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1. The code given above is run once for each subjob in the previous stage If you want to run it only once use command_once instead of command For example extern auxiliary_file modi py mod2 py command_once import os import modl import mod2 def main current_stage does something with mod1 and mod2 os system ls n For scripts that are stage specific your code must provide a main function that takes two argu ments for command or one for command_once The first argument in both cases corresponds to information for the current stage while the second argument for command corresponds to information from the previous stage For very simple scripts your code for command or command_once does not need to provide a main function The following example removes a temporary file if it exists extern command import os Removes a temporary file if os path isfile my_temporary_file os remove my_temporary_file n Without the main function multisim cannot pass the current stage and the current job objects to the Python code but that is presumed to be not needed for simple operations The extern stage is an advanced feature Please do not hesitate to contact us for addition infor mation on its use The keywords for this stage are listed in Table B 9 Desmond 2 2 User Manual Appendix B The multisim Utility Table B 9 Keywords for the extern stage Keyw
2. r Simulation Simulation time ns total 1 2 elapsed 0 0 Recording interval ps energy 1 2 trajectory 4 8 Ensemble class NPyT Temperature K 300 0 Pressure bar 1 01325 Surface tension bar A 4000 0 M Relax model system before simulation Relaxation protocol Use default protocol Browse Advanced Options Desmond Developed by D E Shaw Research Start Read Write Reset Close Help Figure 3 2 The Molecular Dynamics panel 3 4 Molecular Dynamics Simulations Molecular dynamics jobs simulate the Newtonian dynamics of the model system producing a trajectory of the particle coordinates velocities and energies on which statistical analyses can be performed to derive properties of interest about the model system The molecular dynamics task performs a single MD simulation under the chosen ensemble condition for a given model system generating simulation data for post simulation analyses This task is set up in the Molecular Dynamics panel which you open by choosing Applications gt Desmond gt Molecular Dynamics in the main window The controls at the top of the Simulation section allow you to specify the simulation time in ns and the recording period in ps for the energy and the trajectory For the recording period you can enter a value in ps in the text box or use the arrow buttons which change the time in increments of 50 times the far time step size By def
3. h n name f ffname C cthum d ffdir m mergedir p pdir Print usage message including the names of the built in force fields Specify force field name or other annotation to put into the output file If not spec ified a default name is used Specify a built in force field The available force fields are listed in Table 8 2 You can repeat this option to specify multiple force fields one per instance of the option Parameters of force fields listed earlier override parameters of force fields listed later When multiple force fields are specified the order is important if some parameters are intended to override others Specify the index of a single structure CT block in the input file for processing by viparr Structures are numbered starting at 1 Only a single c option is allowed on the command line you cannot specify more than one structure to pro cess The default is to process all structures Specify a user defined force field directory You can repeat this option to specify multiple directories As for the order is important Path to user defined force field directory that is to be merged with previously spec ified force field Multiple directories can be specified with multiple instances of this option Specify the plugin directory The default is to use the directory defined by the environment variable VIPARR_PDIR which contains the standard plugins All necessary plugins including those
4. Specifies the ensemble to be used for the simulation Allowed val ues are NPT NPT_Ber NVT NVT_Ber NVE Default NPT Appendix B The multisim Utility Table B 6 Keywords for the simulate stage Continued Keyword Description jin_file List of auxiliary input files for the stage Usually only needed when custom plugins are used jout List of auxiliary output files for the stage Usually only needed when custom plugins are used pressure Pressure for the simulation in bars Default 1 01325 bar rand_initial_velocities resampling_period temperature thermostat_relaxation time timestep Random number used to generate the initial velocities Set to 0 to use velocities from input cms file Default 2007 Frequency of resampling in picoseconds Temperature for the simulation in kelvin For replica exchange this must be a list of temperatures one for each replica Default 300 K Relaxation time constant for thermostat in picoseconds Default 1 0 ps Simulation time in picoseconds Default 1200 ps RESPA bonded near and far time steps in ps provided as a string or a list Default 2 2 6 or 2 2 6 B 2 8 The minimize Stage The keywords that are specific to the minimize stage are listed in Table B 7 The keyword restrain Section B 2 3 on page 101 can also be used in this stage When it is used the settings are temporary they apply only to the current stage Table B 7 Keywords
5. 3 2 Selecting a Model System In the Model system section you select the model system that you will use for the simulation A valid model system for simulations must contain both the coordinates of the particles and the force field parameters In the case of FEP simulations the model system should also contain additional FEP specific parameters A model system file normally has the cms extension There are two options on the option menu and the tools in this section depend on which option you choose e Load from Workspace Load the model system from the Workspace The Workspace Desmond 2 2 User Manual Chapter 3 Running a Desmond Simulation from Maestro must contain a model system that has already been prepared with the System Builder panel When you choose this item the Load button is displayed which you click to load the model system from the Workspace e Import from file Import the model system from a file You can choose to import a model system file cms or a checkpoint file cpt If you import a model system file it must contain a model system that has already been prepared with the System Builder panel When the file is imported a message about the system is displayed below the option menu If you import a checkpoint file most of the panel controls are unavailable The purpose of the checkpoint file is to restart an interrupted simulation so the parameters of the simula tion cannot be altered You can cha
