be applied to much larger systems such as protein ligand complexes Like LMOD LLMOD methods search conformational space aggressively enough to switch the chirality of atoms within the structures provided Chirality checking should be used for chiral atoms for which such chirality switching is unde sirable see Section 9 2 2 on page 77 See the LMC2 and ARPK opcode descriptions in t
134. el 9 6 User Manual Chapter 2 Basic Molecular Modeling e The paper gives the two nitrogen types different van der Waals parameters but the AMBER 4 1 program uses the same parameters for both We follow the program s con vention MMFF Our implementation is identical to that described by Halgren 9 15 We supply both MMFF94 and MMFF94s the latter enforces planarity about delocalized sp nitrogens OPLS_2001 and OPLS_2005 have much in common In this document we refer to them collectively as OPLSAA where necessary Whenever a current energy calculation ECalc is carried out a listing file jobname mmo can be produced which contains all parameters used in the calculation along with the origin and quality of each parameter Note that any torsion parameter where V1 V3 are all set to zero will not be included in the output To include these in the listing it is necessary to include the DEBG 56 command in the command file see the MacroModel Reference Manual for details This automatic parameter referencing feature provides important information on the quality and reliability of the calculation Different force fields use different defaults for their electrostatic treatment constant or distance dependent dielectric and their cutoff distances van der Waals and electrostatic It is possible to set such options exactly as in the authentic fields using the Electrostatic Treatment and Cutoff option menus in the Potential tab within Maes
135. el Current Energy calculations The Current Energy panel contains 4 tabs each of which contains tools and settings related to a different aspect of a Current Energy calculation Potential Constraints Substructure and ECalc The first three tabs were described in Chapter 4 so only the ECalc tab is described in this chapter To open the Current Energy panel choose Current Energy from the MacroModel submenu of the Applications menu in the main menu bar 5 2 The ECalc Tab The Energy Listing option menu allows you to select the amount of information in the energy listing for the current job Selecting the None setting results in the total molecular mechanics energy being listed in the jobname log file Selecting Minimal prints in addition a minimal summary in the Energy Summary file jobname mmo Selecting Complete lists the complete energy output to the Energy Summary file including all internal coordinate components A complete energy listing is required to use Maestro s force field viewing tool You should note however that performing calculations with a complete energy listing can create large output files MacroModel 9 6 User Manual 39 Chapter 5 Current Energy Calculations 40 Use structures from Workspace included entry Potential Constraints Substructure ECalc Energy listing None 1 Start Write Close Help Figure 5 1 The ECalc tab of the Current Energy panel
136. emmod mmodmae Convert between Maestro and MacroModel file formats mmodmol molmmod Convert between MacroModel and Sybyl Mol2 file formats maesubset Selects a subset of the structures from a multistructure Maestro file propfilter Selects structures from a multistructure Maestro file based on proper ties proplister Lists selected properties present in structures within a multistructure Maestro file sdconvert Converts between SD and Maestro or MacroModel file formats sdsubset Selects a subset of the structures from a multistructure SD file For more information on these utilities see Appendix D of the Maestro User Manual MacroModel 9 6 User Manual 3 Chapter 1 MacroModel Overview 1 6 Running Schr dinger Software To run any Schr dinger program on a UNIX platform or start a Schr dinger job on a remote host from a UNIX platform you must first set the SCHRODINGER environment variable to the installation directory for your Schr dinger software To set this variable enter the following command at a shell prompt csh tesh setenv SCHRODINGER installation directory bash ksh export SCHRODINGER installation directory Once you have set the SCHRODINGER environment variable you can start Maestro with the following command SSCHRODINGER maestro amp It is usually a good idea to change to the desired working directory before starting Maestro This directory then becomes Maestro s working directory For
137. ents of the jobname log file are displayed as it is written While jobs are running the Detach Pause Resume Stop Kill and Update buttons are active When there are no jobs currently running only the Monitor and Delete buttons are active You can choose to monitor or delete the currently selected job by clicking the corresponding buttons To monitor or delete another job in the database first choose the job in the list and then click the appropriate button You can also monitor jobs from other projects For more information on the Monitor panel see Section 5 2 of the Job Control Guide MacroModel 9 6 User Manual 37 38 MacroModel 9 6 User Manual Chapter 5 Current Energy Calculations Determining the current energy for a structure is a basic type of calculation in molecular modeling Setting up a current energy calculation in MacroModel involves many of the same steps as other calculations within MacroModel so be sure to read this chapter carefully In addition to calculating the total energy for the structure MacroModel can be instructed to produce an mmo file during a current energy calculation An mmo file contains detailed infor mation on the various contributions to the potential energy and can lead to a number of insights Maestro s Force Field Viewer is an excellent tool for interactively examining this information 5 1 The Current Energy Panel You can use the Maestro Current Energy panel to prepare and submit MacroMod
138. ependent minimizing the same initial structure using different force fields usually results in similar but not identical structures MacroModel 9 6 User Manual 51 52 MacroModel 9 6 User Manual Chapter 7 Multiple Minimizations Multiple minimization is a tool for automatically minimizing a collection of structures The collection of structures can be different molecules or they can be conformations of the same molecule If the structures are conformers then it is possible to do the minimization in conjunction with the elimination of redundant conformers MacroModel uses multiple minimi zation a number of ways some of which are described in this chapter 7 1 The Multiple Minimization Panel The Multiple Minimization panel is used to set up and submit minimization jobs that use as input either a Maestro or MacroModel formatted file containing the structures to be minimized If the structures are conformers then redundant conformers are eliminated if comparison atoms are specified The Multiple Minimization panel can also be used to perform partition coefficient estimation The Multiple Minimization panel consists of several parts four of which the upper portion Potential Constraints and Substructure tabs are common to all MacroModel energy panels These components are described in detail in Section 4 1 on page 25 through Section 4 5 on page 33 The Mini tab is common to all of the MacroModel panels except Current Energy For
139. ergy conformation found so far We recommend using a large value to permit seed structures with different alignments to be restrained and sampled SUBS Substructures may be used All opcodes related to the substructure SUBS FXAT FXDI FXBA and FXTA should be defined in an sbc file The sbc file should contain only lines referring to the receptor with the receptor atoms numbered starting from 1 In this case we specify arg2 1 to indicate that the name of the original jobname sbc file is to be used READ This READ command obtains the structure of the receptor MCMM The second MCMM selects Monte Carlo Multiple Minimum searching for the search of each isolated ligand and each ligand receptor complex Arg1 defines the number of steps to use for each search This need not match that used in the search of the receptor MCOP Monte Carlo options that determine what and how often data is written to the log file and how many structures are saved for the searches of the ligand receptor complexes argl 1 Print information for every search step to the log file arg3 10000 Use a large number to avoid spurious lines in the eMBrAcE summary table at the end of the run arg6 2 0 Save only the two lowest energy conformations from the complexes for each ligand arg7 4 0 Seed the search for each ligand using all four alignments previously generated using the ALGN command 14 4 3 Distributed eMBrAcE Calculations Any eMBr
140. essary because the final MINI command ensures that the mini mized structure is written to the output file See Section 10 3 1 on page 104 for a description of the other opcodes in this file 10 4 Checking and Interpreting Results It is often difficult to know when you have sampled enough in a molecular dynamics simula tion It usually is helpful to have some prior knowledge of the time scales for crucial processes within the system to know if convergence may have been achieved While molecular dynamics simulations provide a wealth of structural and temporal informa tion the information is often hard to interpret If the goal is to thermally sample the local conformational minimum of a small molecule then you might not need to examine the results carefully provided that you have simulated sufficiently long 50 to 100 ps may be enough However if the system is large and the conformational variation is large simulations likely will not adequately sample the conformations available and careful problem specific consid eration of the results may be needed to learn from such studies In such circumstances it almost always helps to examine the trajectory visually with a tool such as Maestro s ePlayer In addition clustering tools such as XCluster may help you identify when key events occurred during the simulation MacroModel 9 6 User Manual Chapter 11 MC SD Calculations Monte Carlo Stochastic Dynamics MC SD performs constant te
141. estro or from the command line Section 4 7 of the MacroModel Reference Manual contains informa tion on the commands required for a command line coordinate scan 8 1 Performing a Coordinate Scan in Maestro You can use the MacroModel Coordinate Scan panel to set up and submit coordinate scan calculations on either one coordinate or two coordinates of the same type The tools in the Scan tab allow you to define the coordinates for the calculation to set the range through which the coordinates are to be scanned and to specify the increment for each point in the scan All of the components of the Coordinate Scan panel with the exception of the Scan tab appear on other MacroModel energy panels For information about the upper portion of the Coordinate Scan panel the Potential Constraints and Substructure tabs see Section 4 1 on page 25 through Section 4 5 on page 33 For information about the controls in the Mini tab see Section 6 1 on page 45 To open the Coordinate Scan panel choose Coordinate Scan from the MacroModel submenu of the Applications menu on the main menu bar To set up a coordinate scan 1 Choose a coordinate type from the Coordinate type option menu You can choose Distance Angle or Dihedral This choice fixes the coordinate type for the scan if you scan two coordinates they must be of the same type 2 Choose Atoms or Bonds from the Pick menu 3 Pick atoms or bonds in the Workspace to define the coordinate Ma
142. ethers 7 all parameters are native OPLS_2001 The new thio parameters which use appreciably smaller charges on sulfur and which have been validated in liquid phase simula tions on thiols and thiol ethers significantly improve the conformational energetics of CYS and MET residues in proteins OPLS_2005 OPLS_2005 is an enhanced version of the OPLSAA all atom force field devel oped by Schr dinger to provide a larger coverage of organic functionality In particular all torsional parameters have been refit to reproduce the conformational energetics derived at a higher level of quantum theory and additional charges have been fit to support additional organic functionality The parameters for proteins have been updated to the ones published more recently Kaminski G A Friesner R A Tirado Rives J Jorgensen W J J Phys Chem B 2001 105 6474 AMBER94 All force field equations and parameters are the same as in Cornell et al 8 with the following small exceptions e In MacroModel partial charges are specified by bond dipoles rather than as charge values The partial charges may differ slightly between the two implementations these differ ences are typically in the fifth significant figure The atoms defining improper torsions are not specified by the AMBER protocol in situa tions of high local symmetry This may sometimes give rise to small differences in molecular energies or geometries between the two programs MacroMod
143. ethod of free energy perturbation calculations and describes how to perform a free energy perturbation with MacroModel If you intend to perform free energy perturbations we strongly recommend that you become familiar with the current literature on this topic see Section 15 5 on page 154 Note The MM2 and MM3 force fields should not be used for Free Energy Perturbation 15 1 Free Energy Perturbation The fundamental expression for free energy calculations as implemented in MacroModel is Gp G AG RT In exp 22 241 0 where H A and H y are the Hamiltonians for the two systems A and B and the lt gt notation represents an ensemble average over system A This expression is valid only when there is a very small difference between the two systems A and B i e H H RT To perform free energy calculations on meaningful systems you generally perform a series of smaller simula tions windows which can be summed to obtain a total free energy difference The coupling parameter lt A gt is used to define each window in terms of the two endpoints A and B so that at any stage the Hamiltonian over which the ensemble average will be generated for the system is described in terms of the Hamiltonians for the endpoints H A AHg 1 NH 2 Then the overall expression for performing a simulation becomes AG gt RT In exp peau i 3 RT A 1 where n is the number of windows to be used in the simulation At any w
144. f 101 windows can be used in a MacroModel FEP calculation so the minimum permissible value of the difference between arg5 and arg6 is 0 01 When used inside a BGIN END pair as in this example arg5 and arg6 will be incremented each pass through the loop as illustrated in the table below Most simulations require at least 20 windows to ensure that the free energy difference per window which must be lt 3 RT remains sufficiently small MacroModel 9 6 User Manual Chapter 15 Free Energy Simulations Pass Mleft Mmiddle Mright 1 0 00 0 00 0 05 no middle gt left sampling 2 0 0 0 05 0 10 middle gt left and left gt right 3 0 05 0 10 0 15 middle gt left and left gt right 4 0 10 0 15 0 20 middle gt left and left gt right 20 0 90 0 95 1 00 middle gt left and left gt right 21 0 95 1 0 1 0 no middle gt right sampling MDYN Describes the dynamics simulation in which the free energy sampling is done In this simple case we are only doing 100 ps of mixed mode simulation at each window In real cases gt 500 ps simulation per window will probably be required E ND The end of the BGIN END loop The loop terminates when the value of A middle exceeds 1 0 ESU Prepare a summary of the free energy change during the simulation 15 2 3 Other Possible Command Files Performing specific windows Although it is useful to wrap free energy calculations in a BGIN END loop and simulate with all windows
145. fine a combination of fixed frozen atom shells having different force constants around the movable part These shells are defined based on a user selected radius in Angstroms from the flexible part of the system To avoid cutting amino acid residues in two by the radius definition Maestro offers a Fill residues option that ensures that if any atom of a residue is within the defined radius the full residue is included in the shell Additionally there is an option for adding isolated atoms to any shell Each shell can be assigned a different force constant for a fixed shell or can be completely frozen force constant takes a negative value Looking at a protein ligand complex as an example the flexible part is most easily defined by picking By choosing Molecules from the Pick menu in the Freely moving atoms substructure section you can select an atom in the ligand to define the whole ligand as part of the substruc MacroModel 9 6 User Manual Chapter 4 General Settings 30 ture Atoms belonging to the substructure are identified by white markers on screen If parts of the active site are to be included in the substructure as well selected residues can easily be picked by choosing Residues from the Pick menu and clicking on an atom in each residue to be included Alternatively a shell of flexible residues can be defined using the Atom Specification Language ASL in the ASL text box or in the Atom Selection dialog box Assuming t
146. hat the ligand is molecule number one and the protein is molecule number two the following command in the substructure definition field places the ligand and a 3 5 shell of filled out residues in the substructure part m 1 or fillres within 3 5 m 1 The different shells defined around the substructure have markers of different colors orange purple etc in order to easily visualize the various selections on screen After the substructure and shell selections are made the substructure filename sbc file can be written to disk The name of the substructure file must match the input file The substructure file has the following format Command argl arg2 arg3 arg4 arg5arg arg7 arg8 SUBS 1 2 3 4 0 0 0 0 SUBS 5 6 7 8 0 0 0 0 Pass FXAT 123 0 0 0 200 0 0 0 S FXAT 124 0 0 0 Sih Og 0 0 For the SUBS part of the substructure file argl 4 Atom numbers of atoms included in the substructure flexible part of the system arg5 8 Not normally used For the FXAT part of the substructure file argl Atom number of atom to be included in fixed frozen part of the system arg2 4 Not used arg5 Force constant kJ mol A used for atom listed in arg1 If the force constant is neg ative the atom is frozen arg6 8 Desired X Y Z coordinates of atom defined in argl If all are zero the default the starting coordinates are used Note that the SUBS command in the MacroModel command file takes on two meanings depe
147. he MacroModel Reference Manual for a detailed description of this method Large scale low mode sampling can use a large amount of memory If memory issues are encountered consider eliminating the use of solvation In addition reducing non bonded cutoffs also reduces the memory required for the computation You can do this in the Potential tab by selecting Normal from the Cutoff option menu or by selecting User defined and entering the appropriate reduced values in the text boxes Mixed torsional Large scale low mode sampling This method uses a combination of the random changes in torsion angles and or molecular position from the MCMM method together with the low mode steps from the LLMOD method used in Large scale low mode See the MCMM LMC2 and ARPK opcode descriptions in the MacroModel Reference Manual for detailed descriptions of this method 9 2 2 Automatic Setup of Conformational Search Variables Before you start a conformational search the values for certain variables need to be set such as which torsions are to be rotated and which rings are to be opened There are three ways to set up conformational search variables from the CSearch tab using Perform Automatic Setup using Perform automatic setup during calculation or setting variables manually Setting confor mational search variables manually is described in the next section The automatic setup procedures select comparison atoms and other conformational search parameters fo
148. he command files and the log files for the examples given in this section can be found in SSCHRODINGER macromodel vversion samples Examples 9 3 1 Conformational Search Using MCMM An example command file appears below for a conformational search calculation that uses the MCMM search method Descriptions of the opcodes in the file follow mcmm mae mcmm out mae MMOD 0 1 0 0 0 0000 0 0000 0 0000 0 0000 FFLD 10 1 0 1 1 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 41 5692 99999 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MCMM 100 0 0 0 0 0000 0 0000 0 0000 0 0000 MCNV 2 4 0 0 0 0000 0 0000 0 0000 0 0000 MCSS 2 0 0 0 50 0000 0 0000 0 0000 0 0000 MCOP Ki 0 0 0 0 0000 0 0000 0 0000 0 0000 DEMX 0 166 0 0 50 0000 100 0000 0 0000 0 0000 MSYM 0 0 0 0 0 0000 0 0000 0 0000 0 0000 COMP 1 2 3 4 0 0000 0 0000 0 0000 0 0000 COMP 5 6 7 9 0 0000 0 0000 0 0000 0 0000 COMP 10 14 15 16 0 0000 0 0000 0 0000 0 0000 COMP 17 25 26 27 0 0000 0 0000 0 0000 0 0000 COMP 28 29 30 31 0 0000 0 0000 0 0000 0 0000 TORS 1 14 0 0 0 0000 180 0000 0 0000 0 0000 TORS 6 25 0 0 0 0000 180 0000 0 0000 0 0000 TORS 14 15 0 0 0 0000 180 0000 0 0000 0 0000 TORS 15 16 0 0 0 0000 180 0000 0 0000 0 0000 TORS 25 26 0 0 0 0000 180 0000 0 0000 0 0000 CONV 2 0 0 0 0 0500 0 0000 0 0000 0 0000 MINI 9 0 500 0 0 0000 0 0000 0 0000 0 0000 MMOD Creates and updates an intermediate structure file so that structures can be displayed in Maestro as the job progresses MacroMode
149. he experiments 33 The results of this analysis are shown in the following figure and table AH kcal mol AS e u N 1H NMR IR Simulation 1H NMR IR Simulation 4 1 5 1 4 1 65 8 0 6 8 8 6 In this system where there are two well defined states we have been able to obtain thermody namic parameters which agree well with experiment from direct simulation without using any perturbation techniques The reason that both of these simulations were able to obtain quantitative agreement with experiment is that we closely followed this procedure e Careful parametrization of the gas phase conformational energy differences against ab initio calculations at the 6 31G level Use of the GB SA solvent model N ae N ie Figure 15 3 The diamide structure MacroModel 9 6 User Manual 153 Chapter 15 Free Energy Simulations 154 Gellman Diamide n 4 van t Hoff plot comparing data from 10ns 1 1 mixed mode simulations in GB SA CHCI3 with experimental results from H NMR and IR measurements 0 0 0 2 Ink expt IR 1 Ink expt NMR i 0 4 0 6 Ink 0 8 A 7 S Pam 1 4 E 1 6 Figure 15 4 van t Hoff analysis of the diamide e Assuring converged simulations by long runs ns time scale using the mixed mode MC SD procedure We were also careful to test for convergence by ensuring that we could obtained the same results from different starting conformations 15 5 L
150. he minimum energy conformation found so far SUBS Substructures may be used All opcodes related to the substructure SUBS FXAT FXDI FXBA and FXTA should be defined in an sbc file The sbc file should contain only lines referring to the receptor with the receptor atoms numbered starting from 1 READ The first READ command obtains the structure of the receptor AUTO The first AUTO automatically sets up the MCMM conformational search of the receptor Here arg6 must be absent or 0 0 since the search of the receptor is not regarded as part of a serial search MINI Minimize the energy of each conformation generated in the search of the receptor using the PRCG minimization technique arg1 1 for up to arg3 2000 iterations MCMM The second MCMM causes Monte Carlo Multiple Minimum searching to be used in the search of each isolated ligand and each ligand receptor complex Argl defines the number of steps to use for each search This need not match that used in the search of the receptor AUTO The second AUTO sets up the MCMM search for each isolated ligand and each ligand receptor complex Here arg6 should be set to 1 because the searches of the isolated ligands and the complexes are regarded as part of a serial search BGIN Start the loop which processes each ligand in turn MacroModel 9 6 User Manual Chapter 14 eMBrAcE MCOP Monte Carlo options that determine what and how often data is written to the log file