6. Multisim is used by both Desmond and MCPRO for running jobs B 1 Running multisim The basic usage information for multisim including examples is given in Section 6 2 on page 62 This section describes more advanced multisim features such as template multisim commands node locking restarting multisim jobs and obtaining information from multisim checkpoint files B 1 1 Template multisim Commands Most msj files produced by Maestro end with a commented out example of the command needed to run the job For example SSCHRODINGER utilities multisim JOBNAME example HOST master_job_host host subjob_host maxjob 0 cpu 2 2 2 i example cms m example msj cfg example cfg o example out cms To use this command you would replace the following text with the values for your own setup e master_job_host the host on which to run the master job the Python script that manages the multisim job e subjob_host the host on which to run the subjobs which are often cpu intensive e example the job name and the stem of various file names which are constructed in a standard way from the job name e the cpu specification 2 2 2 the specification of the CPUs used by the job This spec ification can either be a triplet of numbers that defines the spatial decomposition of the system with the total number of processors being the product of these three numbers or a single integer which is the total number of processors and mus
7. p P PROCS NPROC Number of processors to use Default 1 JOBNAME name Specify the name for the job The default is the input cfg or cpt file name minus the extension jin filename Files to be transferred to the execution host by Job Control jout filename Files to be copied back to the submission host by Job Control h elp HELP Print usage information v print version information and exit Desmond 2 2 User Manual Chapter 6 Running Desmond Simulations from the Command Line Table 6 1 Options for the desmond command Continued Option Description Program Options exec program Run the specified Desmond program Available programs are mdsim Run a molecular dynamics simulation the default minimize Run a minimization remd Run a replica exchange molecular dynamics simulation vrun Analyze a trajectory c config file Parameter file for simulation Required with in for a new simulation cfg key val Specify extra simulation parameters Multiple instances of this option can be supplied to specify multiple extra parameters comm plugin Use the specified communication plugin Available plugins are serial and mpi Default serial dp Run double precision version Default run single precision version noopt Do not optimize parameters automatically t temperature Specify temperature in a replica exchange MD simulation Include an instance of this option for each temperature in the excha
8. Desmond uses Open MPI for parallel execution Before you can run jobs however you must add entries to the hosts file for parallel execution with Open MPI in addition to any configuration that is needed for the hosts and the queueing system See the Installation Guide for instructions especially Chapter 6 and Section 6 3 3 Desmond 2 2 User Manual Chapter 1 Introduction 1 2 The Maestro Interface to Desmond A number of Maestro panels have been provided to streamline the process of setting up running and understanding the results of Desmond jobs so that you can focus on what you are studying In addition much of the framework for running Desmond jobs has been written in Python to facilitate adaptation to user specific requirements including the automation of larger and more specific workflows System Builder panel e Constructs systems suitable for simulation using periodic boundary conditions Bulk solvent and membrane environments supported e Solvation and neutralization largely automated yet customizable e Seamless force field parameter assignment Minimization panel Molecular Dynamics panel Simulated Annealing panel Replica Exchange panel e Desmond job launching e Ability to intuitively see and adjust the key parameters used by the Desmond program for both minimization and dynamics calculations Default parameters are suitable for many simulations e Intelligent coupling of related settings e Access to both minimi
9. Example 1000 Table C 32 Keywords for the trajectory plugin Keyword Description center Center trajectory frame on the center of mass of the specified atoms Atoms are specified by zero based atom number Example 0 1 2 first First trajectory output interval Interval between frames outdir Directory for trajectory data write_velocity Include velocities in output Allowed values true false Default true periodicfix Adjust atoms to make bonds pretty Allowed values true false Default true C 5 Examples Config files can contain many settings so constructing them from scratch can be tedious and error prone Often it is easier to start with a config file written out from Maestro for a similar type of task This section provides examples and hints for customizing config files for a few common types of tasks These examples involve constructing part of the config file and then taking advantage of a multisim command feature that fills in the missing portions of the config file using default values C 5 1 FEP Calculations Below is an example of a config file that contains the complete settings for running an FEP calculation using multisim with a customized schedule This file would be provided to multisim with the cfg option force gibbs fec_type alchemical i_window 1 lambda bonded coulomb Iwao Desmond 2 2 User Manual 125 Appendix C The Desmond Configuration File 126 0
10. For example changing the far time step can affect the values of the recording periods in the panel because the latter are automatically rounded by the far time step As another example changing the temperature or pressure in the Desmond panel updates the temperature or pressure parameters in the dialog box Changes in the Desmond panel take effect immediately and update parameters in the dialog box whereas changes made in the dialog box only take effect when you click OK or Apply Desmond 2 2 User Manual 27 Chapter 3 Running a Desmond Simulation from Maestro 7 Molecular Dynamics Advanced Options Integration Ensemble Interaction Restraints Output Misc RESPA integrator Time step fs bonded 2 0 near 2 0 far 6 0 M Set time steps automatically based on constraint setting M Constrain heavy atom hydrogen covalent bonds Shake tolerance 1e 8 Maximum iterations 8 a gt Constraint OK Apply Cancel Help Figure 3 5 The Integration tab of the Advanced Options dialog box If you want to clear changes that have not been committed with the Apply button click Reset Any changes made since the last set of changes were committed are discarded and the values in the dialog box are reset to the last set committed 3 8 1 The Integration Tab In this tab you can set parameters for the integration algorithm The tab has two sections RESPA integrator and Constraint RES