151. he molecular structure file contains the structures to be used as input in the calculation The command file contains the name of the input structure file the name of the output structure file and an ordered list of operation codes opcodes for the calculations Once you set up a job in Maestro and click either Start or Write Maestro writes out a molecular structure file and a command file For many types of jobs command files written this way are complete and adequate but for some types of jobs you may need to adjust the Maestro gener ated command file The command files and the log files for the examples given in this section can be found in SSCHRODINGER macromodel vversion samples Examples 10 3 1 Stochastic Dynamics Below is an example of the command file for a stochastic dynamics simulation and explana tions of the opcodes that appear in the file sdyn mae sdyn out mae MMOD 0 1 0 0 0 0000 0 0000 0 0000 0 0000 FFLD 10 1 0 1 1 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 41 5692 99999 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 CONV 2 0 0 0 0 0500 0 0000 0 0000 0 0000 MINI 9 0 500 0 0 0000 0 0000 0 0000 0 0000 MDIT 0 0 0 0 300 0000 0 0000 0 0000 0 0000 MDYN 0 1 1 0 1 5000 1 0000 300 0000 0 0000 MDSA 10 0 0 0 0 0000 0 0000 1 0000 0 0000 MDDA 14 15 16 17 0 0000 0 0000 0 0000 0 0000 MDYN 1 1 1 0 1 5000 10 0000 300 0000 0 0000 WRIT 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MMOD Creates and updates an intermediate struc
152. he receptor with the receptor atoms numbered starting from 1 READ The first READ command obtains the structure of the receptor MINI Minimize the energy of the receptor Argl 1 uses the PRCG minimization technique for up to arg3 2000 iterations BGIN Start the loop which processes each ligand in turn READ Sequentially read the ligand structures MINI Minimize first the current ligand structure then minimize the receptor ligand complex Record the energy differences to the log file and to the output structure file END End the loop for ligands MBAE When argl 1 eMBrAcE is turned off In this example this command is not needed Below is the eMBrAcE output from the 1og file for one ligand in a job run in energy differ ence mode showing the energy differences upon complexation MBAE Energy Differences for Ligand 1 Ligand Name 4erk Total Energy constraints 0 8012573E 02 kJ mol Total Energy no constraints 0 8160452E 02 kJ mol MacroModel 9 6 User Manual Chapter 14 eMBrAcE Valence Energy 0 1018281E 02 kJ mol VDW 0 1592237E 03 kJ mol Electrostatic 0 9869821E 02 kJ mol Explicit Hydrogen Bonds 0 0000000E 00 kJ mol Solvation 0 1661343E 03 kJ mol Constraint 0 1478790E 01 kJ mol Converged Ay In this example Converged T means that all minimization converged If the value were F instead of T then the energy differences would be suspect and the calculation may need to be repe
153. her click Start to set up and launch the job or click Write to write the job commands to a file to be run or manually edited later 9 2 1 Conformational Search Method You can select the conformational search method to be used during a calculation from the Method option menu The conformational search method options are described below Torsional sampling MCMM This is the recommended conformational search method The input structure is modified by random changes in torsion angles and or molecular position as specified in the panels opened by the Torsion Rotations or Molecule Trans Rot buttons Ordinarily whether a single structure MacroModel 9 6 User Manual 75 Chapter 9 Conformational Searches 76 or multiple structures appear in the input file they will first be read in minimized and treated as if already found by the MCMM procedure This allows a new search to be initialized from the output of a previous search by using the output file of the old search as input for the new one See page 73 and the MCMM opcode description in the MacroModel Reference Manual for a detailed description of this method Serial torsional sampling MCMM is an automated procedure for performing a separate MCMM search on each structure in the input structure file and is enabled by selecting Multi ligand next to the Method option menu For this procedure Perform automatic setup during calculation is selected and cannot be deselected Sys
154. hosts file At any one time up to one task is running on comp1 and up to two tasks are running on comp2 For distributed MacroModel calculations that involve a random or accumulated aspect e g MCMM conformational searches the results may differ from those obtained from an equiva lent non distributed calculations However the different results from either type of calculation are valid 3 4 Interacting With a Running MacroModel Job The Schr dinger Job Control facility allows you to interact with running MacroModel jobs Because all jobs submitted either from Maestro or the command line are controlled by the Job Control facility all jobs can be monitored using the Monitor panel in Maestro or using the jobcontrol script from the command line For specific instructions on using the Monitor panel or the jobcontrol script see Chapter 5 of the Job Control Guide MacroModel 9 6 User Manual Chapter 4 General Settings 4 1 General MacroModel Calculation Setup All Maestro energetic calculation panels have the same basic setup process 1 Specify the job input source from the Use structures from option menu see Section 4 1 1 below 2 Specify settings in the tabs e For the Potential tab see Section 4 2 on page 26 e For the Constraints tab see Section 4 4 on page 31 e For the Substructure tab see Section 4 5 on page 33 e For tabs specific to the energetic calculation see the appropriate chapter 3 Click Start to set up
155. html MacroModel 9 6 User Manual 175 Getting Help 176 The manuals are also available in PDF format from the Schr dinger Support Center Informa tion on additions and corrections to the manuals is available from this web page If you have questions that are not answered from any of the above sources contact Schr dinger using the information below 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 e All relevant user input and machine output e MacroModel purchaser company research institution or individual e Primary MacroModel user e Computer platform type e Operating system with version number e MacroModel version number e mmshare version number On UNIX you can obtain the machine and system information listed above by entering the following command at a shell prompt SSCHRODINGER utilities postmortem This command generates a file named username host schrodinger tar gz which you should send to help schrodinger com If you have a job that failed enter the following command S SCHRODINGER utilities postmortem jobid where jobid is the job ID of the failed job which you can
156. ich the atoms that define each geometrical parameter are listed an atom selection tool and Delete and Delete All buttons to delete one or all items from the list You can redefine an item by selecting it and then picking atoms in the workspace When parameters are defined the atoms defining them are marked in the Workspace if Show Markers is selected When you close the panel the markers are automatically cleared The remaining button Reset All removes all entries from all dynamics monitors MacroModel 9 6 User Manual Chapter 10 Dynamics Calculations Monitored Atom Surface Areas Define monitored atom surface areas W Pick Atoms All Selection Previous Select Delete Delete All Close Help Figure 10 2 The Monitored Atoms Surface Area panel 10 2 1 1 Surface Areas Use the Monitored Atom Surface Areas panel to specify the atoms whose surface areas are to be monitored during the simulation To monitor the surface area of specific atoms use the selec tion tool to pick atoms The selection tool allows you to specify atoms in the following ways e Choose a structural unit from a Pick menu and pick atoms in the Workspace belonging to structural units of the selected type e Choose all atoms by clicking the All button e Choose atoms using the Atom Selection dialog box which creates ASL expressions that define the selected atoms Open the Atom Selection dialog box by clicking the Select but to
157. ield solvent and atom typ files override versions in the location speci fied by SCHRODINGER You might also want to specify the default location for temporary scratch files The default scratch directory is set in a schrodinger hosts file which should exist on each host on which you want to run MacroModel This file can be in a local directory in HOME schrodinger or in SSCHRODINGER You can override the default by setting the SCHRODINGER_TMPDIR environment variable 3 1 2 The Command File Every time job files are written or a job is started from Maestro a MacroModel command file and a structure file are created The command file contains all necessary information for MacroModel to perform the job as specified Most MacroModel tasks can be executed from MacroModel 9 6 User Manual Chapter 3 Running MacroModel From the Command Line 20 Maestro However there are a few tasks that still involve manually setting up and executing a command file In this chapter examples of common command files are given that are set up through Maestro and provide some insight to the different commands included in these files At the end of the chapter more advanced command files are presented including tasks that can not currently be set up from Maestro Many of the commands presented in the command files below have additional arguments avail able For more information on any of the commands refer to the MacroModel Referenc
158. ies in the Project Table then select Selected entries in the Use structures from section To use structures that are in a disk file select From file and type a file name in the Input file text box or click Open to open a file selector to choose a file The first structure in this file is read into Maestro and replaces the contents of the Workspace so you can use the picking tools to set up the comparison atoms or torsions 16 1 2 Selecting the Clustering Criterion In the Cluster by section you can select Atomic RMS or Torsional RMS as the distance criterion for the clustering calculation The atom selection tools displayed in the center of the panel depend on which of these options you select The options in the lower section of the panel Calculate RMS In Place no superposition and Compare enantiomers affect how the clus tering is performed MacroModel 9 6 User Manual Chapter 16 Molecular Clustering with XCluster Atomic RMS This option selects the atomic RMS displacement of corresponding atoms as the distance crite rion By default a rigid body superposition is performed before evaluating RMS displace ments The default is overridden by the Calculate RMS In Place no superposition option Torsional RMS This option selects the root mean square difference between corresponding torsion angles in pairs of structures as the distance criterion Calculate RMS in place no superposition This option is not
159. ile for minimization 168 vibrational animation ccccccessceeeees 170 comparison atoms in CSearch calculations oooonncnccnonncinnncnn 85 defining for XCluster eee 159 in multiple minimization calculations 55 conformational search see CSearch calculations conformations mirror image 56 79 165 constraints on bond lengths using SHAKE 0 102 for fixing atoms cinc 28 on positions distances angles torsions 31 TEMO Bisitoliid iii 33 Constraints tab oooooonccconccconccconncconnnonanacnonaninnns 31 conventions dOcUMENE coooooccccnononnccnanannnacinnanans xi convergence guidelines cece eeeeeeeeeee 13 for CSearch JODS vincia dicos 13 for MCSD JODS sisine remers 14 for minimization jobs seese 13 convergence threshoOld oooonccinnnicnnnnninnnnns 48 Coordinate Scan panel cooocccnininnicnnnnnncnincnnnnnss 66 coordinate scans command file examples 0 0 0 0 cee 67 defining range and increment 67 displaying results Of cee eeeeeeeee 68 CSearch calculations cee eeeesseeeeeeeeeeees 73 automatic setup OLiccccnninninncninnonnncnnnanancnonos 78 Chiral Atis cnica iii 86 command file examples cece 90 COMPAriSON AtOMS ose eee eeeeeeeeeees 85 defining ring closures 0 00 eee eee 81 defining torsion rotations cee 82 distance Check cian 87 energy WINGOW eee eeceeeseeeeeeseeeeseteeeeeeees 79 ligand bonds
160. imal to use SD minimization PRCG is usually a better choice FMNR Full Matrix Newton Raphson With this method convergence to saddle points is not uncommon Use FMNR with prem inimized structures having RMS gradients of less than 0 1 kJ mol A Use line searching select after prompt for problematic cases or if the RMS First Derivative is greater than 0 1 The preminimization requirement derives from the Newton Raphson assumption of a quadratic potential surface The method works only if the assumption is valid FMNR is the most effective method for fully converging structures but the computational resources required are significant for large structures To find saddle point structures you will need to start very close to the saddle point and you will have to disable line searching FMNR has excellent convergence properties and typically converges in two to ten iterations e LBFGS Low memory Broyden Fletcher Goldfarb Shanno A method that performs well with large structures Optimal This choice uses the TNCG method if the number of unfixed atoms is less than 1000 and solvation is employed otherwise it uses the PRCG method Sets MINI arg to 20 6 2 2 Convergence Parameters You can specify convergence criteria for your calculation using the Converge on option menu in the Mini tab Choose from Gradient Energy Movement or Nothing Gradient is the default value With the Energy setting Macromodel determines when to halt the
161. imization with 0 and A 1 Record the final minimized energies in each case Now swap the structures in the input mae file and re run the calcula tion For the second run with the order of the structures reversed the energy at the A 1 point should be the same as the energy from the 0 point of the first run Similarly the energy of the 0 point in the second run should be the same as the 1 energy of the first If these do not match exactly then there is likely to be something wrong with the numbering of the input structure files 2 Is sufficient sampling being performed While the expression 1 described above is exact it is implicit that at each window complete sampling of all important conformations is achieved In practice this is very difficult to achieve and we strongly recommend the use of the mixed mode simulation methodology to help solve the sampling problem Even so you should also perform independent tests for convergence with simulations at least as long as the sampling period in the free energy calculations Ideally you should be satisfied that you can achieve a reasonable degree of convergence for simula tions of the starting structures in the length of time used for the sampling in the free energy calculations Good tests for convergence are starting from different starting geometries and for non chiral molecules monitoring the populations of equivalent conformations e g gauche gauche torsion a
162. in shell script located in the SCHRODINGER directory should be used to launch stand alone MacroModel jobs from any directory once the SCHRODINGER environment variable has been set To launch a job enter the following command in a terminal window SCHRODINGER bmin options jobname MacroModel 9 6 User Manual 21 Chapter 3 Running MacroModel From the Command Line 22 replacing jobname with the stem of the input file name not needed if the TEST or HELP options are specified and including any of the following options E Table 3 1 Options for the bmin command Option Meaning DEBUGGER debugger_name Run bmin in the foreground with a debugger called debugger_name DEBUG2 Print out debugging information from the scripts used to start bmin HELP help h Print the bmin command syntax options and their defini tions and exit HOSTFILE hostfilename The name of the hosts file to use for this run INTERVAL The maximum time in seconds for updating the monitoring files LOCAL Do not place files in a temporary directory Keep files in the local directory NO_REDIRECT Run in the foreground and send output to standard output TEST Run the standard test suite jobname not needed WAIT Do not return a prompt until the job finishes or is submitted to a batch queue The options for the bmin command are listed in Table 3 1 The standard Job Control options are also
163. indow the perturba tion is between a state at A and that at A dA The method for performing this simulation as implemented in MacroModel is described as single topology That is at any value of A a set MacroModel 9 6 User Manual 143 Chapter 15 Free Energy Simulations 144 of interactions is generated by mixing the interactions of the endpoints For example if an atom has a charge x in the starting point of the simulation and a charge y in the end point at any given value of i e at any window the charge on the atom will be z yA 1 A x This process will be repeated for all the interactions in the system and the simulation will be performed with this new set of interactions At points during the simulation the energy H A will be evaluated Then the interactions corresponding to the next value of lambda A dA will be generated and H A dA will be calculated These terms are used in the exponential of expression 3 In MacroModel we usually take advantage of the fact that for most values of A the energy at A dA can also be evaluated this procedure is known as double wide sampling and effectively allows a forward and reverse simulation to be performed in one simulation 15 2 Setting Up FEP Calculations Currently free energy calculations can be set up only by direct manipulation of the Macro Model command files There is no Maestro interface for this procedure The individual M
164. ing of high energy conformers during the search Arg5 defines the allowed energy window above the current global minimum New conformers that are not within arg kJ mol are discarded Additionally a preliminary energy test can be performed during the energy minimization to ensure that a reasonable structure has been found Arg2 sets the number of energy iterations to perform before the preliminary test a good value is approximately 1 3 of the total number of energy iterations while arg6 defines the energy above which conformers are discarded a value of about 1 5 2 times arg5 is recom mended BGIN END Defines the start end of a loop All commands between the BGIN and END lines are performed for each structure in the input file READ Directs MacroModel to read the input file CONV Defines convergence criteria Argl 2 signifies derivative convergence The default criterion if no CONV command is present is 0 05 kJ mol A this value is set in arg5 MINI Starts the minimization Argl defines the type of minimization algorithm to be used Arg1 9 means that Truncated Newton Raphson Conjugate Gradient will be used In arg3 the number of minimization steps is defined Arg3 can be set to a large number since the calcula tion will automatically stop as soon as the convergence criterion is reached MacroModel 9 6 User Manual Chapter 7 Multiple Minimizations 7 6 2 Multiple Conformer Minimization With Automatic Redundant Confor
165. ion XCluster calculations can be set up in Maestro on a set of conformers contained in the Project Facility Details about XCluster can be found in the MacroModel XCluster Manual The Maestro interface makes it easy to select atoms to be used in the XCluster analysis Instead of typing in the atom numbers in pairs you can pick the atoms in the Workspace or select the comparison atoms using the flexibility of selection available in the Atom Selection dialog box This is an important feature because more meaningful clustering can be obtained by choosing the minimum number of comparison atoms that are relevant for the clustering to be performed XCluster calculations including the selection of the comparison atoms or torsions are prepared and started from the Maestro XCluster panel When you start the calculation from Maestro the job is transferred to the original XCluster interface which controls the actual computation and the display of the results of the XCluster analysis As in the past XCluster jobs can still be prepared and submitted from the original interface or from the command line This interface can be launched with the command SCHRODINGER xcluster 16 1 The XCluster Panel To open the XCluster panel choose XCluster from the Applications menu This panel allows you to specify the source of structural input select the distance criterion to be used select the comparison atoms or torsions choose the type of RMS calculation and s
166. ions of the opcodes used in the files dscan mae dscan out mae MMOD 0 1 0 0 0 0000 0 0000 0 0000 0 0000 FFLD 10 1 0 1 1 0000 0 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 BGIN 0 0 0 0 0 0000 0 0000 0 0000 0 0000 DRIV 1 14 15 16 0 0000 360 0000 30 0000 0 0000 DRIV 6 25 26 27 0 0000 360 0000 30 0000 0 0000 CONV 2 0 0 0 0 0500 0 0000 0 0000 0 0000 MINI 9 0 500 0 0 0000 0 0000 0 0000 0 0000 END 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MMOD Creates and updates an intermediate structure file so that structures can be displayed in Maestro as the job progresses FFLD Force field selection Arg denotes the actual force field used in the calculation in this case MMFF94 Arg2 defines the electrostatic treatment for the calculation The default arg2 0 is to use the dielectric treatment encoded in the force field In this case a constant dielectric arg2 1 with a dielectric constant of 1 explicitly requested arg5 Arg4 is MacroModel 9 6 User Manual 67 Chapter 8 Coordinate Scans 68 MMFF94 specific Arg4 1 defines the MMFF94s version of the force field ensuring planarity around delocalized sp nitrogens READ Directs MacroModel to read the input file BGIN END Defines the start end of a loop All commands between the BGIN and END lines will be performed for each structure in the input file DRIV Directs MacroModel to carry out a coordinate scan using the indicated dihedral angles arg5 0 to
167. is option Source of energy If you choose to include the energy as a criterion for comparison structures whose energy differs by more than 1 kJ mol are considered inequivalent This test is applied before the geom etries are compared and can considerably speed up the comparison You can choose from the Jaguar energy or the energies for various force fields supplied with MacroModel or you can disable energy comparison by selecting None If the particular energy you selected is not avail able among the properties of the structure the calculation stops You should therefore choose an energy that has been calculated for all structures Energy window for saving structures This is the threshold value for comparison of structures Structures are kept only if their energy is less than this value above the current global minimum Lowering this value results in fewer structures saved The default value is 21 kJ mol 17 2 Command File Examples To run MacroModel calculations a molecular structure file and a command file are required The molecular structure file contains the structures to be used as input in the calculation The command file contains the name of the input structure file the name of the output structure file and an ordered list of operation codes opcodes for the calculations Once you set up a job in Maestro and click either Start or Write Maestro writes out a molecular structure file and a command file For many types of jobs
168. is to click Perform Automatic Setup MacroModel locates chiral atoms and generates a list of the atoms This list appears in the text box at the top of the Chiral Atoms panel MacroModel 9 6 User Manual Chapter 9 Conformational Searches FF Define chiral atoms E Show markers Delete Delete All Close Help Figure 9 6 The Chiral Atoms panel If it is necessary to define chiral atoms manually check that Define chiral atoms is selected the default and pick the atoms in the Workspace to add them to the list Chiral atoms are marked in peach with RIS labels beside them The currently selected atom is colored turquoise To hide these markers deselect Show markers Distance Check Occasionally you might want to restrict the scope of a conformational search to generate only structures that are consistent with certain geometric constraints for example when experi mentally obtained results such as NOE constraints are available Distance checks are used to reject structures in which certain distances do not meet the specified criteria Distance Check Minimum distance 0 000 Maximum distance 0 000 Define distances to check FF Pick Atoms E Show markers Delete Delete All Close Help Figure 9 7 The Distance Check panel MacroModel 9 6 User Manual 87 Chapter 9 Conformational Searches 88 Distance checks cannot be set using the a
169. it This button opens a panel that can be used to set the chosen kind of variable for a conformational search MacroModel 9 6 User Manual Chapter 9 Conformational Searches A description of each of these panels is given below Each panel has some common features a text box at the top that lists the defined features a Show markers button which controls display of the defined features a Delete button which deletes the selected definition from the list and a Delete All button which deletes all the defined features in the list In any of the subpanels you can edit a defined feature by selecting it in the list and picking Workspace atoms Markers can be displayed in the Workspace to identify the conformational search variables Most of the panels have a Show markers option to control the display of markers for the vari ables set in that panel When you close the panel the markers are undisplayed You can also display or undisplay markers for all variables by clicking Display All Markers or Undisplay All Markers To clear any previously set conformational search variables click Reset All Variables 9 2 5 1 Ring Closures During a Monte Carlo based conformational search MCMM or SPMC rings must be opened before varying their torsions Then after random torsion variations have been evaluated the ring must be re closed The appropriate location for ring closures must be defined before a calculation can be started Ring Closures
170. it is possible to run any specific windows The windows are independent and free energy differences obtained from separate runs can be usefully combined It is also sometimes useful to re run specific windows from a simulation to obtain better statistics The command file below performs double wide sampling for two windows with A middle 0 5 and A middle 0 55 fep diala mae fep diala out mae EXNB 0 0 0 0 0 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 0 0000 0 0000 0 0000 0 0000 FFLD 3 0 0 0 0 0000 0 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 FEIA 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MCNV 1 2 0 0 0 0000 0 0000 0 0000 0 0000 MCSD 1 2 0 0 0 0000 0 0000 300 0000 0 0000 TORS 5 6 0 0 30 0000 180 0000 0 0000 0 0000 TORS 6 7 0 0 30 0000 180 0000 0 0000 0 0000 FEAV 0 0 0 0 0 5000 0 0000 0 0000 0 0000 MINI 1 0 1000 0 0 0000 0 0000 0 0000 0 0000 MacroModel 9 6 User Manual 147 Chapter 15 Free Energy Simulations 148 MDIT MDYN FESA MDYN FEAV MINI MDIT MDYN FESA MDYN FESU oO fo oO 2 GOG 2 co oo amp oO Oo oO 2 co co O co Oo O O cl PA AE 1000 a 1 G O OG 10 Cc 2 coo aa 300 0000 5000 4500 5000 5500 0000 0000 5000 5000 5000 0000 Qro 0 0000 10 0000 0 5500 100 0000 0 0000 0 0000 0 0000 10 0000 0 6000 100 0000 0 0000 0 0000 300 0000 0 0000 300 0000 0 0000 0 0000 0 0000 300 0000 0 0000 300 0000 0 0000 O0OO0OO0OOUOOOoOOoo lt ooOo 0000 0000
171. iterature This section is not an exhaustive review of the free energy literature but rather a set of repre sentative reviews and papers covering both theory and applications of free energy calculations Those marked with a are particularly important for their critical analysis of the potential problems of free energy calculations and we urge you to read and understand these reviews before attempting free energy calculations Kollman P A Chem Rev 1993 93 2395 Beveridge D L DiCapua F M Annu Rev Biophys Biophys Chem 1989 18 431 Jorgensen W L Acc Chem Res 1989 22 184 Jorgensen W L J Am Chem Soc 1989 111 755 Cieplak P Kollman P A J Comput Aided Mol Des 1993 7 291 MacroModel 9 6 User Manual Chapter 15 Free Energy Simulations van Gunsteren W F Weiner P K Eds Computer Simulations of Biomolecular Systems ESCOM Leiden 1990 van Gunsteren W F Mark A E Eur J Biochem 1992 204 947 Mark A E van Helden S P Smith P E Janssen L H M van Gunsteren W E J Am Chem Soc 1994 116 6293 Mitchell M J McCammon J A J Comput Chem 1991 12 271 Smith P E van Gunsteren W F J Phys Chem 1994 98 13735 MacroModel 9 6 User Manual 155 156 MacroModel 9 6 User Manual Chapter 16 Molecular Clustering with XCluster XCluster is a powerful structural clustering tool that uses molecular similarity as the clustering criter
172. itions This list appears in the text box at the top of the Molecule Trans Rot panel Maestro labels the selected molecules with peach colored vertical arrows encircled by rota tion arrows if Show markers is selected The currently selected molecule is distinguished by a turquoise label The controls of the Molecule Trans Rot panel are described below Minimum rotation The minimum acceptable rotation of a molecule must be specified Each time a molecule must be rotated an increment for rotation that is larger than this value is selected The default minimum rotation is 0 MacroModel 9 6 User Manual Chapter 9 Conformational Searches Maximum rotation The Maximum rotation text field allows you to specify a value for the maximum acceptable molecule rotation increment Each time a molecule must be rotated an increment for rotation that is smaller than this value is selected The default maximum rotation is 180 Minimum translation The value in the Minimum translation text box sets the lower limit for molecule translation Each time a molecule must be translated a random increment larger than this value is used The default value is 0 0 Maximum translation This text box sets the upper limit for molecule translation Each time a molecule must be trans lated a random increment smaller than this value is used The default value is 1 0 Define molecules to translate rotate To define molecules to be translated or r
173. ization employs a 4r distance dependent dielectric model and uses Macro Model s efficient truncated Newton minimizer As well as the recommended default force field MMFFs premin also supports the OPLS_2001 and OPLS_2005 force fields The syntax for premin is shown below SSCHRODINGER utilities premin options input mae where input mae is the input file that contains the ligand structures The options are described in Table 7 1 Table 7 1 Options for the premin script Option Description h Print help text and exit lic ligprep Use LigPrep license instead of MacroModel license s output Output file for successfully processed structures Default is input min mae for minimizations and input filtered mae for filtering u bad Output file of structures that could not be minimized Default is input bad mae v Print version number and exit doc Print a brief guide to using premin f 11 Use OPLS_2001 instead of the default force field MMFFs MacroModel 9 6 User Manual Chapter 7 Multiple Minimizations Table 7 1 Options for the premin script Continuea Option Description f 14 Use OPLS_2005 instead of the default force field MMFFs custom Use custom filter com and goodmin com files from the current working directory filter Filtering only skip minimization m filter By default successfully minimized structures are saved in input min mae and unsuccessful structures are saved in input bad
174. l 9 6 User Manual Chapter 9 Conformational Searches FFLD Force field selection Argl defines the force field used in the calculation in this case MMFF94 Arg2 defines the electrostatic treatment for the calculation In this case a constant dielectric is used Arg4 is MMFF94 specific arg4 1 defines the MMFF94s version of the force field ensuring planarity around delocalized sp nitrogens BDCO Use the Bond Dipole CutOff BDCO method for truncating electrostatic interactions Arg5 and arg6 are used to specify the cutoffs used for charge dipole and charge charge interac tions respectively READ Read the input file MCMM Use Monte Carlo Multiple Minimum searching Argl defines the number of MC steps for the search MCNV Sets the number of degrees of freedom to be varied at each MC step If argl and arg2 differ the search varies a random number of degrees of freedom between the numbers defined in argl and arg2 We recommend setting argl 2 and arg2 maximum number of degrees of freedom MCSS Select starting structure for the search steps Argl 2 defines use directed selection of starting structures where the least used structures will be used as starting geometries as long as they are low enough in energy as defined in arg5 This is more efficient in exploring new areas of the potential energy surface than for instance a random walk starting geometry scheme Arg5 gives the energy window for selecting a new starting stru
175. l Search panel showing the CSearch tab The eMBrAcE Conformational Search panel is used to set up and submit eMBrAcE conforma tional search jobs To open this panel choose eMBrAcE Conformational Search from the MacroModel submenu of the Applications menu in the main menu bar The upper and lower parts of the panel and the Potential and Substructure tabs are common to all MacroModel panels These components are described in detail in Section 4 1 on page25 through Section 4 5 on page 33 The Mini tab is common to many of the MacroModel panels For an explanation of the controls in this tab see Section 6 1 on page 45 The controls for the eMBrAcE settings are located in the eMBrAcE tab which is described in Section 14 1 on page 121 The conformational search parameters are set up in the CSearch tab This tab contains a subset of the controls found in the CSearch tab for regular conformational searches and is described below eMBrAcE conformation searches automatically employ the AUTO Automatic Setup mecha nism AUTO selects the MCMM and comparison atom parameters for each individual ligand receptor complex Computations prepared from Maestro have the AUTO opcode added to the MacroModel 9 6 User Manual Chapter 14 eMBrAcE job s command file jobname com automatically In addition AUTO is substructure aware Parameters are only indicated for the freely moving receptor and ligand atoms but not for fixed or frozen regions of the receptor
176. l energy surface for low energy struc tures for systems ranging from small molecules to entire proteins Solvation effects can be accounted for using the efficient continuum solvation models employed by MacroModel Additional advanced features include molecular dynamics simulations free energy perturba tion simulations and pure and mixed methods for ensemble sampling MacroModel 9 6 User Manual Chapter 1 MacroModel Overview 1 3 MacroModel and Maestro Interaction Maestro is the graphical user interface for MacroModel MacroModel runs calculations as independent tasks and consequently does not tie up Maestro during lengthy computations Maestro monitors MacroModel tasks so that both numerical and structural information may be viewed while the tasks are running Such monitoring is the default mode of operation for newly started tasks although monitoring can be broken off and reestablished at a later time Thus you can initiate several MacroModel tasks disconnect from them carry out graphical modeling operations and periodically reconnect to and examine the progress of each of the previously submitted MacroModel tasks 1 4 Calculation Preparation and Submission MacroModel calculations can be prepared and launched from the Maestro GUI or from the command line To run a MacroModel job on a remote computer you must first set up the remote hosts according to the instructions in the Job Control Guide An overview of each job submission
177. large eigenvalue problem The arguments to VIBR and VBR2 specify the first and last mode to visualize as well MacroModel 9 6 User Manual 169 Chapter 18 Additional Features 170 as the number of frames to include for the period of each vibration Rotational and translational modes are automatically disregarded The structural output consists of a series of frames structures that together animate the vibration when imported and played in Maestro s ePlayer VIBR and VBR2 computations are started from the command line with an appropriate command file and an input structure file The input structure should be minimized to a low gradient Below is a sample command file for a VIBR calculation vibr mae vibr out mae FFLD 10 1 0 1 1 0000 0 0000 0 0000 0 0000 SOLV 3 1 0 0 0 0000 0 0000 0 0000 0 0000 EXNB 0 0 0 0 0 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 89 4427 99999 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 CONV 2 0 0 0 0 0200 0 0000 0 0000 0 0000 MINI 1 0 500 0 0 0000 0 0000 0 0000 0 0000 VIBR dl 5 5 0 3 0000 0 0000 0 0000 0 0000 The command file specifies vibr mae as the input structure file and the output structural animations will reside in the file vibr out mae The following four opcodes specify the potential settings here MMFFs as the force field with solvation extended non bonded cutoffs and BDCO usage for electrostatic interactions After the structure is read a minimization is requested C
178. lated Annealing Simulated annealing is often used to relax structures into a lower energy state a dynamics tech nique by systematically lowering the temperature used in the simulations Below is an example MacroModel 9 6 User Manual 105 Chapter 10 Dynamics Calculations 106 command file for a simulated annealing calculation where the target temperature for the system is changed in a step wise manner The temperature can also be changed in a continuous manner See the description of the MDFT opcode in the MacroModel Reference Manual for more information sim ann mae sim ann out mae FFLD 10 1 0 il 1 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 41 5692 99999 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 CONV 2 0 0 0 0 0500 0 0000 0 0000 0 0000 MINI 9 0 500 0 0 0000 0 0000 0 0000 0 0000 MDIT 0 0 0 0 300 0000 0 0000 0 0000 0 0000 MDYN 0 1 1 0 1 5000 10 0000 300 0000 0 0000 MDYN 0 1 1 0 1 5000 20 0000 150 0000 5 0000 MDYN 0 1 1 0 2 0000 20 0000 50 0000 5 0000 MINI 9 0 500 0 0 0000 0 0000 0 0000 0 0000 MDYN Note that the three separate MDYN command lines perform different tasks First a 10 ps equilibrium run at 300 K initialized by the MDIT line is performed followed by a 20 ps simu lation coupled to a thermal bath of 150 K Arg8 gives the time constant of the bath in ps This second MDYN command slowly cools the system to 150 K while the last MDYN command cools the system to 50 K A WRIT command is not nec
179. lds require the use of explicit hydrogen atoms on hetero atoms Note also that AMBER requires explicit lone pairs on sulfur Original MM2 implementations have lone pairs on sp oxygen however we recommend removing them for best results in MM2 In Maestro you can modify a structure s hydrogen treatment using settings in the Hydrogen Treatment panel which you open from the Build menu See Section 4 9 of the Maestro User Manual for more information 2 11 2 Hydrogen Treatment in the AMBER Force Field The AMBER force field file contains charge sets appropriate to either united atom or all atom representations however by default the united atom charges are used This means that even those carbons having explicit hydrogens attached will by default get united atom charges In practice this makes little difference in energetic results but in some situations for example when making comparisons with the original AMBER program and also when calculating absolute solvation free energies it is important to use all atom charges if such carbons exist This can be done by selecting Force Field Defined from the Electrostatic Treatment option menu in the Potential tab of the MacroModel panels When using the united atom models in AMBER or OPLS the best results are obtained when explicit hydrogen atoms are used on sp carbons The command SSCHRODINGER utilities applyhtreat in mae out mae where in mae is the name of a file containing st
180. lectrostatic interactions 2 4 1 Energetics of Charges Coulomb s law states that the potential energy of two point charges separated by a distance r scales as 1 1 In contrast the energy of a point charge interacting with a dipole scales as 1 r and the energy of two interacting dipoles scales as 1 r These physical properties determine the length scales for which truncation of the various interaction types is appropriate in order to achieve a given level of accuracy 2 4 2 Molecular Mechanics Description of Charge Common molecular mechanics force fields utilize Coulomb s law to describe the electrostatic interaction between atoms due to the uneven distribution of electron density across bonded atoms with different electronegativities A carbonyl moiety for example is described with a partial negative charge located at the oxygen atom center and an equal but opposite charge located at the carbon atomic center These fixed partial charges can be directly used in Coulomb s law to give molecular mechanics electrostatic energies and the associated forces For groups with net charge such as a carboxyl moiety the formal charge of the group must also be accounted for This can be done by delocalizing the formal charge over the appropriate atoms and adding this delocalized formal charge to the partial charges due to the dipolar nature of bonds between different atoms Thus for the carboxyl moiety one can think of the system as two dipoles
181. les Examples 7 6 1 Energy Minimization of Multiple Non Conformers Below is an example of the command file for an energy minimization of multiple non conformers and explanations of the opcodes used in the file MacroModel 9 6 User Manual 59 Chapter 7 Multiple Minimizations 60 mult min mae mult min out mae MMOD 0 1 0 0 0 0000 0 0000 0 0000 0 0000 FFLD 10 1 0 1 1 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 41 5692 99999 0000 0 0000 0 0000 DEMX 0 0 0 0 50 0000 0 0000 0 0000 0 0000 BGIN 0 0 0 0 0 0000 0 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 CONV 2 0 0 0 0 0500 0 0000 0 0000 0 0000 MINI 9 0 500 0 0 0000 0 0000 0 0000 0 0000 END 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MMOD Creates and updates an intermediate structure file so that structures can be displayed in Maestro as the job progresses FFLD Force field selection Arg denotes the actual force field used in the calculation in this case MMFF94 Arg2 defines the electrostatic treatment for the calculation The default arg 0 is to use the dielectric treatment encoded in the force field Arg4 is MMFF94 specific Arg4 1 defines the MMFF94s version of the force field ensuring planarity around delocalized sp nitrogens BDCO Use the Bond Dipole CutOff BDCO method for truncating electrostatic interactions Arg5 and arg6 specify the cutoffs used for charge dipole and charge charge interactions respectively DEMX This command prevents sav
182. low is an example command file for a minimization calculation Explanations of the opcodes that appear in the file follow mini constr mae mini constr out mae MMOD 0 I 0 0 0 0000 0 0000 0 0000 0 0000 FFLD 10 il 0 1 1 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 41 5692 99999 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 FXTA 14 15 16 17 100 0000 44 7270 5 0000 0 0000 CONV 2 0 0 0 0 0500 0 0000 0 0000 0 0000 MINI 9 0 500 0 0 0000 0 0000 0 0000 0 0000 MMOD Creates and updates an intermediate structure file so that structures can be displayed in Maestro as the job progresses FFLD Force field selection Arg1 denotes the actual force field used in the calculation in this case MMFF94 Arg2 defines the electrostatic treatment for the calculation Default arg 0 is to use the dielectric treatment encoded in the force field However in this case a constant dielectric is used due to the use of solvation model 3 see SOLV below Arg4 is MMFF94 specific Arg4 1 defines the MMFF94s version of the force field ensuring planarity around delocalized sp2 nitrogens BDCO Use the Bond Dipole CutOff BDCO method for truncating electrostatic interactions Arg5 and arg6 are used to specify the cutoffs used for charge dipole and charge charge interac tions respectively READ Directs MacroModel to read the input file FXTA Constrains a torsional angle Argl arg4 give the atom numbers of the four atoms defining the dihedral angle that
183. m 1999 20 1671 MacroModel 9 6 User Manual References 27 28 29 30 31 32 33 van Gunsteren W F Berendsen H J C A leap frog algorithm for stochastic dynamics Mol Simul 1988 1 173 Ryckaert J P Ciccotti G Berendsen H J C Numerical integration of the Cartesian equation of motion of a system with constraints molecular dynamics of N alkanes J Comput Phys 1977 23 327 Guarnieri F Still W C A Rapidly Convergent Simulation Method Mixed Monte Carlo Stochastic Dynamics J Comput Chem 1994 15 1302 1310 Dado G P Gellman S H On the Use of AM1 Calculations for the Study of Intramo lecular Hydrogen Bonding Phenomena in Simple Amides J Am Chem Soc 1992 114 3138 McDonald D Q Still W C An AMBER study of Gellman s amides Tetrahedron Lett 1992 33 7747 Gellman S H Dado G P Liang G B Adams B R Conformation Directing Effects of a Single Intramolecular Amide Amide Hydrogen Bond Variable Temperature NMR and IR Studies on a Homologous Diamide Series J Am Chem Soc 1991 113 1164 McDonald D Q Still W C Conformational Free Energies from Simulation Stochastic Dynamics Monte Carlo Simulations of a Homologous Series of Gellman s Diamides J Am Chem Soc 1994 116 11550 MacroModel 9 6 User Manual 181 182 MacroModel 9 6 User Manual Index A alignment of StrUCLULOS oococonccccnocacoconocancncancnnn 170
184. mae If you choose to filter out problematic structures without minimization filter or m filter successfully filtered structures are saved in the file input filtered mae and problematic structures are again saved in input bad mae The script creates two MacroModel command files filter com and goodmin com and writes them to the current working directory You can then customize these files and use them in place of the default files with the custom option If you perform filtering only the file goodmin com is not used This script uses the SPAT opcode to filter out problematic structures that contain metal ions or generalized atom types 7 6 Command File Examples To run MacroModel calculations a molecular structure file and a command file are required The molecular structure file contains the structures to be used as input in the calculation The command file contains the name of the input structure file the name of the output structure file and an ordered list of operation codes opcodes for the calculations Once you set up a job in Maestro and click either Start or Write Maestro writes out a molecular structure file and a command file For many types of jobs command files written this way are complete and adequate but for some types of jobs you may need to adjust the Maestro gener ated command file The command files and the log files for the examples given in this section can be found in SCHRODINGER macromodel vversion samp