11. Ll be performed Generate Mutants 1 in total 0 mutant selected 1 ilf No Mutation N Sr 1_ H Glu97IAlAsp_ zz Desmond Developed by D E Shaw Research Start Write Reset Close Help Figure 4 3 The Protein Residue Mutation by FEP panel Define Perturbation tab 6 Click Start set the job parameters in the Start dialog box and click Start in the dialog box to run the job 4 4 Protein Residue Mutation In protein residue mutation a protein residue is mutated into another residue in the presence of a ligand and the change in the ligand binding free energy due to the mutation is calculated The FEP calculations for ligand mutation are set up in the Protein Residue Mutation by FEP panel which you open by choosing Applications gt Desmond gt Protein Residue Mutation by FEP Desmond 2 2 User Manual Chapter 4 Running FEP Simulations To run a protein residue mutation job 1 Include in the Maestro Workspace the system that contains the ligand to be mutated the receptor protein and any other key molecules of the system This step can be performed prior to opening the panel Select Pick atom to identify ligand then pick a ligand atom in the Workspace In the Define Mutations section select Pick residue Pick a protein residue in the Workspace The residue is added to the table as a mutation site In the Substitutes column choose the residue f
12. The keywords for the minimize section are listed in Table C 20 Table C 20 Keywords for the minimize section Keyword Description plugins Output plugins Default maeff_output m Number of vectors to keep in LBFGS Default 3 maxsteps Maximum number of steps to iterate Default 200 tol Convergence threshold for gradient norm Default 1 0 stepsize Norm of first step Default 0 005 switch Minimum gradient before switching to LBFGS Default 25 0 sdsteps Minimum number of initial SD steps Default 10 C 3 9 The remd Section The keywords that are unique to the remd section are listed in Table C 21 The rest of the keywords are the same as in the mdsim section Section C 3 7 on page 120 Table C 21 Keywords for the remd section Keyword Description first First exchange trial time interval Simulation time between two exchange trials type Exchange trial scheme Allowed values 0 1 A value of 0 means exchange with neighbors a value of 1 means exchange with a randomly selected replica seed Random number seed Desmond 2 2 User Manual 121 Appendix C The Desmond Configuration File 122 C 3 10 The vrun Section The keywords for the vrun section are listed in Table C 22 All keywords are optional Table C 22 Keywords for the vrun section Keyword Description frameset Input trajectory plugins List of plugins used first Earliest frame to process last_time Last frame to proc
13. The selection of atoms that is in each group can be set up in the Misc tab by defining multiple groups named thermostat with the group numbers corre sponding to the entries in the Values column Any atoms not explicitly added to a group are automatically assigned to group 0 the default group This means that you do not need to define a group if you only want to use one thermostat and that you only need to define groups for the extra thermostats starting from thermostat 1 Desmond 2 2 User Manual 29 Chapter 3 Running a Desmond Simulation from Maestro 30 Molecular Dynamics Advanced Options Integration Ensemble Interaction Restraints Output Misc Thermostat method Nose Hoover Number of groups 1 Thermostat group 0 barostat Reference temperature K 300 0 300 0 Relaxation time ps 1 0 1 0 t Z Barostat method Martyna Tobias Klein Relaxation time ps 2 0 Coupling style Isotropic Reference pressure bar 1 01325 Compressibility 1 bar 4 5e 5 Reset OK Apply Cancel Help Figure 3 6 The Ensemble tab of the Advanced Options dialog box The Thermostat group settings table provides text boxes for making settings for each thermo stat group For the Nos Hoover method you can also make barostat settings The settings that can be made are Reference temperature K Relaxation time ps not for Langevin Nos Ho
14. use the Atom Selection dialog box to select the desired set of residues You should select resi dues that are within or near the binding site When ions are placed they will not be placed near these residues The residues that you select are colored blue and rendered in CPK See Section 5 3 of the Maestro User Manual for more information on the Atom Selection dialog box The region is defined by the distance in the Exclude ion and salt placement within text box Ions will not be placed within the specified distance of the selected atoms 2 5 2 lon Placement Ions are placed in the solvent according to your selection in the lon placement section of the lons tab Each ion replaces a solvent molecule You can of course choose not to add ions by selecting None If you select Neutralize the minimum number of sodium or chloride ions required to balance the system charge is placed randomly in the solvent Desmond 2 2 User Manual Chapter 2 Building a Model System 7 Advanced lon Placement Candidates 0 selected 0 remained 15 total A LYS 7 A ARG 39 A LYS 61 A LYS 66 A LYS 1 A HID 110 OK Cancel Figure 2 4 The Advanced lon Placement dialog box If you select Add you can choose the ion type from the option menu and enter the number of ions to add which need not neutralize the system The option menu only displays ions that are opposite in charge to that of the system Ions are no
15. This file contains information on the location of the trajectory and should be in the temporary directory for the job There may also be a copy of the output CMS file in the working directory on the local host but the trajectory will not be present until the job finishes Once you have imported the file click the T button for the imported entry To update the trajectory later you must reimport the file 5 2 Simulation Quality Analysis The Simulation Quality Analysis panel displays a simulation summary and an analysis of the total energy potential energy temperature pressure and volume over the length of the simula tion The analysis includes the average value the standard deviation and the slope of a linear fit to the values of the property as a function of time You can run the analysis on a completed simulation or while the simulation is running To open the Simulation Quality Analysis panel choose Applications gt Desmond gt Simulation in the main window To load the desired simulation click Browse and navigate to the desired Energy Sequence file for the simulation which has a ene suffix If you want to perform the analysis on a running simulation you must use the file from the host on which the simulation is running Desmond 2 2 User Manual Chapter 5 Analyzing Simulations The analysis performs averaging of the results over short time periods blocks to reduce the noise and eliminate correlation between conse
16. To run mold_gpcr_membrane py use the following command SSCHRODINGER run mold_gpcr_membrane py options input mae file output cms file The input Maestro file contains one or more model GPCR systems as separate structures An output structure file is generated for each structure present in the input file The files are named jobname n out cms where n is the index of the structure in the input file starting from 1 If there is only one input GPCR structure then n is omitted The options are given in Table 9 2 Desmond 2 2 User Manual Chapter 9 Utilities Table 9 2 Options for the mold_gpcr_membrane py script Option Description j JOBNAME jobname f reference_file filename r eference reference z _dist distance h elp v ersion Job name Default gpcr User reference structure file Reference template structure Default b2ar_popc Buffer distance for solvation of the system Default 10 A Show usage message and exit Show program version and exit 9 5 forceconfig py This script generates global cell and force config sections for Desmond based on parameters found in a CMS file and optional additional parameters that are supplied These sections are written to standard output They should be appended to the config file for the job and the job should be run with the noopt option The syntax for this command is SSCHRODINGER run FROM desmond forceconfig py options