185. mation on the Atom Selection dialog box MacroModel 9 6 User Manual 55 Chapter 7 Multiple Minimizations 56 e Select all atoms Click All to add all the atoms in a structure to the list of comparison atoms When comparison atoms are picked Maestro places light green labels on them To distin guish the currently selected atom the program colors its label turquoise To hide these markers clear the Show Markers button To delete a defined comparison atom select it in the list of comparison atoms then click Delete To redefine a comparison atom pick a new atom while the comparison atom is selected in the list To delete all the defined comparison atoms click Delete All Distance cutoff for redundant conformers The threshold for determining whether structures should be considered to be equivalent is set by default to 0 25 When the structures are compared the maximum distance between pairs of corresponding atoms for all such pairs must be less than this threshold for the structures to be considered equivalent You can change the threshold in this text box This text box is only available when comparison atoms have been defined Distinguish mirror image conformations If this option is selected mirror image conformations are treated as separate conformers and are not eliminated as redundant This option is only available when comparison atoms have been defined Energy window for saving structures If a
186. med with any valid UNIX filename The resulting output structure file is given the name listed on the second line of the instruction file The full path to the structure files may be given if the files are not in the current directory MacroModel 9 6 User Manual Chapter 3 Running MacroModel From the Command Line In addition any input substructure sbc or velocity vel files should contain the same prefix as the input structure file Similarly the output energy listing mmo substructure and dihedral drive grd files have the same base name as the output structure file The jobname 1og file contains text messages tracing the progress of the job Experienced users of MacroModel should be aware that this mechanism has not changed from previous versions of MacroModel There are some default file naming changes indicated in the sample file above that are used by the Maestro interface due to the advent of Maestro formatted structure files Although not mandated to be consistent all Maestro formatted structure files are given the suffix mae This is a different default behavior from the former MacroModel user interface and the older MacroModel structure format Previously input files were given the names jobname dat and jobname out Now that all Maestro formatted structure files are by default named with the mae extension Maestro automatically names the input structure file jobname mae and the output structure file jobname out m
187. mer Elimination Below are two examples of command files for energy minimization of multiple conformers with redundant conformer elimination The first uses the AUTO opcode the second uses the COMP opcode with arg1 0 Explanations of the opcodes used in the file that are essential to this example are given mult_conformers mae mult_auto out mae MMOD 0 il 0 0 0 0000 0 0000 0 0000 0 0000 FFLD 10 il 0 1 1 0000 0 0000 0 0000 0 0000 SOLV 3 dl 0 0 0 0000 0 0000 0 0000 0 0000 EXNB 0 0 0 0 0 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 89 4427 99999 0000 0 0000 0 0000 CRMS 0 0 0 0 0 0000 0 2400 0 0000 0 0000 DEMX 0 0 0 0 51 0000 0 0000 0 0000 0 0000 MULT 0 0 0 0 0 0000 0 0000 0 0000 0 0000 BGIN 0 0 0 0 0 0000 0 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 CONV 2 0 0 0 0 0100 0 0000 0 0000 0 0000 MSYM 0 0 0 0 0 0000 0 0000 0 0000 0 0000 AUTO 1 0 0 0 1 0000 0 0000 0 0000 0 0000 MINI 1 0 5000 0 0 0000 0 0000 0 0000 0 0000 END 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MULT Mandatory for this computation due to the presence of the AUTO opcode AUTO Automatic parameter assignment Arg turns on AUTO only for the first conformer Arg5 turns off torsional parameters which are not needed for this minimization mult_conformers mae mult_comp out mae MMOD 0 1 0 0 0 0000 0 0000 0 0000 0 0000 FFLD 10 1 0 1 1 0000 0 0000 0 0000 0 0000 SOLV 3 1 0 0 0 0000 0 0000 0 0000 0 0000 EXNB 0 0 0 0 0 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 89 4427 99999 0000
188. more information on starting Maestro including starting Maestro on a Windows platform see Section 2 1 of the Maestro User Manual To run remote jobs you must have access to a hosts file named schrodinger hosts that lists hosts on which Schr dinger software is installed for execution Details of setting up this file can be found in Chapter 2 of the Job Control Guide 1 7 Citing MacroModel in Publications The use of this product should be acknowledged in publications as MacroModel version 9 6 Schr dinger LLC New York NY 2008 MacroModel 9 6 User Manual Chapter 2 Basic Molecular Modeling The potential energy model used for MacroModel energy calculations is the classical one known as molecular mechanics It is an empirical model which is parameterized to reproduce known data from experiment or quantum mechanical calculations The equation and parameter sets which allow calculation of energy from a molecular geometry are known as force fields Generally MacroModel uses equations and parameters from published standard force fields However the MacroModel implementations differ in various ways from the authentic force fields We distinguish the MacroModel implementation from the original force fields by adding a to the end of the force field name MacroModel force field parameters and equations selectors are found in force field files having suffixes fld e g mm2 f1d Differences between the MacroModel force field
189. mory The memory requirements are similar to the equivalent non eMBrAcE search of the complex of the protein with the largest ligand Because of these requirements for nearly all receptors it will likely be necessary to specify a substructure to reduce the required resources to a practical level If you want to perform only the eMBrAcE search on the ligand within an essentially static receptor then the substructure used should not include SUBS lines but only list the receptor atoms as fixed or frozen see the FXAT opcode description for more information and use only one step for the first MCMM or LMOD line the one for the search of the receptor 14 4 2 1 MCMM Conformational Search This example uses Monte Carlo Multiple Minimum searching A copy of this file is available at SSCHRODINGER macromodel vversion samples Examples MBAE_MCMM com SEARCH_MCMM mae SEARCH_MCMM out mae FFLD 11 1 0 0 1 0000 0 0000 0 0000 0 0000 SOLV 3 1 0 0 0 0000 0 0000 0 0000 0 0000 EXNB 0 0 0 0 0 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 89 4427 99999 0000 0 0000 0 0000 MSYM 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MacroModel 9 6 User Manual Chapter 14 eMBrAcE MBAE 1 il 0 0 0 0000 0 0000 0 0000 0 0000 MCMM 50 0 0 0 0 0000 0 0000 0 0000 0 0000 MCNV 1 4 0 0 0 0000 0 0000 0 0000 0 0000 MCSS 2 0 0 0 500 0000 0 0000 0 0000 0 0000 MCOP 1 0 10000 0 0 0000 1 0000 0 0000 0 0000 DEMX 0 0 0 0 500 0000 0 0000 0 0000 0 0000 SUBS 0 0 0 0 0 0000 0 0000 0 0000 0 0000
190. mperature calculations that take advantage of the strengths of Monte Carlo methods for quickly introducing large changes in a few degrees of freedom and stochastic dynamics for its effective local sampling of collec tive motions MC SD is a good general choice for studying a system at constant temperature 11 1 The MC SD Panel You can prepare write job files for and submit a Monte Carlo Stochastic Dynamics calcula tion from the Maestro MC SD panel The MC SD panel has a general setting section and a Potential tab a Constraints tab and a Substructure tab like other MacroModel energy panels These portions of the panels are described in detail in Section 4 1 on page 25 through Section 4 5 on page 33 The MC SD panel also has Monitor and Dynamics tabs These tabs also appear on the Dynamics panel and are discussed in Section 10 2 on page 97 The MCSD tab is unique to the MC SD panel This tab contains reaction condition settings To open the MC SD panel choose MC SD from the MacroModel submenu of the Applications menu in the main menu bar 11 2 Setting Up MC SD Calculations The MC SD procedure 29 differs from a normal dynamics simulation in that it uses a mixture of Metropolis Monte Carlo and dynamics steps in order to greatly increase the rate at which a simulation explores conformational space For MC SD simulations you must specify torsions to be rotated and if there is more than one molecule in the system molecules to be translated
191. mum distance The maximum acceptable distance between the second and third atoms of a re closed ring can be specified If the distance between the ring closure atoms is greater than this maximum distance the ring is reopened and a different set of random variations is performed The default value for this is 2 5 A This value should suffice for most searches Define ring closures To define the location of a ring closure manually choose Atom or Bond from the Pick menu and pick four atoms or three bonds from the ring Picked atoms are marked by purple boxes The bond is broken between the second and third picked atoms Once four atoms have been picked a new entry is displayed in the list and the ring closure is marked by the green line and light ning bolt as described above 9 2 5 2 Torsion Rotations During a Monte Carlo conformational search random changes are performed on the structure of the molecule Structure energies are then evaluated To set up a Monte Carlo based search using either the MCMM or SPMC method you must specify which torsions in the molecule can be rotated These torsions are defined by pairs of atoms defining bonds around which the structures can be rotated using the Torsion Rotations panel The simplest way to define torsion rotations is to use the Perform Automatic Setup button MacroModel detects torsions that need to be rotated and generates a list of torsion rotation definitions This list appears in the text box
192. n After each atom is picked a new entry appears in the list of atoms in the Monitored Atoms List located at the top of the panel When an atom is picked Maestro marks it and places an eye icon beside it The currently selected atom is colored teal the other selected atoms are colored green 10 2 1 2 Distances Use the Monitored Distances panel to specify interatomic distances for monitoring To define a distance to be monitored choose Atom or Bond from the Pick menu and click on two atoms or one bond in the Workspace When the distance is defined the two atoms appear in the list at the top of the panel The defined distances are marked with a purple dotted line and eye icon The currently selected distance is distinguished by a solid line on either side of the dotted line MacroModel 9 6 User Manual 99 Chapter 10 Dynamics Calculations 100 Figure 10 3 The Monitored Distances panel left and the Monitored Angles panel right 10 2 1 3 Angles Use the Monitored Angles panel to specify angles for monitoring To define an angle to be monitored choose Atom or Bond from the Pick menu and click on three atoms or two bonds in the Workspace that define an angle When the angle is defined the three atoms appear in the list at the top of the panel The defined angles are marked with a green solid line a dotted line through the angle and an eye icon The currently selected angle is di
193. n The time step in fs is set in arg5 the length of the simulation in ps in arg6 and the tempera ture in K of the simulation in arg7 Two MDYN command lines appear in this command file The first performs a short equilibration run while the second is where the actual sampling occurs Argl defines printing of energy listing In the first MDYN line arg1 0 meaning that a summary of the energies is printed to the log file only In the second MDYN line argl1 1 signifying that energies as well as monitoring results are written to the mmo file MDSA Perform structure sampling during the stochastic dynamics simulation Intermediate structures generated in the dynamics simulation are saved to the output structure file at regular intervals during the calculation Argl defines the total number of structures to sample number of snapshots to take during the simulation Structures can also be written out based on time intervals in ps using arg5 Arg7 1 forces deletion of all structures stored in the out mae file prior to each simulation MDDA Monitor a dihedral angle during the simulation Argl arg4 defines the atom numbers of the angle to be monitored The default arg5 divides the reported results into 10 degree incre ments Average values are reported in the 1og file while more detailed information including the distribution of angles is reported in the mmo file WRIT Write the final structure to the output file 10 3 2 Simu
194. n receptor atoms from complete residues within 4 0 of the previously defined shell follow the same procedure and select Freeze atoms 14 4 Command File Examples To run MacroModel calculations a molecular structure file and a command file are required The molecular structure file contains the structures to be used as input in the calculation The command file contains the name of the input structure file the name of the output structure file and an ordered list of operation codes opcodes for the calculations Once you set up a job in Maestro and click either Start or Write Maestro writes out a molecular structure file and a command file For many types of jobs command files written this way are complete and adequate For some types of jobs however including eMBrAcE conformational searches you will need to adjust the Maestro generated command file The command files and the log files for the examples given in this section can be found in SCHRODINGER macromodel vversion samples Examples 14 4 1 eMBrAcE Minimization Calculations You can set up the files for eMBrAcE minimization calculations using Maestro This is the recommend mechanism for setting up such calculations This section explains the structures of eMBrAcE minimization com files if you want to customize them 14 4 1 1 Interaction Mode Interaction mode uses the ASET mechanism to define atom sets and to calculate interaction energies within and among all s
195. nce like FMNR The minimization sequence ceases when the convergence criteria as defined by the CONV opcode is reached MWRT can be applied to minimizations and conformational searches including multi struc ture computations This feature is supported with a particular set of choices as the Optimal minimization method in Maestro To make your own choices use the MWRT opcode in the command file Section 6 3 2 on page 50 contains examples of MWRT minimizations and section 9 3 4 contains examples of MWRT conformational searches 6 3 Command File Examples To run MacroModel calculations a molecular structure file and a command file are required The molecular structure file contains the structures to be used as input in the calculation The command file contains the name of the input structure file the name of the output structure file and an ordered list of operation codes opcodes for the calculations Once you set up a job in Maestro and click either Start or Write Maestro writes out a molecular structure file and a command file For many types of jobs command files written this way are complete and adequate but for some types of jobs you may need to adjust the Maestro gener ated command file The command files and the log files for the examples given in this section can be found in SSCHRODINGER macromodel vversion samples Examples MacroModel 9 6 User Manual Chapter 6 Minimizations 6 3 1 Constrained Minimization Be
196. nd MM3 programs do not use non bonded cutoffs When making comparisons with these programs MacroModel calculations should be performed using non bonded cutoff distances which are effectively infinite that is the values should be larger than the largest molecular dimension See Section 2 1 on page 5 for other consider ations involving comparisons between MacroModel results and results from the standard implementations of other force fields e We recommend that calculations performed using the MacroModel solvation model be carried out with effectively infinite cutoffs 2 8 Electrostatic Treatments By default MacroModel uses a constant dielectric constant during the evaluation of electro static interactions between atoms In most situations the use of a constant dielectric is appro priate for such calculations One such place is when making comparisons with gas phase ab initio molecular orbital calculations Additionally use of the MacroModel GB SA continuum solvation model also requires the constant dielectric electrostatic treatment When this model is utilized electrostatic interactions are automatically calculated using this method Alterna tively a distance dependent dielectric electrostatic treatment may be specified by selecting Distance Dependant from the Electrostatic Treatment option menu in the Potential tab of the MacroModel panels 2 9 File Conversion Maestro reads Protein Data Bank PDB MDL SD mo1 files and Sybyl mol2 f
197. nding on whether or not a substructure file is to be used If argl of SUBS is zero in the command file MacroModel looks for a substructure file to obtain information on flexible and MacroModel 9 6 User Manual Chapter 4 General Settings fixed frozen parts of the system There are other possible uses of the SUBS command in partic ular it may be useful to combine the use of substructures both in a filename sbc file and sepa rate SUBS lines in the MacroModel command file Please refer to the SUBS command in the MacroModel Reference Manual The substructure file also supports the use of ASL expressions with the commands ASL1 and ASL2 The syntax of their use is described in the MacroModel Reference Manual ASL1 performs the same function as SUBS to specify atoms for a substructure and ASL2 performs the same function as FXAT to specify atoms to be fixed or frozen For more information on using Maestro s substructure facility see Section 4 5 on page 33 4 4 The Constraints Tab In MacroModel subsets of atoms can be constrained in almost all energetic calculations and the constraints can be of two basic types The atoms can be completely frozen and not allowed to move or atoms can be fixed which means that the atoms in question are tethered in place using a constraint Fixed atoms have the ability to move frozen atoms do not The following two sections describe how to prepare MacroModel computations from Maestro that include fixed
198. neeeeees 29 4 3 3 The Substructure Facility asirio nta nani sia dialers 29 4 4 The Constraints Tab until lalalala lidia 31 4 4 1 Constraining Atoms Distances Angles and TorsiONS ooiocccnnncnnccnconccconccnnns 31 4420 REE ALOIS ria 33 4 5 The Substructure Tab once ncrden caia aa 33 4 5 1 Delining a SUBSIMICIUIIG ui id 33 4 5 2 Greatingia Shell of Atoms unica eben 35 4 5 3 Reading and Writing SUbStructures 0 0 ee eee eeeeeeeeseeeeaeeeeeeeaeeeaeneeeeneeeeees 36 4 6 Setting Up Running And Monitoring Jobs 0 0 0 00 cece cece eeeeeeeeteeeeetees 36 MacroModel 9 6 User Manual Contents Chapter 5 Current Energy CallCulations sssssssssssssssssssssssssssssssssssssssssssssssssess 39 5 1 The Current Energy Pannell ccccccsscscssssecsseececenneeneeeeeeeeneeeneensentenseaeeeneeenees 39 5 2 THe EGA Tab catastro a Oi a a 39 5 3 Command Fil EXamples oir 40 5 4 The Force Field ViGwer iia 42 5 5 Checking and Interpreting Results ooooocicnnnnncinnononcnnnnnicnnnnccnnnccnncncnnanancnnn 43 Chapter 6 MINIMIZATION S cercanos 45 6 1 The Minimization Panel i ooo rr iia 45 6 2 Performing a Minimization Calculation ononccninnininidnnicinnnnnicnnnnnicnaenncc 45 6 2 1 Minimization Methods socia ies 46 6 2 2 Convergence Para mete iii AN E A 47 6 2 3 Using Multiple Minimization Stages During a MinimizatiON ooononnnnnnnnon 48 6 3 Command File Examples o oooconcicnonnconnnc
199. nergy range for the plot Full Scale Restores a plot whose range has been altered to its full scale MacroModel 9 6 User Manual Chapter 8 Coordinate Scans Energy Units These options allow you to display data in either kJ mol or kcal mol energy units Energy Scale These options allow you to display the energy as either an absolute or a relative value The Relative option is useful for estimating rotational barriers Constrain to Square This option forces the plot to be displayed as a square regardless of how the panel is resized Coordinate Energy These text boxes Coordinate 1 and Coordinate 2 for 2D plots display the values of the coordi nate or coordinates and the energy at the pointer position when you middle click and hold in the plot area In addition the structure corresponding to the given coordinates is displayed in the Workspace DAE Open Och3och3_drive out Och3sch3_drive out PostScript Tabular Data Energy kJ mol 25 0 Minimum coordinate 0 0 Maximum coordinate 360 0 Minimum energy 10 0 Maximum energy 25 0 Full Scale Energy units 4 kJ mol w kcal mol Energy scale 4 Absolute w Relative 4 Constrain to square Coordinate Energy Decimal places X Axis D Y Axis 1 0 60 120 180 240 300 360 Data Sets Coordinate Close Help Figure 8 2 The 1D Plot panel MacroModel 9 6 User Manual
200. ngles Another possibility is to compare structures sampled from a simulation with those obtained from an extensive conformational search Most importantly note that stable values for the average free energy change over several tens of picoseconds of sampling while required for a converged simulation are not alone proof of convergence If the simulation is stuck in one particular minimum then the average quantities will look to be converged but the actual free energy may be incorrect 3 Is the force field adequate Free energy perturbation assumes that the potential energy of the system is well described by force field parameters You cannot expect to get quantitative agreement with experimental free energies or make useful predictions unless you are using a high quality force field You MacroModel 9 6 User Manual 151 Chapter 15 Free Energy Simulations 152 should carefully check the quality of all the parameters in use in a free energy calculations A summary of the parameter quality is printed at the top of the log file 4 Are the dummy atom parameters appropriate Natural bond lengths to dummy atoms may need to be set to approximate the length of the real counterpart of the dummy atom e g the atom into which the dummy grows In the past we have used very short ca 0 5 A natural bond lengths for dummy atoms However this can cause problems when the dummy atom has significant non bonded interaction with o
201. non adaptive mode integration Set arg3 not equal to O and arg4 to values from 1 to 10 for adaptive integra tion Arg4 defines the number of soft or low frequency vibrational modes degrees of freedom for which numerical integration should be applied The default is to apply numerical integration to all degrees of freedom However this is recommended only for very small mole cules about 20 atoms or fewer It is strongly recommended not to use values of arg4 greater than 50 Arg5 sets the simulation temperature while arg6 and arg7 define hard and soft limits for sampling along normal modes 12 3 Checking and Interpreting Results For many MINTA calculations the input set of conformations must be generated in a separate calculation such as a conformational search The set of conformations needed for accurate MINTA calculations should be fairly extensive and include all low lying conformers MacroModel 9 6 User Manual Chapter 13 Protein Loop Construction Before analyzing how a given protein ligand pair will interact you may want to refine the protein structure This commonly involves examining the structure of loops short sequences of amino acids which typically occur on the surface of the protein but in the middle of the protein sequence The reasons for refining a protein structure include The structure of this portion of the protein was not well resolved e The conformation of the loop changed upon solvation