17. also choose whether to incorporate the output CMS file back into the Maestro project by choosing Append new entries from the Incorporate option menu This is useful if you want to continue on to set up a simulation in Maestro If you choose Do not incorporate the CMS file is placed in the current working directory but is not added to the project If you want to run the job from the command line click Write The Write dialog box opens in which you can specify a name and then write the file The name is used to construct the file names by adding the appropriate extension 2 7 Quick Setup Instructions The sets of instructions below take you through the simplest setup procedures It is assumed that you have imported the prepared protein and ligand structures into Maestro and displayed them in the Workspace To add solvent 1 Select Predefined for the Solvent model option and choose a model from the option menu 2 Choose a box shape Desmond 2 2 User Manual Chapter 2 Building a Model System 3 Choose a box size calculation method Buffer for adding a buffer region to the solutes or Absolute size for specifying the actual box size 4 Enter buffer distances or side lengths in the available text boxes 5 Enter angles if you selected Triclinic for the box shape To add ions 1 In the lons tab choose an option for the addition of ions If you selected Add enter the number of ions to add in the text box Choose an i
18. available in Appendix C Desmond jobs run under Schr dinger s Job Control facility This facility manages the execu tion and monitoring of jobs and handles the input and output files and the incorporation of results into a Maestro project The Job Control Guide describes how to set up the information needed for Job Control to run on the computers to which you have access It includes informa tion on remote hosts clusters and batch queues As is the case for all Schr dinger software the environment variable SCHRODINGER must be set to the directory where the Schr dinger software including Desmond was installed In addition there are other environment variables that can be set to override default resource values See Appendix B of the Job Control Guide for more information By default the Schr dinger job control facility uses ssh to communicate between remote nodes For more information see Section 6 1 of the Installation Guide This chapter describes the command syntax for running single stage and multistage Desmond jobs and for building the input composite model system For details of the file formats and technical background see the Desmond User s Guide from D E Shaw Research 6 1 The desmond Command Desmond is run from the command line by executing the shell script desmond which is located in the SCHRODINGER directory The desmond script determines the proper executa bles to run for the host being used Additional
19. be large and thus take a long time to cross during a simulation Adjusting the conformation can reduce clashes and help the simulation to sample the appropriate conformations Once the fragment is displayed you can reorient the fragment with the adjustment tools which are available from the Adjust toolbar button T Desmond 2 2 User Manual 41 Chapter 4 Running FEP Simulations or with the local transformation tools which are available from the Local transformation toolbar button E For more information on these tools see Section 4 8 and Section 7 2 of the Maestro User Manual You can also add to the fragment using the Build toolbar or the Build panel for example replacing a hydrogen with a methyl or a hydroxyl group Since the quality of the results goes down as you increase the size of the fragment it is not advisable to add too much to the fragment You can revert to the original fragment by clicking the button in the Reset column You should not make modifications to the ligand core or other molecules in the system 5 In the Plan Calculation tab select the calculation types e For binding free energy calculations select In complex and In pure solvent e For solvation free energy calculations select In pure solvent and In vacuum 6 Choose the FEP protocol you want to use for each calculation type from the FEP protocol option menu You should choose the same ensemble type for both the complex and pure
20. correspond to the types of FEP that are set up with the specialized FEP panels e Mutation Mutate one set of atoms into another The atom set may be a molecule or a fragment Select this option for ligand functional group mutation or ring atom mutation e Total free energy Select this option for total free energy simulations in which a set of atoms is annihilated by the perturbation Desmond 2 2 User Manual Chapter 4 Running FEP Simulations Model system Load from Workspace Load The system is not specified Simulation FEP type Mutation Total free energy Soft core parameter 0 5 Number of windows 12 M Set lambda values automatically Window index vo vi v2 v3 va Vv VdwA lambda 1 0 1 0 1 0 1 0 1 0 0 67 VdwB lambda 0 0 0 1185140 1897780 2474140 3250480 45 ChargeA lambda 1 0 0 75 0 5 0 25 0 0 0 0 ChargeB lambda 0 0 0 0 0 0 0 0 0 0 0 0 BondingA lambda 1 0 1 0 1 0 1 0 1 0 0 85 BondingB lambda 0 0 0 1428570 2857140 4285710 57142 0 71 N Select All Windows Deselect All Windows Simulation time ns total 1 2 elapsed 0 0 Recording interval ps energy 1 2 trajectory 4 8 E Ensemble class NPT Temperature K 300 0 Pressure bar 1 01325 M Relax model system before simulation Relaxation protocol Use default protocol Browse Advanced Options Desmond Developed by D E Shaw Research Start Read Write Reset Clo
21. entire stage B 2 The multisim File Syntax The multisim input file msj file generally adheres to the Ark format from D E Shaw Research This is the same syntax that is used in Desmond configuration c g files which are described in brief in Appendix C and in full in the Desmond User s Guide Ark format is completely compatible with the syntax used in multisim files in Schr dinger Suite 2008 but supports other features The syntax rules of the Ark format can be summarized as follows e Values are assigned to a keyword with the keyword value syntax e Values can be numbers strings lists or blocks Numbers can be integers or real numbers Strings do not need to be enclosed in quotes unless they contain embedded blanks Desmond 2 2 User Manual Appendix B The multisim Utility e A block is one or more settings within a pair of braces Forexample a b 3 c 4 The block in this example contains two keyword value assignments e A list is a sequence values that is enclosed by a pair of square brackets Elements of a list do not have to be of the same type Anexampleis 1 a 1 5 23 e Hierarchical expressions involving blocks and lists can be created there is no limit on nesting of lists and blocks e Individual elements of a hierarchy can be set by joining the names of the parents with periods to form a compound key For example a b c 3 sets element c of block b in block a to 3 e If a keyword