202. ns MacroModel 9 6 User Manual 113 Chapter 12 Minta Calculations 114 BDCO Use the Bond Dipole CutOff BDCO method for truncating electrostatic interactions Arg5 and arg6 are used to specify the cutoffs used for charge dipole and charge charge interac tions respectively BGIN END The loop reads structures from a preceding conformational search The input file should contain only conformers of the same molecule or molecular complex READ Read the input file CONV Defines convergence criteria Arg1 2 signifies derivative convergence default criterion if no CONV command is present is 0 05kJ mol This value is set in arg5 MINI Starts the minimization Argl defines the type of minimization algorithm to be used Arg1 9 means that Truncated Newton Raphson Conjugate Gradient will be used In arg3 the number of minimization steps is defined Arg3 can be set to a large number since the calcula tion will automatically stop as soon as the convergence criterion is reached MNTA A Minta free energy calculation will be performed Minta numerical integrations are performed in blocks in order to achieve better convergence and argl defines the number of such blocks Arg2 gives the number of energy evaluations per block hence the total number of energy evaluations per structure is argl arg2 Minta can be run in an adaptive manner which is slightly more accurate than the non adaptive mode Arg3 0 specifies the use of
203. nual for more information MacroModel 9 6 User Manual Chapter 2 Basic Molecular Modeling 2 5 General Guidelines for Convergence It is as important to fully explore the potential energy surface as it is to describe that surface correctly by means of a high quality force field We use the term convergence to describe this issue A common problem in modeling is obtaining unconverged results i e the calcula tion gives a significantly different answer if the calculation continues or is repeated from different initial conditions The term convergence has somewhat different implications depending on the nature of the procedure that is being carried out and for each type of energy calculation there are different convergence issues These issues are discussed in the following sections 2 5 1 Minimization It is important that during energy minimization the energy is minimized to a low gradient norm Energy minimization calculations generally converge readily although there is no guar antee that final structures are low in energy relative to the actual global minimum By default we set a convergence criterion for minimization of a gradient to lt 0 05 kJ A mol and this is usually satisfactory However the default setting for the maximum number of iterations for a minimization calculation may not be sufficient to meet the convergence criterion particularly for large structures or ones with poor starting geometries The latte
204. o be different if the RMS deviation for all compared atoms exceeds the threshold given in the Cutoff text box The default cutoff is 0 5 A for both options Unless there are fixed or frozen atoms the struc tures are superimposed prior to calculating the distances 9 2 4 Low Mode Parameters In the lower portion of the Customize the search section are three text areas that are relevant only to low mode searches These are active only when any of the four methods involving Low Mode Conformational Searching is the current search method Probability of a torsion rotation molecule translation This control is available only with the mixed methods This text box allows you to set a proba bility that any defined torsion rotations and molecule translations will be made during the search The value should be a number from 0 0 to 1 0 Minimum distance for low mode move Maximum distance for low mode move Used for setting the minimum and maximum distance for a low mode move During a search the fastest moving atom is moved at randomly generated distances that are between the minimum and maximum values specified in these text boxes 9 2 5 Setting Conformational Search Variables Manually Automatic setup of search variables can be used for most purposes There are occasions in which you may want to set conformational search variables manually or to examine them To do so select the search variable from the Search variables option menu and click Ed
205. oblems differ greatly we cannot make categorical pronouncements setting forth the largest problem one can reason ably address Instead we encourage you to consider the issues of convergence as described below and use the principles described there as a guide 2 7 Nonbonded Cutoffs By default MacroModel energy calculations are performed with cutoff distances in place for nonbonded interactions If the distance between any nonbonded pair of atoms is greater than the cutoff distance then the non bonded term electrostatic or van der Waals energies for that pair will be ignored These terms decrease in magnitude with increasing interatomic distance and so terms for nonbonded atom pairs separated by a distance greater than a reasonable cutoff distance will not contribute greatly to the overall energy The introduction of nonbonded cutoffs greatly reduces the time it takes to compute the energy for a large molecular system Several implications of using cutoffs however deserve special mention MacroModel 9 6 User Manual Chapter 2 Basic Molecular Modeling 16 e For systems with formally charged atoms the default cutoff distances 7 A for van der Waals interactions and 12 A for electrostatics are probably too small for accurate results Better values might be 8 A and 20 A respectively These values can be set by selecting Extended from the Cutoff option menu in the Potential tabs of the MacroModel panels The original MM2 a
206. odel 9 6 User Manual 121 Chapter 14 eMBrAcE 122 eMBrAcE Minimization Ja Potential Substructure Mini eMBrAcE Source of ligands y Selected entries 4 Input file Browse Receptor 4 First structure in file v Entry Association energy mode 4 Energy difference mode wv Interaction energy mode Structures saved 4 Complexes only v Ligands only y Receptor ligands and complexes Start Write Close Help Figure 14 1 The eMBrAcE Minimization panel showing the eMBrAcE tab Receptor For an eMBrAcE calculation to execute correctly it must correctly identify which structure is to be treated as the receptor If you are reading the ligands from file you can nominate the first structure in the file as the receptor or you can specify it as an entry in the current project If the receptor is not in the file you must specify it as an entry in the current project You can either type the entry name in the text box or click Choose and select an entry in the Choose Entry dialog box that is displayed In this case the receptor is written to a separate file for the job If the ligands are entries in the current project you can nominate the first selected entry as the receptor or you can choose another entry for the receptor To choose an entry type the entry name in the text box or click Choose and select an entry in the entry selection dialog box that is displayed MacroMo
207. odeling study it is up to you to demonstrate that results are converged and what the bounds of uncertainty are Unconverged results are meaningless 2 5 3 Molecular and Stochastic Dynamics Obtaining convergence in dynamics simulations has traditionally been problematic because of the slow frequency at which systems undergoing these processes cross barriers between the various minima on the potential energy surface Stochastic dynamics may search conforma tional space more efficiently than does regular molecular dynamics but neither method gives frequent crossing of barriers much larger that 3 kcal mol 13 kJ mol A much higher rate of convergence can be obtained by the use of the mixed mode Monte Carlo Stochastic Dynamics MCSD procedure We therefore recommend using this procedure whenever appropriate such as for simulations of acyclic systems in which generation of the canonical ensemble is desired and no time dependent information is required For cyclic systems the Jumping Between Wells JBW method can be used However even with these methods it is important to test MacroModel 9 6 User Manual Chapter 2 Basic Molecular Modeling that converged results have been obtained Converged simulations will satisfy the criteria listed below Satisfaction of these criteria like those described in the last section are necessary but not sufficient to prove convergence e Average quantities for example potential energy or the fraction
208. of times a hydrogen bond appears should exhibit numerical stability For example once the simulation is converged doubling the length of the simulation should not change the averages It is possible to obtain the average values of geometric and hydrogen bond monitors periodi cally during the simulation e Dihedral angle distributions in achiral compounds should be symmetric For example dihedral angle distributions produced using the MDDA command should exhibit the same populations of gauche and gauche values for three way torsions e Simulations starting from different starting geometries should give the same results 2 6 Problem Size Limits of Operation MacroModel is distributed with a number of arbitrary fixed limits on its operation Some of these restrictions have been lifted since the program has gone to dynamic memory allocation but some still remain For example we distribute a version of MacroModel that can perform Monte Carlo conformational searches on up to 500 rotatable bonds however these limits usually far exceed the size of a calculation that can be reasonably performed It is highly unlikely that a converged conformational search could be performed in a reasonable amount of time on a system with even 100 degrees of rotational freedom Because of the wide variety of platforms on which MacroModel is used ranging from Linux based PCs to super computers or a network of scores of workstations and also because chemical pr
209. ollowing full dynamics run MDYN Perform full MC SD dynamics run for 10 ps at 1 5 fs intervals 11 4 Checking and Interpreting Results As with normal dynamics simulations it is often difficult to know when you have sampled enough in a MC SD simulation It is usually helpful to have some prior knowledge of the time scales for crucial processes within the system to know if convergence may have been achieved While MC SD simulations provide a wealth of structural and temporal information this infor mation is often hard to interpret If the goal is to thermally sample the local conformational minimum of a small molecule then you may not need to examine the results carefully provided that you have simulated sufficiently long 50 to 100 ps may be enough However if the system is large and the conformational variation is large simulations likely will not adequately sample the conformations available and careful problem specific consideration of the results may be needed to learn from such studies In such circumstances it almost always helps to examine the monitored trajectory with a tool such as Maestro s ePlayer In addition clustering tools such as XCluster may help identify when key events occurred during the simu lation If the MC SD simulation is unstable and fails consider turning off long range constant deriva tives by setting EXNB argl to 1 and increasing the non bonded cutoffs to a large number such as 100 A by choo
210. ols in the Constraints tab within the various MacroModel energy panels in Maestro The desired atom is selected through on screen picking and is then assigned values for how much it should be allowed to move half width in A and the penalty for moving outside the defined limits force constant in kJ mol A This process is repeated for all atoms to be constrained See Section 4 4 on page 31 for more information on specifying constraints using Maestro For additional information about using the FXAT command when manually constructing MacroModel command files jobname com refer to the pages describing the FXAT opcode in the MacroModel Reference Manual All atoms not defined by a FXAT command remain fully flexible free to sample the potential energy surface defined by the force field 4 3 3 The Substructure Facility You can define substructures by manually placing the appropriate lines in the MacroModel command file jobname com or by using the Substructure tab in the MacroModel energy panels to define groups of flexible fixed and frozen atoms The settings are saved in a substructure file consisting of SUBS commands for the flexible atoms and FXAT commands for fixed frozen atoms Note that atoms not defined by either SUBS or FXAT commands are completely ignored as if they had been deleted during the calculation After defining the flexible part of the system typically the ligand and atoms in its near vicinity you can de
211. ometimes the molecular mechanics potential energy surface differs enough from the ab initio potential energy surface that structures considered distinct in the original conformational search minimize to the same structure in the Jaguar calculations The redundant conformer elimination facility can then be used to remove these redundant conformers without adjusting the energy or geometry of the molecules Another use of the redundant conformer elimination facility is to reprocess the results of a MacroModel conformational search with less strict criteria for distinguishing conformers or a smaller energy range for retained conformers As well on occasions MacroModel conforma tional searches might not eliminate all of the redundant conformers Running the structures through this facility provides a rapid mechanism for dealing with such cases 17 1 Eliminating Redundant Conformers Using Maestro You can set up and run jobs to eliminate redundant conformers from a set of conformers with the Redundant Conformer Elimination panel To open this panel choose Redundant Conformer Elimination from the MacroModel submenu of the Applications menu in the main menu bar The upper and lower parts of the panel are common to all MacroModel panels These components are described in detail in Section 4 1 on page 25 Redundant conformer elimination performs no energy calculations so the tabs present in other MacroModel panels are not present The remaining controls in thi
212. on Angle button and the Improper Torsion buttons are never active simultaneously since they perform similar operations but are associated with different force fields Wilson angles are used in MMFF and MMFFs force field calculations and improper torsions are used in the others A brief summary of each button and its corresponding panel is given below Stretch The Stretch panel is used to display the stretching interactions for a given calculation The selected interaction is marked with a dashed yellow line Bond Angle The Bend panel opened by clicking Bond Angle is used to display the bending interactions for a given calculation The selected interaction is marked with a dashed red line Torsion Angle The Torsion Angle panel displays the torsion interactions for a calculation The selected inter action is marked with a pale green dashed line Improper Torsion In the Improper Torsion panel the improper torsion interactions associated with a particular calculation can be viewed The selected improper torsion in the displayed structure is marked with a gold colored asterisk MacroModel 9 6 User Manual Chapter 5 Current Energy Calculations _ Force Field Viewer Stretch Bond Angle Torsion Angle Improper Torsion Angir GB Solvation SA Solvation van Electrostatic MMO file name fmmod_energy out mmol Browse Close Help Figure 5 2 The Force Field Viewer panel Wilson Angle The Wils
213. on Angle panel displays the Wilson angle interactions for a given calculation The selected Wilson angle is marked with a peach colored asterisk GB Solvation The GB Solvation panel can be used to view the Generalized Born GB portion of the solva tion interactions for a given calculation The selected atom in the displayed structure is marked with a yellow asterisk SA Solvation The SA Solvation panel can be used to view the Surface Area SA solvation interaction components for a given calculation The selected entry in the SA Solvation List is marked with a peach colored line Van der Waals The Van der Waals panel can be used to view all van der Waals interactions for a given calcula tion The selected interaction in the displayed structure is marked with a dashed orange line Electrostatic The Electrostatic panel can be used to view all electrostatic interactions for a given calculation The selected interaction is marked with a dashed purple line 5 5 Checking and Interpreting Results The energy estimate for an energy calculation depends critically on the nature of the structure it is applied to It is often crucial that the particular structure was produced using a calculation such as a minimization or a dynamics simulation employing the same force field Otherwise the energy may contain significant contributions due to strain resulting from differences in the equilibrium structures for the different force fields MacroMo
214. onder J W Richards F M An Efficient Newton like Method for Molecular Mechanics Energy Minimization of Large Molecules J Comput Chem 1987 8 1016 Oren S S Spedicato E Optimal conditioning of self scaling variable metric algo rithms Mathematical Programming 1976 10 70 Chang G Guida W Still W C An internal coordinate Monte Carlo method for searching conformational space J Am Chem Soc 1989 111 4379 Saunders M Houk K N Wu Y D Still W C Lipton M Chang G Guida W C Conformations of Cycloheptadecane A Comparison of Methods for Conformational Searching J Am Chem Soc 1990 112 1419 Goodman J M Still W C Searching Conformation Space J Comput Chem 1991 12 1110 Kolossvary I Guida W C Low Mode Search An efficient automated computational method for conformational analysis application to cyclic and acyclic alkanes and cyclic peptides J Am Chem Soc 1996 118 5011 Kolossvary I Keseru G M Hessian Free Low Mode Conformational Search for Large Scale Protein Loop Optimization Application to c jun N Terminal Kinase JNK3 J Comput Chem 2001 22 21 Keseru G M Kolossvary I Fully Flexible Low Mode Docking Application to Induced Fit in HIV Integrase J Am Chem Soc 2001 123 12708 Kolossvary I Guida W C Low mode Conformational Search Elucidated Application to C35Hg and Flexible Docking of 9 Deazaguanine Inhibitors to PNP J Comput Che
215. one across each C O bond as well as point charges of 0 5 located in the oxygen atoms to account for the net negative charge of the group Some force fields such as MMFF have been conceptualized using this scheme and the charge parametrization for an arbitrary molecule is achieved by assigning dipoles across bonds as well as delocalized formal charges on atomic centers and summing up these values to obtain fixed partial charges on atomic centers Other force fields such as AMBER assign charges to arbi trary molecules by dividing a given molecule into small groups of atoms with unit charge like amino acids for which there exist fixed partial charge data Even in the latter case the fixed partial charges can be transformed into a system of bond dipoles and delocalized formal charges In addition to assigning partial charges based on the selection of a force field MacroModel allows you to specify custom partial charges for a system in the input structure file see the CHGF opcode in the MacroModel Reference Manual MacroModel is capable of decomposing this list of partial charges into delocalized formal charges and bond dipoles In the event that the partial charges so specified for a molecule do not sum to the net formal charge of that mole MacroModel 9 6 User Manual Chapter 2 Basic Molecular Modeling 12 cule the input structure partial charges will be modified to meet this constraint before the decomposition is performed
216. ormatted structure files You can then use these structures in MacroModel calculations Note however that Maestro may have some difficulty with some of these files It may be necessary to examine the file in detail and to make repairs If you have problems reading a PDB file see Section 3 1 3 of the Maestro User Manual which explains Maestro s color coded warning system File conversion can also be performed from the command line using the pdbconvert sdconvert molmmod and mmodmae scripts in the SCHRODINGER utilities directory MacroModel 9 6 User Manual Chapter 2 Basic Molecular Modeling 2 10 Modified Force Field Solvent or Atom Type Files When a job is launched MacroModel searches in the current working directory for a copy of the force field 1d solvent slv and atom type atom typ files If it finds any of these files there it uses them to perform the energy calculation If MacroModel does not find copies of these files locally it then looks in HOME schrodinger macromodel Only if MacroModel does not find the files in schrodinger does it use the global settings in SSCHRODINGER If you do create locally modified files manage them closely The uninten tional use of forgotten locally modified files can give surprising energetic results 2 11 Hydrogen Treatment 2 11 1 Hydrogens on Hetero Atoms While the AMBER and OPLS force fields can be used without explicit hydrogen atoms on carbon atoms all force fie
217. otated manually click on an atom in the Workspace structure Define molecules to translate rotate is selected by default A new entry is displayed in the list at the top of the panel The atom is colored peach and the vertical arrow icon is placed by the atom in the Workspace Although only the picked atom is marked the entire molecule is selected You should not pick more than one atom in any molecule even though this operation is allowed 9 2 5 4 Comparison Atoms During conformational searches new structures are generated and minimized The structures are compared against other low energy structures that have already been found in the search The comparison is performed by rigid superposition comparing only those atoms specified as comparison atoms in the setup The simplest way to define comparison atoms is to click Perform Automatic Setup Macro Model locates comparison atoms and generates a list of the atoms This list appears in the text box at the top of the Comparison Atoms panel The features of the Comparison Atoms panel work in the same way as for multiple minimiza tion see page 55 To define comparison atoms use one or more of the following options e Click Heavy Atoms O H S H This adds all non hydrogen atoms and the hydrogen atoms attached to oxygen and sulfur to the list of comparison atoms MacroModel 9 6 User Manual 85 Chapter 9 Conformational Searches 86 Comparison Atoms
218. other Macro Model panels The controls in these tabs and those in the upper portion of the panel are discussed in detail in Section 4 1 on page 25 through Section 4 5 on page 33 To open the Minimization panel choose Minimization from the MacroModel submenu of the Applications menu in the main menu bar 6 2 Performing a Minimization Calculation To set up a minimization calculation 1 Select the entry that you want to use as input or display the structure you want to use in the Workspace 2 Open the Minimization panel 3 Set the controls in the upper portion of the panel and in the first three tabs Potential Constraints and Substructure 4 In the Mini tab select a minimization method the maximum number of iterations and the convergence criterion and threshold The features of the Mini tab are described in detail in the next few sections MacroModel 9 6 User Manual 45 46 Chapter 6 Minimizations Minimization Ja Use structures from Workspace included entry Potential Constraints Substructure Mini Method PRCG 1 Maximum iterations 500 Converge on Gradient 4 Convergence threshold 0 0500 Start Write Close Help Figure 6 1 The Mini tab of the Minimization panel 6 2 1 Minimization Methods From the Method option menu select a minimization method for your calculation Choose from the following supported methods e PRCG Polak Ribiere
219. out mae NPRC 2 16 0 0 0 0000 0 0000 0 0000 0 0000 FFLD 1I 1 0 0 1 0000 0 0000 0 0000 0 0000 SOLV 3 1 0 0 0 0000 0 0000 0 0000 0 0000 EXNB 0 0 0 0 0 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 89 4427 99999 0000 0 0000 0 0000 MSYM 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MBAE 1 1 1 0 0 0000 0 0000 0 0000 0 0000 MCMM 50 0 0 0 0 0000 0 0000 0 0000 0 0000 MCNV 1 4 0 0 0 0000 0 0000 0 0000 0 0000 MCSS 2 0 0 0 500 0000 0 0000 0 0000 0 0000 MCOP 1 0 10000 0 0 0000 1 0000 0 0000 0 0000 DEMX 0 0 0 O0 1000 0000 0 0000 0 0000 0 0000 SUBS 0 0 0 0 0 0000 0 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 AUTO 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MINI 1 0 10 0 0 0000 0 0000 0 0000 0 0000 AUTO 0 0 0 0 0 0000 1 0000 0 0000 0 0000 MCMM 50 0 0 0 0 0000 0 0000 0 0000 0 0000 BGIN 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MCOP 1 0 10000 0 0 0000 2 0000 4 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MINI al 0 10 0 0 0000 0 0000 0 0000 0 0000 END 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MBAE 0 0 0 0 0000 0 0000 0 0000 0 0000 NPRC Distribute the calculation Argl is the number of processors to use and arg2 is the number of input structures to process in each subjob Arg2 should be a multiple of 4 for ligands prepared with ALGN so that all four alignments of each ligand are sent to the same child process 142 MacroModel 9 6 User Manual Chapter 15 Free Energy Simulations This chapter provides some of the theory behind the powerful simulation m