22. fields viparr does the following e If any residue matches more than one template in a force field viparr exits with an error No viparr force field should contain identical templates e If any residue name is matched to a force field template with a different name a message is printed A maximum of 5 messages are printed per residue template name pair e If there are any unmatched residues viparr prints all unmatched residues and exits with an error A maximum of 5 messages are printed per unmatched residue name e If any residue is matched by more than one of the selected force fields viparr prints a warning message You should be sure that you intended multiple force fields to match and if so that the appropriate one was selected 8 5 User Defined Force Fields A force field is composed of the following files e atemplate file e a force field parameter file generally for each component of the force field Angles proper dihedrals van der Waals etc are examples of force field components e a set of plugin programs that process the parameter files e arules file which includes a list of plugin programs that viparr can call A set of plugin programs has been provided for the built in force fields In most cases user defined force fields can use these plugin programs These plugin programs are located in VIPARR_PDIR VIPARR_PDIR is an environment variable that should be set to S SCHRODINGER desmond vversion 1ib Linux x86 viparr_pl
23. file prmtop is the Amber parameter and topology file and cms file is the output CMS file The Amber parameter and topology file can be generated by the PARM or LeaP programs in the Amber package As well AnteChamber which is available for free under a GNU general public license from http ambermd org antechamber antechamber html can also be used to construct Amber input files 9 4 mold_gpcr_membrane py The utility mold_gpcr_membrane py can be used to embed a GPCR in a membrane With more GPCR X ray structures being determined over the last few years and the inherent flexibility of GPCR structures there is great interest in simulating them particularly within a membrane Properly constructing the system to simulate can be tedious time consuming and error prone Proper alignment of the GPCR in the membrane can be difficult to attain As well the relaxation of the membrane around the protein can take a very long time Most GPCR proteins are simulated based on either b2 or rhodopsin structures As a result membranes that are equilibrated around b2 or rhodopsin structures are likely to be able to accommodate another GPCR structure with only relatively mild clashes The utility mold_gpcr_membrane py can automatically align a GPCR model to b2 or rhodopsin and use the pre equilibrated membrane structure from the latter to reduce the membrane relaxation time and the potential structural problems that can arise during membrane equilibration
24. for the built in force fields must be in the directory specified by p The available force fields are listed in Table 8 2 with references Table 8 2 Force fields available with viparr Force Field Ref Force Field Ref Amber OPLS AA amber94 8 oplsaa_impact_2001 22 27 amber96 9 oplsaa_impact_2005 22 29 amber99 10 oplsaa_ions_Jensen_2005 30 amber99SB 10 11 Water models amber03 12 spc 32 CHARMM spce 33 charmm22nocmap 13 15 tip3p 34 Desmond 2 2 User Manual Chapter 8 Using Alternate Force Field Parameters and Constraints Table 8 2 Force fields available with viparr Continued Force Field Ref Force Field Ref charmm27 13 20 tip3p_charmm 35 charmm32 13 14 19 21 tip4p 36 tip4pew 37 tip5p 38 a Parameter assignment as implemented in the OPLS_2001 force field in Impact Parameter assignment as implemented in the OPLS_2005 force field in Impact c Note that the system_builder s implementation of OPLS_2005 has more general coverage of ligand like molecules than viparr 8 2 The build_constraints Utility To create a constraint block use the following command SCHRODINGER run FROM desmond build_constraints py options input file output file where input file is a structure file that has been previously processed with viparr and output file is a new structure file for the system with the constraints added The options are given in Table 8 3 The following constraint types are detected and automatically a
25. force fields and their associated plugins is written into the output struc ture file in the f i0_version field You are responsible for versioning your custom force fields using Perforce for instance Desmond 2 2 User Manual Chapter 8 Using Alternate Force Field Parameters and Constraints Potential Sources for Errors If viparr reports that it cannot match a residue please check the following e The template for the residue is really in the force field selected e Atom numbers for the residue are correct in the input structure file Bonds for the residue are correct in the input structure file 8 4 Specifying Multiple Force Fields Multiple force fields can be specified using viparr Common scenarios for this are outlined below Different force fields for different parts of a chemical system In this scenario one force field is used for one part of a chemical system e g the protein and another force field for another part e g the water molecules In this case each residue in your chemical system matches a template in exactly one of the specified force fields warning messages are printed otherwise Examples use spc water model SSCHRODINGER run FROM desmond viparr py f amber99 f spc example mae output mae use tip3p water model SSCHRODINGER run FROM desmond viparr py f amber99 f tip3p example mae output mae Combining components of two or more force fields In this case residues
26. in Appendix 6 2 3 Treatment of Intermediate Files In general the files from each stage are copied back to the launch directory as a gzipped tar archive with the name jobname_stage number tgz The production simulation stage is treated differently and the files are directly copied back without being archived This treatment would be similar to a simple molecular dynamics simulation i e not a multisim job This allows the final output CMS file to be incorporated and the trajectory to be played as a normal job 6 3 Building a Model System To prepare a model system from the command line you can use the system builder utility system_builder You can choose to add solvent ions and insert the solute into a membrane The system_builder utility takes a composite system builder CSB file as input This file contains all the required information to convert a solute file into a solvated system The syntax of the system_builder command is as follows SCHRODINGER utilities system_builder input csb The standard Job Control options described in Table 2 1 of the Job Control Guide are accepted as are the options WAIT LOCAL and NOJOBID described in Table 2 2 of the Job Control Guide The possible steps involved in the conversion are Reading the solute from a file e Reading the water model Desmond 2 2 User Manual 67 Chapter 6 Running Desmond Simulations from the Command Line 68 Reading the positive ion d
27. in the chemical system match templates in more than one of the specified force fields warning messages are printed All matching force fields are applied For example one force field provides the angle parameters for the residues while another force field provides the dihedral parameters This can work if the force field components are disjoint and there is no conflict in what parameters are assigned to each component Overriding parameters in a force field Similar to the scenario mentioned above residues in the chemical system match templates in more than one of the specified force fields warning messages are printed when this happens and all matching force fields are applied However if two or more force fields provide parame ters for the same term e g two force fields provide parameters for the angle between atoms 1 2 and 3 the conflict is resolved by using the parameters from the first force field listed on the command line that matches the residue Desmond 2 2 User Manual 81 Chapter 8 Using Alternate Force Field Parameters and Constraints 82 In all cases if a bond exists between two residues that are not matched by the same force field viparr exits with an error message You should correct the problem so that this bond is recog nized by one of the selected force fields The force fields must have consistent van der Waals mixing rules viparr exits with an error message if they do not When using multiple force
28. input cms The options are described in Table 9 3 Table 9 3 Options for the forceconfig py command Option Description h help Show usage message and exit f rms RMS force threshold for the structure Used to determine the cutoff if force rms rms v maxvel maxvel maxvel c cutoff cutoff cutoff m margin margin margin n nprocs nprocs nprocs not provided Default 5e 5 kcal mol A Maximum expected particle velocity in A ps The default is 25 A ps which is calculated based on a 300K Maxwellian distribution Cutoff radius for van der Waals interaction in A Margin between cutoff radius r_cut and lazy radius r_lazy the maximum distance of all pairs of particles included in the pairlist at the time of its assembly Default 0 5 A Number of processes that are allocated to the simulation The number of processes must be a power of two integer Desmond 2 2 User Manual 91 Chapter 9 Utilities 92 Table 9 3 Options for the forceconfig py command Continued Option Description p partition Global cell partition among processes as n n2 n3 nl n2 n3 are partition partition the number of processes along the x y z axes respectively If any of nl n2 or n3 is set to 0 the number of processes assigned to the corre sponding axis is derived automatically The partition is set automati cally by default If both nprocs and partition are specified n1 n2 n3 must be equal
29. into a Maestro file from within VMD This can be a useful way to convert configurations produced by various programs into a format that will function with Maestro To export a Maestro file from VMD 1 Select the molecule that you want to export in the VMD main window 2 Choose Save Coordinates from the File menu The Save Trajectory panel opens 3 Set the File type to mae0 4 Click Save Desmond 2 2 User Manual Chapter 7 Using VMD for Desmond Trajectories 5 In the Filename text box edit the directory and append the name for the new file to the directory This is a plain Maestro file whose extension should be mae 6 Click OK Desmond 2 2 User Manual 75 76 Desmond 2 2 User Manual Chapter 8 Using Alternate Force Field Parameters and Constraints The Desmond installation includes two utilities viparr and build_constraints that can be used to add or adjust the force field parameters and the accompanying constraints for chem ical systems prior to simulating them with Desmond Both programs read and write Maestro structure files Viparr is a template based force field assignment utility that comes with a number of built in force fields including some developed for Amber and CHARMM see below for more informa tion User defined force fields are also supported by viparr if they are provided in viparr s file format Viparr can be used to specify different force fields for various components of the system provi
30. is assigned a value twice the second takes precedence If the value is a block the blocks are merged and keywords present in each block are assigned the values from the latter block e The sign can be omitted if the value is a block value This means thata b 1 anda b 1 are equivalent This syntax is used to specify the multisim stages Multisim processing deviates from the Ark standard in the following ways e Multisim stages with the same name remain separate otherwise stages that appear more than once in an msj file such as simulate or minimize would be combined into one stage The multisim input file consists of a sequence of stages each of which specifies a particular calculation to be run Each stage has its own distinct data structure A stage begins with a label identifying the type of stage followed by braces enclosing parameters for that stage A msj file will in general look something like an outline for a msj file first_stage_name parameterl 3000 0 parameter2 this is a string parameter3 list element 1 2 list element 3 second_stage_name parameter5 20 The types of stages that are supported for Desmond include the following e task describes the type of job e minimize minimize the system Desmond 2 2 User Manual 99 Appendix B The multisim Utility 100 e simulate run an MD simulation on the system e system_builder trun the system builder e replica_ex
31. of the Job Control Guide e Read Read a configuration c g file to set up the simulation Opens a file selector in which you can navigate to the desired file Desmond 2 2 User Manual Chapter 3 Running a Desmond Simulation from Maestro 18 e Write Write the input files for the job but do not start it Opens a dialog box in which you can provide the job name which is used to name the files The job can be run from the command line as described in Chapter 6 e Reset Reset the values in the panel to their defaults To run a job 1 4 a Specify the model system either by loading it from the Maestro Workspace or importing it from a file Choose the task from the Simulation task option menu Adjust the simulation parameters as necessary For parameters that are not available in the main panel open the Advanced Options dialog box Click Start Set the job parameters in the Start dialog box and click Start to run the job To restart a molecular dynamics job 1 Import the checkpoint file generated by the interrupted simulation The default name of this file is jobname cpt When the checkpoint file is imported the Run Desmond panel enters a read only state in which most of the controls are set by the information read and cannot be changed Adjust the total simulation time if necessary Click Start Set the job parameters in the Start dialog box and click Start to run the job