220. ow quality torsions one low quality bend and one low quality stretch are in use in the calculation Consequently conformational energy differences and solvation energies may be unreliable By looking in the job s jobname 1log file you can see which line s in the force field file is the source of the low quality parameters Listings of the specific torsions having low quality type 3 parameters can be found in the job s mmo file after running the job with a Complete energy listing If the file notes that low quality parameters are being used first attempt to find improved parameters by trying the system of interest with each MacroModel force field MacroModel supports a number of different force fields and each has its own strengths If you are unable to find a force field with acceptable parameters for your particular system you should seriously consider developing your own parameters or try to obtain parameters from other practitioners in the field Typically low quality torsional parameters are generalized ones e g any bond between two sp carbons has a 3 fold rotational barrier of 3 kcal mol Thus for a specific torsion involving for example Cl C sp C sp O a new torsional parameter line would be added to the force field file with specific V1 V3 terms which reproduce reliable experimental data or high quality ab initio calculations e g 6 31G on for example B chloroethyl methyl ether To make the calculation more
221. p a substructure for the receptor The substructure will contain a shell of all receptor atoms from complete residues that lie within 6 0 A of the ligand Two additional shells one fixed and one frozen are also specified 1 Include the receptor in the Workspace and then include the ligand It is important to include the receptor first to ensure that its atoms are assigned atom num bers starting from 1 You can now create a substructure in the usual manner Maestro s support for the eMBrAcE utility automatically ignores atoms within the substructure that are numbered higher than the atoms in the receptor so the inclusion of ligand atoms is not a problem when you use the Maestro interface For each ligand that eMBrAcE is applied to all atoms in the ligand are automatically added to the substructure without constraints 2 In the Atoms for substructure section select Molecule from the Pick menu and pick a ligand atom 3 Select Complete residues and enter 6 0 in the Expand to atoms within radius of text box Alternatively enter the following ASL expression in the ASL text box fillres within 6 0 entry name our_lig MacroModel 9 6 User Manual 127 Chapter 14 eMBrAcE 128 Now add a shell of fixed receptor atoms from complete residues within 5 0 of the substruc ture atoms 4 Click New Shell to create a new shell 5 In the Radius text box enter 5 0 and select Complete Residues To add another shell containing froze
222. pecify whether enantiomers are to be considered The following sections describe the use of the XCluster panel to set up an XCluster calculation When you have set up the calculation click Start The original XCluster interface is launched the computation transferred to its control and the job is run When the job is finished you can investigate the clustering statistics and use the visualization tools from the Visualize menu of the XCluster interface 16 1 1 Selecting the Structure Source To perform an XCluster analysis you must provide a collection of conformers as input The input can be taken from Maestro s project facility for instance from the incorporated struc tural output of a conformational search or dynamics simulation or from an external structure file XCluster cannot perform clustering calculations on non conformers MacroModel 9 6 User Manual 157 Chapter 16 Molecular Clustering with XCluster 158 EJE Use structures from File File name Browse Cluster by 4 Atomic RMS w Torsional RMS Delete Delete All Define comparison atoms Pick Atoms All Selection Previous Select MM Show markers Heavy Atoms O H S H Heavy Atoms 4 Calculate RMS in place no superposition W Distinguish mirror image conformations Start Write Close Help Figure 16 1 The XCluster panel To use structures from the current project select the entr
223. pick two atoms or one bond in the Workspace structure to define the torsion rotation When you pick the first of a pair of torsion rotation atoms Maestro places a crimson box around it Once both the atoms have been picked a new entry is displayed in the list at the top of the panel and the bond is marked as described above if Show markers is selected MacroModel 9 6 User Manual 83 Chapter 9 Conformational Searches 84 Minimum rotation 0 0 Maximum rotation 180 0 Minimum translation 0 000 Maximum translation 1 000 F Define molecules to translate rotate WE Show markers Delete Delete All Close Help Figure 9 4 The Molecule Trans Rot panel 9 2 5 3 Molecule Trans Rot During a Monte Carlo conformational search random changes are performed on the structure of the molecule Structure energies are then evaluated to find the lowest energy structure possible To set up a Monte Carlo based search using either the MCMM or SPMC method you must specify which molecules will be translated and rotated The Molecule Trans Rot panel facilitates the specification of molecules to be rotated and translated during a Monte Carlo MCMM or SPMC conformational search The simplest way to define molecules for translation and rotation is to use the Perform Auto matic Setup button MacroModel locates molecules that need to be translated and rotated and generates a list of molecule translation and rotation defin
224. ple of the use of Python scripting with Macro Model It has limited Job Control features e get_rep_confs py Runs a conformation search then uses Cluster to produce repre sentative collections It is intended as an example of the use of Python scripting with MacroModel It has limited Job Control features In addition the following script is available from the Script Center e aset py Provides a graphical user interace for creating ASET con files For more information on using Python for scripting see Scripting with Python See also Chapter 13 of the Maestro User Manual for information on using scripts with Maestro MacroModel 9 6 User Manual 173 174 MacroModel 9 6 User Manual Getting Help Schr dinger software is distributed with documentation in PDF format If the documentation is not installed in SCHRODINGER docs on a computer that you have access to you should install it or ask your system administrator to install it For help installing and setting up licenses for Schr dinger software and installing documenta tion see the Installation Guide For information on running jobs see the Job Control Guide Maestro has automatic context sensitive help Auto Help and Balloon Help or tooltips and an online help system To get help follow the steps below e Check the Auto Help text box which is located at the foot of the main window If help is available for the task you are performing it is automatically displayed
225. pter 13 Protein Loop Construction e Standard three letter abbreviations are used e Nonstandard D alpha amino acids from the Maestro fragment tables can also be used but these require the four letter abbreviation e g DALA 13 3 Command File Examples To run MacroModel calculations a molecular structure file and a command file are required The molecular structure file contains the structures to be used as input in the calculation The command file contains the name of the input structure file the name of the output structure file and an ordered list of operation codes opcodes for the calculations This section includes example command files for using LOOP when using a LOOP sequence from an input protein structure and using the LOOP sequence from a file The command files and the log files for the examples given in this section can be found in SCHRODINGER macromodel vversion samples Examples 13 3 1 LOOP Job Using the Input Structure Sequence An example command file for a LOOP sequence from an input protein structure appears below Descriptions of the opcodes used in the file follow loop_input mae loop_input out mae SOLV 3 1 0 0 0 0000 0 0000 0 0000 0 0000 FFLD 11 0 0 0 0 0000 0 0000 0 0000 0 0000 EXNB 0 0 0 0 0 0000 0 0000 0 0000 0 0000 SUBS 0 0 0 0 0 0000 0 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 LOOP 423 467 0 4 0 0 0 26 0 0000 0 0000 DEMX 0 0 0 o 1000 0 0 0000 0 0000 0 0000 MSYM 0 1
226. r situation often arises during conformational searching For this reason we suggest that all structures located in a conformational search be reminimized with a large value 5000 for the maximum number of iterations and with all the tests for uniqueness in place This will help ensure that the set of conformations obtained in the conformational search represent unique conformations and not structures that would be duplicates of other structures if completely minimized The final report for a conformational search highlights with an asterisk any structure that did not converge to the criterion in force during minimization 2 5 2 Conformational Searching Conformational searches involving structures with up to a dozen rotatable bonds generally converge easily but convergence can be problematic with more flexible structures When performing conformational searches with these more flexible molecules it is therefore wise to carry out multiple searches with different starting geometries to verify that the same final struc tures are found In addition to ensuring that the final set of conformers obtained from a conformational search is completely minimized there is another issue of convergence which affects the stochastic searching methods LMOD LLMOD MCMM and SPMC For these methods it is important to establish that the structures obtained in a given search represent a thorough sampling of all MacroModel 9 6 User Manual Chapter 2 Basic Molec
227. r you For MCMM and mixed MCMM LMOD calculations comparison atoms chiral atoms torsion checks molecule moves variable torsions and ring closures are automat ically set up For low mode and large scale low mode calculations comparison atoms chiral atoms and torsion checks are automatically set up MacroModel 9 6 User Manual 77 Chapter 9 Conformational Searches 78 Perform Automatic Setup Use the Perform Automatic Setup button to automatically generate all the necessary variables for the search The settings chosen by the automatic setup procedure can then be reviewed by choosing a variable type from the Search variables option menu and clicking Edit The corre sponding panel opens in which you can define and edit the conformational search variables These panels are described in Section 9 2 5 on page 80 Automatic setup may not be available for all conformational search methods If it is not available the Perform Automatic Setup button is dimmed Perform Automatic Setup applies only to the structures in the Workspace To set up conformational search variables for other structures use Perform automatic setup during calculation If you perform an automatic setup on an entry that contains a substructure only the atoms in the substructure are automatically set up with MCMM parameters and comparison atoms Atoms in fixed and frozen regions are not included in automatic setup To clear any previously set conformational search
228. re combinations However for such systems low mode searches can be compara tively efficient MCMM conformational searches are less memory intensive and thus may be used on larger portions of the system provided that the number of degrees of freedom changed at any one time is limited and the substructure carefully selected Number of steps The number of steps that will be performed in any search is determined by the value entered in this text box When the number of generated trial structures matches the value given the conformational search is terminated Number of input conformations available to seed each search The value in this text box specifies the number of conformers available for each ligand to seed the search The file containing the ligands must have exactly the number of conformers speci fied for each ligand otherwise the search will fail when it reaches the ligand that does not have the specified number Multiple conformers could for example come from the use of COPY MacroModel 9 6 User Manual 125 Chapter 14 eMBrAcE 126 ALGN from a separate conformational search in which a specified number of conformations is kept or from Glide poses Number of structures to save for each search Specify the number of structures to save for each search counting from the lowest in energy A zero value means save all structures Energy window for saving structures This is the threshold value for comparison of
229. re deviates significantly from these conditions the solvation energy estimates and hence the calculated log Pyoivisolv2 become less reliable 7 4 Automatic Setup AUTO You can use automatic setup for multiple minimizations of a collection of conformers with redundant conformer elimination Automatic setup is enabled by adding the AUTO opcode to the command file for a calculation You should place the AUTO opcode with appropriate argu ments just before the MINI opcode in the command file You must also add a MULT opcode to the command file as seen in the example in Section 7 6 2 on page 61 AUTO is available from Maestro only for conformational searches Automatic setup should not be used with minimiza tions of single structures or minimizations with multiple non conformers as input AUTO selects comparison atoms COMP so that redundant conformers can be identified and removed without explicitly designating comparison atoms in the command file or from Maestro In addition chiral atoms CHIG and torsion checks TORC are automatically identi fied by AUTO AUTO applies the desired structural criteria to the minimized conformers as if the CHIG and TORC opcodes were present in the command file AUTO has options to adjust or turn off these features See the AUTO opcode in the MacroModel Reference Manual for more infor mation In addition AUTO uses the information in any substructure specified for the computation including information on
230. reliable new parameters that fit experimental or high quality ab initio data need to be determined and added to the force field file However if you are comparing conformations that do not involve significant changes in the torsions having low quality parameters then errors may not be large Obtaining correct torsional profiles around rotatable bonds is one of the most commonly encountered problems in reparameterizing a potential energy surface For example if a new charge set is introduced the non bonded interactions on either side of a rotatable bond may alter the torsional profile It is important to test that the relative energies of the minima and maxima are in agreement with the results of high level molecular orbital calculations on model compounds In order to make this sort of comparison the molecular mechanics calculations should be performed in the gas phase that is with the solvation model turned off and with constant dielectric electrostatics Once the potential energy surface is correctly described in the gas phase the solvation model should correctly describe the potential energy surface in solution To determine the force field quality for the problem at hand check the summary of low quality parameters in use by using Maestro s Force Field Viewer panel which is opened from the Tools menu Additional information on developing parameters can be found in the MacroModel Technical Manual MacroModel 9 6 User Manual Chapter 2
231. rom a File oo ooonniccnnonnnonnacnnnanononrnanon 119 13 4 Example LOOP Job Output oococinonicicnnconionncnocccnocnocnncnnncnonanor canon cacon 119 13 4 1 Atom Renumbering Using Input Protein Structure ooooconcninnnncnoconccnnannnn 119 13 4 2 Conformational Search Using Input Protein Structure ee 119 13 4 3 LOOP Run Using an sq File as INput conos 120 Chapter 14 e 7 0 cee epee en eet eee lidia 121 14 1 Minimizations With CMBrACE 00 00 00 eee eneeneeeeeeeeeeeeeesaeteeeeneeeeeeeeeaes 121 14 2 Conformational Searches With eMBrACE 0 0 000c eee 123 14 3 Specifying a Substructure for eMBrAcE ccccecceecceeseeeeeeeeeeeeeeeaeeeeees 127 14 4 Command File EXamples iii cea 14 4 1 eMBrAcE Minimization Calculations 14 4 1 1 Interaction Mode mmnnonococ 14 4 1 2 Energy Difference Madeira 14 4 2 Conformational Searches With eMBrAcE ooooconncccincccconcccnonccnoncnnnncnnanaccnnn non 134 14 4 2 1 MCMM Conformational SearCh ocoonococcnnnocccccnnonccnonnnncnnonnnnannnn nano nnns 134 14 4 2 2 Low Mode Conformational Search oooonccccnonicccnnnocccnnnnncncnnnnnancnnnnnno noo 137 14 4 2 3 MCMM Conformation Search With COPY ALGN nsee 138 14 4 3 Distributed eMBrAcE Calculations oooococinnnnnnncccnncccnononcnncccnoncnnnccnnancnnnnncnn 140 Chapter 15 Free Energy Simulations sssssssssssssssssssssssssssssssssssssssesssseeeesee 143 15 1 Free Energy Perturbation 0 0 0 0
232. ructures to which hydrogen atoms should be added produces a file called out mae containing the corresponding structures containing the additional hydrogen atoms MacroModel 9 6 User Manual 18 MacroModel 9 6 User Manual Chapter 3 Running MacroModel From the Command Line Running MacroModel from the command line gives you the ability to customize batch processing In addition some types of MacroModel calculations are not supported by the Maestro GUI This chapter gives instructions on how to launch MacroModel jobs from the command line For information on starting MacroModel jobs from the Maestro graphical user interface see the chapter in this manual that corresponds to the particular type of job you want to submit 3 1 Preparing for MacroModel Calculations Before you can submit MacroModel jobs from the command line you must set the SCHRODINGER environment variable and must have a valid input structure file and a command jobname com file 3 1 1 Environment Variables The SCHRODINGER environment variable specifies the installation directory for your Schr dinger software These files include the force field files the solvent files and the atom typ file To run MacroModel as a stand alone application you must first define this environment variable See page 6 of the Maestro Overview for more information on setting SCHRODINGER Whether you start MacroModel from the UNIX shell or from Maestro local versions of the force f
233. s Lit command file examples 0 eee 113 energy evaluations per iteration 112 hard limit ooooonoccnonccconnnconnncnnnncconnncnnncconnnos 112 inp t leia arpas 111 number of iteratiOWS ooccooccnocccoonconnnnonnnos 111 o rnnr ies EENS 113 AAA RaR ea 112 MINTA panel srecen 114 mixed MCMM Low mode search method 74 ARA 5 MMI e Ti I E E EEEREN ETET E E S 6 MMFF oerein roire nnair retr EERS 7 Monit r tab ricino 97 Monte Carlo Multiple Minimum search method 73 multi ligand structure files preminimization of 58 multiple minimization calculations 53 comparison atoms fOr cooconcocnoniciccnnnananononinns 29 energy WIN dOW ococnccccnoconononnnnononncunanonocnnno 56 input HETO hiisi 54 Multiple Minimization panel c ooononnniinnninnn 33 N nonbonded cutoffs ST A sezsacdieviessscsceacosssecseceiaasaeesd O PCS il 21 OP usina A 6 OPES 2007 iviiitiinssniann ardid 6 compatible H treatMent oooooconnnncinnninnome I7 OPIS 2005 vsiuiinaco datada 6 OPES A Avianca inn 6 OSVM minimization method eee 47 P TO 24 parameter quality considerations oococoncinnn 7 partition coefficient estimation cee 37 SA cesssgetassicssesssbsasedessyecencsesaaed 62 Potential tab nin tedes 26 PRCG minimization method 46 PESIMISTA Plains 58 product installation eee eeeeeeeeeeeeeeees 175 Python scripting tutorial eee 173 R receptor specifying entry for eMBrAcE
234. s and temperatures from a dynamics calculation correspond to e The instantaneous value The block average since the last monitored structure The average of all steps since the start of the simulation The distance output also includes for distance r Block average of 1 r e The average over all steps of 1 r 10 2 2 The Dynamics Tab The Dynamics tab of the Dynamics panel contains settings for defining the dynamics calcula tion method and the calculation conditions The controls in the Dynamics tab are described below Method This menu contains two options e Stochastic dynamics default The most common method because it includes random forces that simulate the buffeting of a system by solvent molecules In combination with damping forces the random forces provide a simple robust method for controlling tem perature in a simulation The random forces can also assist in sampling the potential energy surface See Reference 27 for more information e Molecular dynamics Uses a standard constant temperature velocity Verlet algorithm SHAKE The SHAKE procedure 28 constrains selected bond lengths to their original values This procedure allows the use of larger time steps than unconstrained simulations For most simula tions the Bonds to Hydrogens choice from the SHAKE option menu should be sufficient This choice allows time steps up to 2 fs Simulation temperature K The temperature at which a simulation is
235. s opcodes for the calculations Once you set up a job in Maestro and click either Start or Write Maestro writes out a molecular structure file and a command file For many types of jobs command files written this way are complete and adequate but for some types of jobs you may need to adjust the Maestro gener ated command file The command file and the log file for the example given in this section can be found in SCHRODINGER macromodel vversion samples Examples MintaMae mae MintaMae out mae MMOD 0 di 0 0 0 0000 0 0000 0 0000 0 0000 FFLD 10 dl 0 1 1 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 41 5692 99999 0000 0 0000 0 0000 BGIN 0 0 0 0 0 0000 0 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 CONV 2 0 0 0 0 0500 0 0000 0 0000 0 0000 MINI 9 0 500 0 0 0000 0 0000 0 0000 0 0000 MNTA 5 2000 0 0 300 0000 1 0000 3 0000 0 0000 END 0 0 0 0 0 0000 0 0000 0 0000 0 0000 MMOD Creates and updates an intermediate structure file so that structures can be displayed in Maestro as the job progresses FFLD Force field selection Argl denotes the actual force field used in the calculation in this case MMFF94 Arg2 defines the electrostatic treatment for the calculation The default arg2 0 is to use the dielectric treatment encoded in the force field However in this case a constant dielectric is used Arg4 is MMFF94 specific Arg4 1 defines the MMFF94s version of the force field ensuring planarity around delocalized sp2 nitroge
236. s and the standard fields are summarized below 2 1 MacroModel Force Field Implementation All MacroModel force field files contain the authentic parameter set published by the original authors of the force field In addition to these parameters are other parameters from other sources e g the literature or work at Columbia Parameters in the force field files are labeled as to their origin O original from the force field authors M modified from the original values and A added from some other source where no original parameter exists They are also labeled by quality 1 high quality final value 2 tentative value based on more than one experimental or quantum calculation 3 crude low quality parameter Sources of A and M parameters are given at the ends of the lines in the force field files and recent additions to the force fields are documented in the MacroModel Technical Manual The MacroModel implementations of standard force fields differ from the authentic force fields in the following ways MM2 All force field equations are identical with those of authentic MM2 from Allinger 1 with the exception of the following e The electrostatic equation MM2 uses partial charges and Coulomb s law whereas MM2 uses bond dipoles and the Jeans equation e The out of plane bending equation MM2 uses an improper torsion while MM2 uses a pyramidalization distance the difference being insignificant except for substantially dis
237. s encountered it will generate an interaction array with the value of lambda as given in arg5 When placed inside a BGIN END pair as in this example the behavior is slightly different when subsequently encountered the FEAV command will increment the current value of A i e the middle of the SA command In this case it will be incremented to 0 05 the first time through the BGIN END loop q double wide sampling window by the difference between arg5 and arg6 in the following F MINT Once the interactions are generated it is necessary to minimize the structure with this set of interactions in order to remove any excess potential energy before beginning the dynamics part of the simulation MDIT Sets initial random velocities corresponding to an initial temperature of the value of arg5 in this case 300 K MDYN At any given value of i e at the start of every window it is good practice to first perform a short equilibration simulation before collecting data for the free energy calculation FESA Begins the collection of free energy samples for the current value of A the middle of the window The values of arg5 and arg6 indicate the values of the left side of the window and the right side of the window for double wide sampling The difference between the values of arg5 and arg6 controls the number of windows which will be performed in the simulation the relationship is windows 1 arg6 arg5 1 A maximum o
238. s of the opcodes contained in the file geom mae geom out mae BGIN READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 GEOM 14 15 16 17 0 0000 0 0000 0 0000 0 0000 END BGIN END Geometries can be calculated for a number of input structures within this loop READ Read the input file GEOM Use the number of non zero arguments in argl arg4 to define whether atom coordinates distances bond angles or dihedral angles should be calculated For all of argl arg4 non zero the value of the dihedral angle defined by the atom numbers listed in argl arg4 is reported Arg5 is used for calculation of spin spin coupling constants For details of argl arg5 of the GEOM opcode see Section 4 15 of the MacroModel Reference Manual 18 2 Calculating Interaction Energies Using ASET ASET can be used to examine the interaction energies between sets of atoms within a structure In the sample below the interaction energy between LYS 33 and the ligand in the CDK2 struc ture lelv is computed There is also a Python script available from the Script Center http www schrodinger com scripts for ASET calculations MacroModel 9 6 User Manual 167 Chapter 18 Additional Features 168 aset mae aset out mae DEBG 1 0 0 0 0 0000 0 0000 0 0000 0 0000 FFLD 11 1 0 0 1 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 89 4427 99999 0000 0 0000 0 0000 ASET 466 487 0 0 1 0000 2 0000 0 0000 0 0000 ASET 4599 4633 0 0 2 0000 2 0000 0 0000 0 0000 ASNT 1 2 1
239. s panel are for selecting atoms and settings for structural comparison Define comparison atoms You can define comparison atoms by picking atoms in one of the conformers which must be included in the Workspace or by selecting one of the predefined sets of comparison atoms Heavy Atoms O H S H or Heavy Atoms Heavy atoms are defined as non hydrogen atoms MacroModel 9 6 User Manual 163 Chapter 17 Redundant Conformer Elimination 164 The first option of the two predefined sets includes hydrogen atoms attached to O and S atoms The comparison atoms are listed as atom numbers in the Comparison atoms list To delete one or more atoms from the list select them in the list and click Delete You can delete all compar ison atoms from the list by clicking Delete All Eliminate redundant conformers using If comparison atoms are chosen or Perform automatic setup during calculation is selected structures produced during a conformational search are compared to see if they are unique Two options are available for the conditions for structures to be considered different Maximum atom deviation consider structures to be different if the maximum atom devi ation for any atom exceeds the threshold given in the Cutoff text box RMSD consider structures to be different if the RMS deviation for all compared atoms exceeds the threshold given in the Cutoff text box The default cutoff is 0 5 A for both options
240. same 1og file as the excerpt above This 1og file was gener ated using the loop sequence from the actual protein structure Step 1 New global minimum E kJ mol Conf 1 E 3830 85 0 057 is unique and stored as Search initialized with 1 structures from the dat f 2 E 3668 40 0 077 is unique and stored as Conf 3 E 3652 38 0 043 is unique and stored as 4 E 3630 91 0 096 is unique and stored as 00 00 00 00 00 00 00 00 00 00 00 00 00 00 e 000 0 0 0 0 0 0 01 0 0 0 9 D O O O OG GOG TT OT O QO O O qT wG D OO CTO OT SO OO Ors 3830 85 structure ile structure structure structure MacroModel 9 6 User Manual 000 000 000 000 000 119 Chapter 13 Protein Loop Construction 120 Final report 4 unique conformations found 4 minimized with good convergence 1 confs within 1 00 kcal mol Found Global minimum E 3830 85 found BatchMin normal termination 4 18 kJ mol 1 times Total number of structures processed 4 Conformations with poor convergence marked with a Conformation 1 3830 854 Conformation 2 3668 398 Conformation 341 3652 378 Conformation 4 3630 911 MC Statistics kJ mol was found was found kJ mol was found was found kJ mol kJ mol of glob min times times times times bere Percent of minimized structures within energetic window 100 0000000 Average number of duplica
241. selected by default If this option is selected there is no rigid body superpo sition but the distance matrix is computed without translating or rotating the input conformers This option is useful if the input conformers have a relationship to another structure such as a receptor for which the relative coordinates between conformers should not be adjusted in the clustering analysis Distinguish mirror image conformations This option is selected by default When selected the analysis generates the mirror image of each input conformer and uses the smallest of the distances computed for the input structure and its mirror image as the distance entry in the distance matrix for the conformer If the option is not selected mirror images of input conformers are not considered in the analysis 16 1 3 Defining the Comparison Atoms or Torsions The XCluster panel makes it easy to designate the comparison atoms quickly If you are using project entries as the source of the set of conformers ensure that one conformer and only one is included in the Workspace If you are using an external file as input source the first structure in the file is automatically imported and included in the Workspace when you open the file If the distance criterion is Atomic RMS there are several ways to select the comparison atoms The buttons Heavy Atoms and Heavy Atoms O H S H select all atoms of the type indicated Atoms can also be defined by picking in the Worksp
242. ser Manual 171 Chapter 18 Additional Features 172 18 7 serial_split Split Serial Search Output Structure Files A serial search produces an output structure file that contains the collections of conformations produced from a number of different molecules The serial_split utility can be used to produce separate files each containing the conformers produced for a different molecule The serial_split utility can be used on the output files of eMBrAcE conformational searches if there are only ligands or only complexes in the file The syntax of the command is SCHRODINGER utilities serial_split options input mae basename where input mae contains the results of the previously performed serial conformational search The options are given in Table 18 1 Table 18 1 Options for the serial_split utility Option Description h Print usage summary and exit bnumber The serial number of the first molecule for which conformations should be extracted If omitted start with the first serial number present e number The serial number of the last molecule for which conformations should be extracted If omitted continue to the last serial number present p property Use values of the specified property for basename which can then be omitted The property must be a string property s_family_propertyname v Print the version number The files produced are named basename lt serial number gt mae where lt serial number g
243. sereaees 4 Chapter 2 Basic Molecular Modeling sssssssssssssssssssssssssssssssssssssssssseeeeeseeeeseeeseees 5 2 1 MacroModel Force Field Implementation 0 0 eeren 5 2 2 Parameter Quality Considerations cecceceeeeeeceeeeeeeeeeeeeeeseeeeeeeseetaeeeseneaes 7 2 3 MacroModel Solvation Treatment 0 cceccceceeeeeeeeeeeeeeeeeeseeeeeeeeaeeeseesaeeeseeeaes 9 2 4 Truncation of Electrostatic Interactions 10 24 1 Energetics of Charges cinc ni ii i 11 2 4 2 Molecular Mechanics Description of Charge oooooconcccincnnncnonncocncarnnnncnaracancnnan AA 2 43 Bond Dipole Cutoits BD GO ici 12 2 444 BDCO and Molecular Modeling izr incatinati iaae 12 2 5 General Guidelines for Convergence ooocccicoiccicnioncccnconcoconnoncnnonnnncanonana nani 13 2 5 1 MiNIMIZANON iu iia ia 13 2 5 2 Conformational Searching ui rin dado 13 2 5 3 Molecular and Stochastic DYNANMES s lt cciscicsceaccasteatetaessarsinaccisessaccanacsborsaccoinnessens 14 2 6 Problem Size Limits of Operation oonocoicnnninnininnncinnnnocncccnnnncncccnanananinnn 15 2 1 Nonbonded G utoffS oa a 15 2 8 Electrostatic Treatments o oomononnininnnnnnininnnnornorenennrncnrrnrrrrnrrnncanna rn rre 16 2 9 File CONVE iii asnos 16 MacroModel 9 6 User Manual Contents 2 10 Modified Force Field Solvent or Atom Type Files cece 17 2 11 Hydrogen Treatment oocomoinoiian aries 17 2 11 1 TAYGROGSMS
244. set the options in the upper portion of the panel and in the Poten tial Constraints and Substructure tabs then set the options in the Mini tab MacroModel 9 6 User Manual Chapter 9 Conformational Searches Conformational Search 0 x Use structures from Workspace included entries Potential Constraints Substructure Mini CSearch Method Mixed torsional Low mode sampling _f Multi ligand 4 Perform automatic setup during calculation Perform Automatic Setup Reset All Variables Customize the search 7 Torsion sampling options Intermediate MW Retain mirror image conformations Search variables Comparison Atoms Edit Display All Markers Undisplay All Markers Maximum number of steps 1000 e J iis 100 Number of structures to save for each search D Energy window for saving structures 21 0 kJ mol 5 02 kcal mol Cutoft 0 50 A 2 jo so A y iS Probability of a torsion rotation molecule translation 0 50 Minimum distance for low mode move 3 000 Maximum distance for low mode move 6 000 Start write Close Help Figure 9 1 The CSearch tab of the Conformational Search panel With these portions of the job setup complete set the parameters of the conformational search in the CSearch tab The controls in this tab are described below When you have finished adjusting the settings in the CSearch tab eit
245. sing User defined from the Cutoff option menu in the Potential tab and entering values in the text boxes MacroModel 9 6 User Manual Chapter 12 Minta Calculations MINTA can be used for fast computation of the conformational free energy of small and medium sized molecular systems in vacuo and in the presence of a continuum solvent model MINTA is an excellent tool for calculating the binding free energy of molecular complexes composed of substrate molecules bound to small receptors used in the molecular recognition field or enzyme receptor models used in pharmaceutical research Unlike available free energy simulation programs MINTA calculations are user friendly and are a simple tool for medicinal chemists familiar with conformational analysis For more information on MINTA calculations see Appendix G of the MacroModel Reference Manual 12 1 The MINTA Panel You can run the MINTA program from the MINTA panel using the Workspace contents project table entries or structures in a separate file as input The MINTA panel has a general setting portion which is described in Section 4 1 on page 25 The panel also contains four tabs Poten tial Substructure Mini and MINTA For information on settings in the Potential tab see Section 4 2 on page 26 For substructure related material see Section 4 5 on page 33 For the Mini tab description see Section 6 2 on page 45 To open the MINTA panel choose MINTA from the MacroModel submenu of the
246. sting of residues within 2 5 of the ligand is added to the substructure The fifth line indicates that the ligand should not be part of this substructure eMBrAcE calcu lations handle ligands separately MacroModel 9 6 User Manual 133 Chapter 14 eMBrAcE 134 The sixth line specifies the atoms that are to be constrained with a force constant of 100 0 kJ mol A The ASL expression selects atoms that are within 3 0 A of the atoms defined by the fourth line excluding atoms defined by the fourth line The seventh line specifies the atoms that are to be frozen The ASL expression selects atoms that are within 3 0 A of the atoms defined by the sixth line excluding atoms defined by the sixth line In this case the receptor is only one molecule In cases where receptor consists of more than one molecule use mol num norm n for the ligand definition where n is the molecule number of the ligand 14 4 2 Conformational Searches With eMBrAcE Below are example com files for an MCMM and an LMOD conformational search with eMBrAcE After these an example is provided using COPY and ALGN in conjunction with an MCMM MBAI conformational search Gl Like eMBrAcE minimization calculations eMBrAcE conformational searches include a table of results at the end of the 1log file Energetic properties are also included in this output struc ture file eMBrAcE conformational searches can use very large amounts of computer time and me
247. stinguished by a solid line on either side of the dotted line 10 2 1 4 Torsions Use the Monitored Torsions panel to select dihedral angles for monitoring To define a dihedral angle to be monitored choose Atom or Bond from the Pick menu and click on four atoms or three bonds in the Workspace that define a dihedral angle When the dihedral angle is defined the four atoms appear in the list at the top of the panel The defined dihedral angles are marked with a red solid line a dotted line through the dihedral angle and an eye icon The currently selected angle has a solid line on either side of the dotted line 10 2 1 5 H Bonds During a dynamics simulation MacroModel periodically examines the geometry around each monitored H bond If the bond meets the three user specified H bond criteria 1t is counted in the H bond population survey To select H bonds from the structure in the Workspace click the four atoms that define the bond and the associated angles and distances The picking order of the atoms is important Start with the heavy atom of the donor pair designated X followed by the hydrogen atom designated H the acceptor designated Y and an atom attached to the acceptor designated Z to define an angle MacroModel 9 6 User Manual Chapter 10 Dynamics Calculations Monitored Torsions Define monitored torsions FF Pick Atoms E Show markers Delete Delete All Close Help Figure 10 4
248. structure is minimized and found to be above the global minimum by more than the energy window value in kJ mol it is rejected and not included in the output file Maximum number of structures to save You can limit the number of structures returned in the output structure file by selecting this option and entering a value in this text box 7 3 Partition Coefficient Estimation Multiple minimization calculations can also be used to obtain estimates of the partition coeffi cients of a set of solutes between two solvents After you have set up other parameters for a multiple minimization including a primary solvent select LogP estimation in the Mult tab and choose the secondary solvent from the Secondary Solvent menu MacroModel 9 6 User Manual Chapter 7 Multiple Minimizations Each molecule in the input file is minimized twice once in each solvent The results of each minimization are used to evaluate the free energy difference for the two solvents Hence the logarithm of the partition coefficient log P which is defined by the relationship solv1 solv2 gt log P 2 AGoro AG so11 2 30RT solv1 solv solv2 where Prot sowv2 Solute o1y Solute o2 AGso1yy is the free energy of solvation of the molecule in solvent N R is the gas constant and T is the temperature in kelvin The results are collected in a table at the end of the log file The solvation models are parametrized for ambient conditions If the temperatu
249. t is the i_mmod_Serial_Number property listed for each structure in the input structure file This number is usually a running count of the distinct structures present The base for the serial number can be controlled with the SRNO opcode in the MacroModel calculation 18 8 Python Scripts The MacroModel distribution contains several Python scripts that can be used for running various jobs These scripts are stored in SCHRODINGER macromodel vversion python To run a script use the following syntax SCHRODINGER run script name options The scripts are described briefly here You can obtain usage information with the h option MacroModel 9 6 User Manual Chapter 18 Additional Features e cluster py This script provides a command line interface to run noninteractive clus ter tasks under Job Control You can run Cluster without creating a jobname clu file first but the job is restricted to a blind reduction Running under Job Control facilitates using this tool in other scripts that need to do Cluster jobs converge_search py This script runs a series of conformation search multiple mini mization conformer eliminations jobs to exhaustively collect all low energy structures It is intended as an example of the use of Python scripting with MacroModel It has limited Job Control features e get_lead_confs py Runs a conformation search then uses Cluster to produce lead ing collections It is intended as an exam
250. t box RMSD consider structures to be different if the RMS deviation for all compared atoms exceeds the threshold given in the Cutoff text box The default cutoff is 0 5 A for both options MacroModel 9 6 User Manual Chapter 14 eMBrAcE 14 3 Specifying a Substructure for eMBrAcE The use of substructures can dramatically speed up eMBrAcE calculations Specifying substructures is described in Section 4 5 on page 33 Substructures used in eMBrAcE must meet an additional requirement the receptor atoms must be numbered starting from 1 when constructing the substructure Below are two simple recipes for setting up substructures In the first all atoms in the receptor are either fixed or frozen In the second you can define shells of constrained atoms near the association site in the receptor If you already have a suitable substructure you can simply read it in by clicking Read sbc File near the bottom of the Substructure tab Creating a Substructure With All Receptor Atoms Fixed or Frozen 1 Include the receptor and only the receptor in the Workspace 2 Click New Shell 3 In the Additional atoms for shell section click All By default all atoms are fixed that is constrained to their current positions using a harmonic potential 4 To freeze the atoms in place select Freeze atoms Using a Ligand to Assist in Creating a Receptor Substructure In this example we will use a ligand from an entry called our_1lig to set u
251. t of comparison atoms and arg6 1 0000 indicates that this is a serial calculation In the 1og file produced when such a calculation is run a report appears for each ligand processed LOGP octanol water Calculation for ligand 1 Ligand Name Case74C LOGP octanol water 1 41024 LOGP octanol water Results Ligand Solvation Free Energies LOGP octanol water Converged octanol water kJ mol kJ mol I 26 99 18 94 1 41 T 2 20 93 12 48 1 48 T 3 20 02 11 02 1 58 T 4 29 41 16 19 2 32 T 12 16 84 15 40 0 25 P Here T or F in the Converged column signifies whether or not the minimizations one in each solvent for each molecule converged If they did not converge the results should not be considered reliable MacroModel 9 6 User Manual 63 64 MacroModel 9 6 User Manual Chapter 8 Coordinate Scans Coordinate scans can be used to probe the energy of a molecule as a function of a small number of geometric parameters distances angles or dihedral angles The process involves stepping through the specified parameters restraining the parameters and performing a mini mization on the remaining geometric parameters For example dihedral angle scans formerly known as dihedral drives are used to map out the potential energy for one or two dihedral angles such as a Ramachandran y plot for amino acids and can be very useful in under standing conformational behavior Coordinate scans can be performed either from Ma
252. tematic torsional sampling SPMC This method is similar to MCMM but uses a systematic search instead of a random search The search begins at low torsional resolution 120 searches all angles without duplicating coverage then doubles the resolution This method has the advantage of not retracing its path and consequently converges the final stages of the conformational search more efficiently than MCMM Like MCMM the method is effectively open ended it will search conformational space until you stop it See page 73 and the SPMC opcode command description in the Macro Model Reference Manual for a detailed description of this method Low mode sampling This method termed LMOD is highly efficient and has the advantage that ring structures and variable torsion angles do not need to be specified This conformational search method works by exploring the low frequency eigenvectors of the system which are expected to follow soft degrees of freedom such as torsions LMOD methods search conformational space aggres sively enough to switch the chirality of atoms within the structures provided Chirality checking should be used for chiral atoms for which such chirality switching is undesirable see Section 9 2 2 on page 77 See page 73 and the LMCS opcode description in the MacroModel Reference Manual for a detailed description of this method Serial low mode sampling is an automated procedure for performing a separate low mode search on
253. tes 1 000000000 Duplication standard deviation 0 0000000000E 00 5 structures generated 0 rejected by ring closure 2 rejected by van der Waals 0 duplicate minimised structures Time in Monte Carlo generation loop Time in energy minimizations Time in geometry optimisation 13 4 3 LOOP Run Using an Isq File as Input 5 8 CPU sec 153 4 CPU sec 0 0 CPU sec The 1og file for LOOP runs that use auxiliary filename 1sq files looks essentially the same as those in the previous two examples except that when an 1sq file is used the following statement appears in the 1og file output LOOP being generated using sequence in lsq file MacroModel 9 6 User Manual Chapter 14 eMBrAcE You can obtain a set of ligands that have been pre positioned with respect to a receptor from various sources including Schr dinger s docking program Glide To study the association of the ligands with the receptor further you can use the automated mechanism of Multi Ligand Bimolecular Association with Energetics MBrAcB With eMBrAcE complexes can be studied using simple minimizations or conformational searches 14 1 Minimizations With eMBrAcE An eMBrAcE minimization is a type of multiple minimization in which each of the specified pre positioned ligands is minimized in turn with the receptor You can perform eMBrAcE minimization calculations in two modes Interaction Mode in which the interaction between each ligand and the subs