32. on the temperatures is displayed in the replica table You can edit the temperatures by selecting manual for the temperature profile Some guidance on selecting temperatures is available in Ref 40 Setting up the temperatures and the number of replicas for a meaningful simulation can be difficult For assistance with this task contact help schrodinger com The replica exchange simulation produces one trajectory for each replica labeled Jobname_replicanum_trj where num is the index of the replica starting from 0 and corre sponds to the replica index in the replica table 3 7 Simulations on Systems with Membranes Simulations of systems that contain membranes require some special consideration This is because nearly all current all atom membrane potential models in existence do not on their own maintain the appropriate surface areas on the time scale of tens of ns in simulations of pure membranes If non lipid components make up a significant fraction of the membrane region such as a protein in a relatively small amount of lipid this issue is much less pronounced and many not require special treatment In this case the semi isotropic NPT ensemble may work well However if the simulated membrane is pure or only contains a small solute e g ligand sized the following practical approach may be useful When a solute is placed in a pure membrane some lipids are usually removed to make room for the new molecule during the system building
33. restrain all heavy non hydrogen atoms none Remove the temporary restraints those set in the previous simulate or minimize stage but do not change permanent restraints such as those set in the system_builder stage or present in the original cms file given to the multisim job If you use this value in a system_builder stage it removes all restraints This is the default retain Keep the restraints as set in the previous stage solute Restrain all solute atoms solute_heavy_atom Restrain all heavy atoms in the solute solvent Restrain all solvent atoms restrain atom asl all force constant 10 restrains all atoms with a force constant of 10 kcal mol A Restraints can be applied with respect to the positions of the atoms at the start of the current stage by setting reference_position to reset or the positions from the previous stage by setting reference_position to retain The default is reference_position reset Different groups of atoms in the system can be restrained with different force constants by listing the restraint blocks for each set of atoms within a list using the syntax restrain atom asl ASLI force_constant valuel atom asl ASL2 force_constant value2 If the ASL expression contains quotes they must be escaped either by using a backslash or by using double quotes in the ASL expression and surrounding the entire expression in single quotes B 2 4 The atom_group Keyword The atom_group key
34. short_dist 1 0 chemical_potential 7 17 This file instructs solvate_pocket to sample water within a cube 16 Aona side centered at 0 0 10 000 passes will be used to equilibrate the system before the production simulation starts The production simulation will run up to 100 000 passes but will terminate before that number is reached if the slope of the standard deviation for the number of molecules drops below 0 00001 over a window of 10 000 passes Desmond 2 2 User Manual Chapter 9 Utilities 9 2 manipulate_trj py This script can be used to generate a new trajectory from a list of input trajectories The trajec tory includes the cms and idx files that are needed to display the trajectory in Maestro The command syntax is as follows SSCHRODINGER run FROM desmond manipulate_trj py h help mode merge concat output trj input trjl input trj2 This script currently supports two modes of operation specified by the mode option e merge Multiple input trajectories are merged into one new trajectory based upon the chemical time For example if the trajectories A ag a and B b b are merged all frames from trajectory A whose chemical time is larger than that for by are discarded Here the trajectories are represented as a list of frames a and b This is the default mode and is useful for merging trajectories that are continued in a new run e concat Frames from the input
35. the cutoff_radius set to 16 0 However if you also provide the stage 5 tgz file and some subjobs from stage 5 have finished only the unfinished jobs will run with the new settings You can also restart a job with a different msj file For instance the command SCHRODINGER utilities multisim r myjob multisim_checkpoint d myjob_5 out tgz JOBNAME myjob m newworkflow msj runs the uncompleted stages according to newworkflow msj This new msj file must contain the same completed stages as the original job Any of the remaining stages can be modified or deleted and new stages may be inserted Some other changes that you can or cannot make are e You can restart the job with a different cfg file by specifying the new cfg file with the cfg option e You can restart the job with a different maximum number of simultaneously running sub jobs by using the maxjob option e You cannot change the node locking mode In most cases multisim automatically detects and uses additional input files needed for a job when it is restarted If the job fails because an existing input file was not detected when restarting a job you can specify that file by using the ADD_FILE option B 1 4 Obtaining Information from multisim Checkpoint Files To obtain information on the contents of a multisim_checkpoint file you can use the multisim command with the probe option SSCHRODINGER utilities multisim probe myjob multisim_checkpoint T
36. the atoms that are visible when frames are displayed you can use the toolbar buttons that control the atom display tk G d q if When you play through the trajectory the choice that you make for the atoms that are displayed is applied to each frame The other controls for what is visible in the Workspace during frame display are e Show simulation box Show the edges of the simulation box in purple e Show axes Show the coordinate axes in green e Replicate system Enter the number of replicas of the system to display in each of the three directions This enables you to visualize the movement across the simulation box boundaries These text boxes are unavailable if there are no periodic boundary conditions e Trajectory smoothing Smooth the trajectory by averaging the coordinates over the spec ified number of frames e Superimpose on frame Align the structure in each frame by superimposing a selection of atoms on the corresponding atoms in the frame number given in the text box Use the Pick atoms to superimpose picking controls to make the atom selection You should con sider picking atoms that do not change their position much during the simulation The output buttons allow you to export the trajectory data in various forms You can export individual frames all frames or the selection of frames defined by using the Start End and Step text boxes The buttons have the following actions e Structure Save structures fro