254. ther parts of the molecule early in the simulation For example in the case of perturbing axial methyl cyclohexane to equatorial methyl cyclohexane using the united atom model for AMBER if the dummy atoms start at 0 5 A the free energy difference between the two conformations is greatly overestimated Setting the dummy atom natural bond length to ca 1 5 A gives a much more reasonable free energy difference Unfortunately there is not one perfect length for all systems and you should experiment with the dummy atom natural bond length to ascertain that the results obtained are independent of the dummy atom parameters 15 4 Other Types of Free Energy Calculations Free energy calculations have been possible for some time most of the simulation methods in MacroModel result in ensembles that actually sample the free energy surface of the molecule In some cases actual values for free energy differences between well defined conformational states can be obtained This is best illustrated with two examples from our own laboratory 15 4 1 Hydrogen Bonding Preference of a Glycyl Lactam in Organic Solution Infrared studies of the glycyl lactam in CH Cl 30 suggest that both hydrogen bonded and non hydrogen bonded forms are significantly populated at room temperature In this case conformational searching which can be considered an Enthalpy at 0 K was apparently at variance with experiment because the global minimum a hydrogen bonded form
255. there Auto Help contains a single line of information For more detailed information use the online help e If you want information about a GUI element such as a button or option there may be Balloon Help for the item Pause the cursor over the element If the Balloon Help does not appear check that Show Balloon Help is selected in the Help menu of the main win dow If there is Balloon Help for the element it appears within a few seconds e For information about a panel or the tab that is displayed in a panel click the Help button in the panel The help topic is displayed in your browser e For other information in the online help open the default help topic by choosing Help from the Help menu on the main menu bar or by pressing CTRL H This topic is dis played in your browser You can navigate to topics in the navigation bar If you do not find the information you need in the Maestro help system check the following sources Maestro User Manual for detailed information on using Maestro Maestro Command Reference Manual for information on Maestro commands e Maestro Overview for an overview of the main features of Maestro Maestro Tutorial for a tutorial introduction to basic Maestro features e MacroModel Quick Start Guide for a tutorial introduction to MacroModel e MacroModel Reference Manual for information on MacroModel commands e MacroModel Frequently Asked Questions pages at https www schrodinger com MacroModel FAQ
256. this may only indicate that the simulation is stuck in one of a number of accessible potential energy minima After the actual sampling phase is over a summary of the free energy change for this window will be printed as shown above Note that the component e g Bonded Nonbonded and Solvation free energies are only approximate and do not necessarily sum to the Total value After all windows are completed a summary is printed of the perturbation over all windows with the forward and reverse simulations shown side by side At the end of the file is a summary of the complete perturbation Summary of total perturbation Lambda 0 000 gt 1 000 Forward Reverse Average G bonded 0 10200 0 07908 0 09054 kJ mol G nonbonded 1 08893 1 12791 0 01949 kJ mol G solvation 0 00000 0 00000 0 00000 kJ mol G total 1 03701 0 90759 0 06471 kJ mol Standard dev 0 31498 0 29871 kJ mol This is probably the most important part of the output The average of the forward and reverse total free energies gives an estimate of the free energy change for the entire simula tion In this case it is close to zero as expected sampling for 500 ps per window reduces the value to 0 02 kJ mol The standard deviation of the free energy is useful as an estimate of the error In this case the free energy would be reported as 0 1 0 3kJ mol At 500 ps sampling it is 0 02 0 14 kJ mol Note that we use the larger of the forward
257. ting an Electrostatic Treatment The default electrostatic treatment for all built in force fields is to use a dielectric constant of 1 0 You can also select a distance dependent dielectric from the Electrostatic treatment option menu You can set the dielectric constant the default value is 1 0 which corresponds to Coulomb s law in a vacuum Selecting the force field defined treatment is equivalent to choosing a constant dielectric with a value of 1 0 The MMFF and MMFFs force fields use a buffered constant dielectric treatment see Halgren 9 10 Using Charges From a Structure File The charges used in the electrostatic portion of an energy calculation can either be assigned by the force field or obtained from the structure Regardless of the source charges are written to the structure file when a job is started By default the Force field option is used To use charge information from the structure select Structure file from the Charges from option menu Using an Existing Command File To read a MacroModel command file and have the settings on the energetics panel update to reflect all potential energy settings click Read Settings From Command File Setting up MacroModel calculations in this way is helpful because you can easily reproduce your potential energy settings for multiple calculations Choosing a Nonbonded Cutoff Setting The maximum distances over which hydrogen bonding van der Waals and electrostatic contributions to the
258. toms simultaneously by entering an appropriate ASL expression in the ASL text box in the Atoms for substructure section For example the expression fillres within 6 0 mol n 3 picks all the atoms within 6 of molecule number 3 and also adds to the selection the remainder of any residues partially selected using the 6 proximity criterion You can also construct ASL expressions using the Atom Selection dialog box To open this dialog box click Select Once you have picked atoms from the Workspace structure or have specified substructure atoms using ASL you can expand the shell of atoms to a specified distance from the defined substructure atoms To expand the shell enter the desired radius in the Expand to atoms within radius of text box Current Energy Loli Use structures from Workspace included entry Potential Constraints Substructure ECalc Atoms for substructure ASL at n 1 11 x All Selection Previous Select Pick Atoms M Show markers Expand to atoms within radius of 0 00 1 Complete residues Shells Selected shell EA Radius 0 00 W Complete residues Force constant 200 00 l Freeze atoms Additional atoms for shell ASL All Selection Previous Select Pick Atoms 1 M Show markers New Delete Read she File 4 Write ASL formatted sbe file Write sbe File Write absolute atom coordinates Start Write Close
259. trate is studied and Energy Difference Mode in which energy changes upon association are estimated The eMBrAcE Minimization panel is used to set up and submit eMBrAcE minimization jobs To open this panel choose eMBrAcE Minimization from the MacroModel submenu of the Applica tions menu in the main menu bar The upper and lower parts of the panel and the Potential and Substructure tabs are common to all MacroModel panels These components are described in detail in Section 4 1 on page 25 through Section 4 5 on page 33 The Mini tab is common to many of the MacroModel panels For an explanation of the controls in this tab see Section 6 1 on page 45 The controls for the eMBrAcE minimization settings are located in the eMBrAcE tab To perform an eMBrAcE minimization first configure the general job settings in the upper portion of the eMBrAcE Minimization panel and the Potential and Substructure tabs as described in Chapter 4 Because the receptor is usually large you should consider defining substructures and fixing or freezing atoms that are far from the active site to speed up the calculations Then configure the eMBrAcE settings in the eMBrAcE tab discussed below Source of ligands You can select ligands for an eMBrAcE calculation from the entries in the Project Table or you can read the ligands from a file To specify the file you can enter the path to the file in the text box or you can click Browse and navigate to the file MacroM
260. tro s MacroModel panels 2 2 Parameter Quality Considerations Molecular mechanics force fields are empirical and the accuracy of the results rest entirely on the ability of the parameters and functional forms used to mimic the real potential energy of molecules If the parameters are deficient is it impossible to obtain agreement with experiment or to make useful predictions When MacroModel performs an energy calculation the program checks the quality of each parameter in use Use of low quality quality 3 parameters especially torsional ones may result in inaccurate conformational energy differences and geometries Low quality stretches often indicate crude partial charges since charge information often originates from bond dipoles Using such low quality parameter values can cause charges and solvation energies to be inaccurate Consequently whenever MacroModel initiates an energy calculation a warning and the numbers of low quality stretch bend and torsional parameters in use are listed in the MacroModel jobname 1og file and in the Maestro Monitor panel viewing window An example is shown below WARNING Conformational Energies May Not Be Accurate WARNING Solvation Energies Charges May Not Be Accurate Low quality force field parameters in use MacroModel 9 6 User Manual Chapter 2 Basic Molecular Modeling Number of low quality stretches bends amp torsions 1 1 8 The above message indicates that eight l
261. ture file so that structures can be displayed in Maestro as the job progresses FFLD Force field selection Argl denotes the actual force field used in the calculation in this case MMFF94 Arg2 defines the electrostatic treatment for the calculation The default arg 0 is to use the dielectric treatment encoded in the force field however in this case a constant dielectric is used Arg4 is MMFF94 specific Arg4 1 defines the MMFF94s version of the force field ensuring planarity around delocalized sp nitrogens MacroModel 9 6 User Manual Chapter 10 Dynamics Calculations BDCO Use the Bond Dipole CutOff BDCO method for truncating electrostatic interactions Arg5 and arg6 are used to specify the cutoffs used for charge dipole and charge charge interac tions respectively READ Read the input file CONV Defines convergence criteria Argl 2 signifies derivative convergence default if no CONV command is present criterion is 0 05 kJ mol A this value is set in arg5 MINT An energy minimization precedes the dynamics calculation in order to eliminate excess potential energy Argl 9 indicates that the TNCG minimization method should be used for arg3 minization iterations MDIT Apply random initial velocities corresponding to 300K arg5 to all atoms MDYN Perform the dynamics simulation Arg2 1 selects the use of the SHAKE protocol to constrain hydrogen bonds to their natural values Arg3 1 sets up a stochastic dynamics ru
262. ual Chapter 13 Protein Loop Construction 13 3 2 LOOP Job Using the Sequence From a This example is identical to the previous command file except that arg3 of LOOP is 1 indicating that a filename 1sq is used to specify the sequence for the loop 13 4 Example LOOP Job Output File 13 4 1 Atom Renumbering Using Input Protein Structure The excerpt below shows the atom renumbering formation from the 1log file generated during a run in which the loop sequence from the actual protein structure was used as input LOOP being generated using sequence from input structur Note Substructure information may have changed Recording Substructure information in MCPC603 out sbc Beginning of new list of COMP and CHIG commands COMP 6607 6608 6609 6610 0 0000 0 0000 0 COMP 6611 6612 6613 6614 0 0000 0 0000 0 COMP 6615 6616 6617 6618 0 0000 0 0000 0 COMP 6619 6620 6621 6622 0 0000 0 0000 0 COMP 6623 6624 6625 6626 0 0000 0 0000 0 COMP 6627 6628 6629 6630 0 0000 0 0000 0 COMP 6631 6632 6633 6634 0 0000 0 0000 0 COMP 6635 6636 6637 6638 0 0000 0 0000 0 COMP 6639 6640 6641 6642 0 0000 0 0000 0 COMP 6643 6644 6645 6646 0 0000 0 0000 0 COMP 6647 6648 6649 6650 0 0000 0 0000 0 COMP 6651 6652 6653 6654 0 0000 0 0000 0 CHIG 6612 6617 6623 6626 0 0000 0 0000 0 CHIG 6630 6641 6650 0 0 0000 0 0000 0 End of new list of COMP and CHIG commands 13 4 2 Conformational Search Using Input Protein Structure The excerpt below is from the
263. uch set for each ligand in the analysis set Note that Conf 2 refers to the first ligand in the file which is the second structure in the input structure file Note also that only the energetic results between sets and 2 are recorded in the output structure file A table is given at the end of the log file containing a summary of the results for all the ligands Conf 2 E 14227 220 0 048 kJ mol Using numerical surfaces and analytical Born radii Solvation GB set energies do not include constant contributions exclusively involving fixed frozen atoms Energetic Interactions Within Atom Sets with no of interactions Atom set I Total Energy kJ mol 0 5221442D 05 2513327 Stretch 0 1725957D 03 3133 Bend 0 1620882D 03 659 Proper Torsion 0 2545627D 03 779 Out of Plane 0 6995831D 01 90 Electrostatic 0 6687509D 04 444935 Part of nonbonded Van der Waals 0 6857149D 03 61959 Part of nonbonded Solvation SA 0 1683423D 03 637 MacroModel 9 6 User Manual Chapter 14 eMBrAcE Solvation GB Fixed atom constraint Non bonded Atom set 2 Total Energy kJ mol Stretch Bend Proper Torsion Out of Plane Electrostatic Van der Waals Solvation SA Solvation GB Fixed atom constraint Non bonded 0 0 4576560 1598148 7373224 1137470 3625181 4390021 3172877 2464711 2183937 5127575 1506673 2985466 0000000 1671179 D 05 D 03 D 04 D 03 D 01 D 02 D 02
264. uch sets All results for sets are saved in the log file for the run Only interaction energies between sets 1 and 2 are saved as project properties within the output structure file Note that the surface energy contribution in GB SA calculations is associated with the interaction of a set with itself Below is an example command file for an eMBrAcE job run in interaction energy mode The input file MBAE_Interaction mae follows the Glide pose viewer pattern that is the first structure in the file must be the receptor and the remaining structures should be ligands previ ously positioned appropriately relative to the receptor A description of the opcodes used in the file follows then an excerpt from the output MacroModel 9 6 User Manual Chapter 14 eMBrAcE MBAE_Interaction mae MBAE_Interaction out mae SOLV 3 1 0 0 0 0000 0 0000 0 0000 0 0000 FFLD 11 1 0 0 0 0000 0 0000 0 0000 0 0000 EXNB 0 0 0 0 0 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 89 4427 99999 0000 0 0000 0 0000 MBAE 0 0 0 0 0 0000 0 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 SUBS 0 0 0 0 0 0000 0 0000 0 0000 0 0000 BGIN 0 0 0 0 0 0000 0 0000 0 0000 0 0000 READ 0 0 0 0 0 0000 0 0000 0 0000 0 0000 ASET 0 0 0 0 0 0000 0 0000 0 0000 0 0000 ASET 0 0 0 0 2 0000 0 0000 0 0000 0 0000 ASET 1 4729 0 0 2 0000 2 0000 0 0000 0 0000 ASET di 4729 0 0 1 0000 2 0000 0 0000 0 0000 MINI al 0 2000 0 0 0000 0 0000 0 0000 0 0000 ELST 1 0 0 0 0 0000 0 0000 0 0000 0 0000
265. ular Modeling 14 possibilities There is no way to prove that the search was fully convergent but there are several methods which can at least indicate that it was not As the search approaches convergence the number of new unique conformations which are found should begin to approach zero That is to say after the search has been in progress for some time many many trials should elapse between the finding of previously unobserved unique structures In practice however this may not be a good test unless all conformations found minimized to low gradients as described in the previous section We generally recommend the following procedure to ensure that a stochastic search has been exhaustive e Conduct a search of approximately 1000 2000 MC steps for every variable degree of freedom Ensure all the structures saved are thoroughly minimized as described above Runa second search possibly seeded with the selected structures from the of the first search see the MacroModel Reference Manual for details on how to do this Ensure that a SEED command is used so that a different sequence of random numbers will be used in the search e Combine the results of the two searches and reminimize keeping only the unique confor mations e Repeat this procedure of searching and combining the results until the total number of accumulated conformations especially those in the low energy region becomes con stant In any m
266. ulation you can monitor a number of geometrical parame ters These are angles inter atomic distances dihedral angles the surface areas of individual atoms and the population of hydrogen bonds The Monitor tab of the Dynamics panel contains a series of buttons that open panels that allow you to define these parameters The results of the monitoring appear in the jobname mmo file Information is also recorded in the jobname 10g and the jobname out mae files The latter is used to convey the property values to Maestro s project table MacroModel 9 6 User Manual 97 Chapter 10 Dynamics Calculations 98 Use structures from Project Table selected entry Potential Constraints Substructure mini Monitor Dynamics Number of structures to sample o Surface reas Torsions Distances H Bonds Angles Reset All Start Write Close Help Figure 10 1 The Monitor tab of the Dynamics panel You can also sample structures during a simulation To do this simply enter the total number of structures you want to sample in the Number of structures to sample text box This number of structures is selected at regular intervals throughout the simulation and written to the output jobname out mae file Five of the buttons in the Monitor tab open panels that allow you to choose what to monitor Each of these panels is described in a section below Each panel has a text area in wh
267. ulations in MacroModel use classical mechanics Newton s equations of motion to mimic how the system would behave as a function of time typically at or close to the temperature of interest You can use molecular dynamics studies to learn about the thermal variations within a system or to permit it to relax out of a local minimum structure into related but more probable structures 10 1 The Dynamics Panel Using the Dynamics panel you can set up dynamics calculations and either submit the calcula tion or write the job files for later use The Dynamics panel consists of the upper general portion that is common to other MacroModel panels This section is discussed in Section 4 1 on page 25 The panel contains six tabs Potential Constraints Substructure Mini Monitor and Dynamics The Monitor and Dynamics tabs are unique to the Dynamics panel The controls in these tabs are explained below For information on the other tabs see Section 4 2 on page 26 through Section 4 5 on page 33 To open the Dynamics panel select Dynamics from the MacroModel submenu of the Applica tions menu on the main menu bar 10 2 Performing a Dynamics Calculation To set up parameters for a dynamics calculation first set values in the upper part of the Dynamics panel and in the Potential Constraints Substructure and Mini tabs then set values in the Monitor and Dynamics tabs which are described below 10 2 1 The Monitor Tab During a molecular dynamics sim
268. utomatic setup process They must be added by picking atoms from the structure in the Workspace To define a distance for checking choose either Atom or Bond from the Pick menu then pick two atoms or one bond in the Workspace A new entry is added to the list at the top of the Distance Check panel Maestro marks the defined distance check with a purple dotted line and a check icon The currently selected distance check is distinguished by two solid lines on either side of the dotted line For each pair of atoms that you select you must define the minimum and maximum distances in the Minimum distance and Maximum distance text boxes Structures with distances that lie outside this range are rejected 9 2 5 7 Torsion Check Because highly strained structures may be generated during Monte Carlo conformational searches the geometry around double or amide bonds may be changed from E to Z isomers for example You might want to restrict the scope of the conformational search to structures that retain the original torsions around these bonds Torsion checks can be used to reject struc tures that do not retain the original geometry for these special cases The simplest way to define torsion checks is to click Perform Automatic Setup MacroModel generates a list of the amides and double bonds in a structure This list appears in the text box at the top of the Torsion Check panel Torsion Check Minimum allowed value degrees
269. ximum number of torsions to vary in an MC step in the corresponding text boxes The number of torsions varied is randomly selected from the range defined by the minimum and maximum values The default is to vary only one torsion We recommend against the use of SHAKE during MC SD simulations as it can result in less than optimal temperature control MacroModel 9 6 User Manual Chapter 11 MC SD Calculations 11 3 File Examples To run MacroModel calculations a molecular structure file and a command file are required The molecular structure file contains the structures to be used as input in the calculation The command file contains the name of the input structure file the name of the output structure file and an ordered list of operation codes opcodes for the calculations Once you set up a job in Maestro and click either Start or Write Maestro writes out a molecular structure file and a command file For many types of jobs command files written this way are complete and adequate but for some types of jobs you may need to adjust the Maestro gener ated command file This section contains an example of an MC SD computation using a small organic molecule The command files and the log files for the examples given in this section can be found in SCHRODINGER macromodel vversion samples Examples mcsd mae mcsd out mae MMOD 0 1 0 0 0 0000 0 0000 0 0000 0 0000 FFLD 10 1 0 T 1 0000 0 0000 0 0000 0 0000 BDCO 0 0 0 0 41 5692
270. ystem This fact can make it hard to put the minimized system in the proper context without additional calculations e g conformational searches Typical output for a MacroModel minimization looks like this Starting conjugate gradient minimization Minimization converged gradient 0 387E 01 LT 0 500E 01 Iterations 110 out of 500 Conf 1 E 594 116 0 039 kJ mol BatchMin normal termination Total number of structures processed 1 BatchMin normal termination 20 Feb 2002 15 31 29 The line Minimization converged gradient 0 387E 01 LT 0 500E 01 indicates that the minimization met the convergence conditions In this case the gradient attained 0 0387 kJ mol A was less than the level required 0 05 kJ mol A If the calculation had not converged the minimization converged line would be missing and the number of iterations would match the total specified Unconverged results typically have little or no value If the minimization does not converge within the specified number of iterations you may need to repeat or continue the minimization with more iterations Most MacroModel calculations consider minimizations converged when the RMS gradient of the energy is less than 0 05 kJ mol A While this is adequate for most types of calculations this value may be modified or another property such as atomic motion may be used to detect when a minimization is sufficiently converged The results of a minimization are force field d

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