37. the complex and pure solvent two ensembles Desmond NPT and Desmond NVT with two options for the relaxation part stan dard or quick relaxation The protocol for the simulation is the same for both ensembles NVT and NPT For calculations in vacuum there is the choice of the standard or quick relaxation Desmond 2 2 User Manual 47 Chapter 4 Running FEP Simulations 48 Rn Ligand Functional Group Mutation by FEP o x Define Perturbation Plan Calculation m M In complex This calculates the relative free energy for each ligand mutant in the ligand receptor complex environment The results are needed to derive the relative binding free energies FEP protocol Desmond NPT Buffer size A 5 0 Production simulation time ns 0 6 r M In pure solvent This calculates the relative free energy for each ligand mutant in the pure solvent environment The results are needed to derive the relative binding free energies and the relative solvation free energies FEP protocol Desmond NPT Buffer size A 10 0 Production simulation time ns 0 6 nr In vacuum Desmond Developed by D E Shaw Research Start Write Reset Close Help Figure 4 5 The Plan Calculation tab In addition you can read in a protocol by choosing User defined from the FEP protocol option menu A file name text box and Browse button is displayed You can enter the name of the protocol file w
38. time steps are set to 2 fs 2 fs and 6 fs respectively whereas with this option dese lected the time steps are set to 0 5 fs 2 fs and 6 fs respectively The larger time step permitted for bonded interactions when constraints are used reduces the CPU time needed for a given amount of simulation time Shake tolerance text box Enter the tolerance used to check convergence of the relative bond length error for bond constraints in the text box Maximum iterations text box Enter the maximum number of iterations used in bond constraint calculations in this text box or use the arrow buttons to change the value in increments of 1 3 8 2 The Ensemble Tab In this tab you can set the thermostat method and the barostat method and adjust the settings for these methods The thermostat method and the barostat method are coupled the choice you make from the Thermostat method option menu changes the selection from the Barostat method option menu and vice versa The exception is that you can choose None for the barostat method for any of the thermostat methods The Thermostat method option menu offers four choices Nose Hoover Berendsen Langevin and None Although in most circumstances only one thermostat group is needed you can specify multiple thermostat groups by entering the number of groups in the Number of groups text box and supplying information on these groups in the Thermostat group settings table The maximum number of groups is 8
39. trajectories are simply concatenated and the time for each frame is reset to account for the new ordering You can select a subset of the frames present in each input trajectory with a syntax similar to that used for Python lists If a list is used the entire trajectory specification must be quoted The examples below illustrate the syntax in_trj include all frames from in_trj Man trey psc include all frames from in_trj in_trj 0 6 8 10 include frames 0 6 8 and 10 from in_trj win stry EL 3 sy B include frames 1 2 and 5 from in_trj in_trj 0 4 11 2 20 include frames 0 4 6 8 10 4 11 in increments of 2 and 20 from in_trj The frame index is sorted in ascending order for each trajectory before any subset is selected Some examples are given below To merge in1_trj and in2_trj SSCHRODINGER run FROM desmond manipulate_trj py out_trj inl_trj in2_trj To concatenate frame 0 3 6 13 5 of in1_trj and all frames of in2_trj SSCHRODINGER run FROM desmond manipulate_trj py mode concat out try nL tr71 0 7 3 13 5S In2ctryl Desmond 2 2 User Manual 89 Chapter 9 Utilities 90 9 3 amber_prm2cms py The utility amber_prm2cms py can be used to convert Amber input files a prmtop file plus a prmerd file into a Desmond cms file The syntax for this command is SCHRODINGER run amber_prm2cms py c prmcrd p prmtop o cms file where prmcrd is the Amber prmcrd coordinate or restart
40. 0 This block indicates that the block values for the property called E in an input sba file should have following properties e Standard deviation lt 5 0 e Slope i e drift with respect to time lt 4 3 e Average should be within 435320 2 4000 Desmond 2 2 User Manual 131 132 Desmond 2 2 User Manual References 11 Bowers K J Chow E Xu H Dror R O Eastwood M P Gregerson B A Klepeis J L Kolossvary I Moraes M A Sacerdoti F D Salmon J K Shan Y Shaw D E Scalable Algorithms for Molecular Dynamics Simulations on Commodity Clusters Proceedings of the ACM IEEE Conference on Supercomputing SC06 Tampa Florida November 11 17 2006 http sc06 supercomputing org schedule event detail php evid 9088 Shaw D E A fast scalable method for the parallel evaluation of distance limited pair wise particle interactions J Comput Chem 2005 26 1318 Bowers K J Dror R O Shaw D E The midpoint method for parallelization of particle simulations J Chem Phys 2006 124 184109 Bowers K J Dror R O Shaw D E Zonal methods for the parallel execution of range limited N body simulations J Comput Phys 2007 221 303 Lippert R A Bowers K J Dror R O Eastwood M P Gregersen B A Klepeis J L Kolossvary I Shaw D E A common avoidable source of error in molecular dynamics integrators J Chem Phys 2007 126 046101 Arkin LT et al Mec
41. 0 9050 ions MacKerell A D Jr et al J Phys Chem B 1998 102 3586 proteins MacKerell Jr A D Feig M Brooks A D HI J Comput Chem 2004 25 1400 protein CMAP Missing CMAP term applied to protonated HIS Foloppe N MacKerell A D Jr J Comp Chem 2000 21 86 nucleic acids MacKerell A D Jr Banavali N K J Comp Chem 2000 21 105 nucleic acids Feller S E MacKerell A D Jr J Phys Chem B 2000 104 7510 lipids Feller S E Gawrisch K MacKerell A D Jr J Am Chem Soc 2002 124 318 lipids Klauda J B Brooks B R MacKerell A D Jr J Phys Chem B 2005 109 5300 alkanes lipids Jorgensen W L Maxwell D S Tirado Rives J J Am Chem Soc 1996 118 11225 Damm W Frontera A Tirado Rives J Jorgensen W L J Comput Chem 1997 18 1955 Jorgensen W L et al Theochem 1998 424 145 McDonald N A Jorgensen W L J Phys Chem B 1998 102 8049 Rizzo R C Jorgensen W L J Am Chem Soc 1999 121 4827 Watkins E K Jorgensen W L J Phys Chem A 2001 205 4118 Kaminski G A Friesner R A Tirado Rives J Jorgensen W L J Phys Chem B 2001 105 6474 OPLSAA L reparameterization version 1 torsions used for SER version 1 for ASP version 3 combined for LEU VAL Jacobson M P et al J Phys Chem B 2002 106 11673 The charges for HISE used in this force field have not been published t
42. 428571428571 0 285714285714 0 142857142857 0 0 0 714285714286 0 857142857143 1 0 1 0 1 0 1 0 1 0 bondedA 1 0 1 0 1 0 1 0 1 0 0 857142857143 0 714285714286 0 571428571429 bondedB 0 0 0 142857142857 0 285714285714 0 428571428571 0 571428571429 chargeA 1 0 0 75 0 5 0 25 0 0 0 0 0 0 chargeB 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 vdw vdwA 1 0 1 0 1 0 1 0 1 0 0 674789989504 0 456296209913 0 325045439067 0 0 0 0 0 0 0 0 0 0 0 0 25 0 5 0 75 1 0 0 24741405481 0 189778434985 0 118514957434 0 0 vdwB 0 0 0 118514957434 0 189778434985 0 24741405481 0 325045439067 0 456296209913 0 674789989504 1 0 1 0 1 0 1 0 1 0 gui n_windows 12 f selected_lambda_ win 0 1234567891011 should_autoset_fep false For multisim FEP jobs Ensure that force gibbs i_window is set to 1 or a negative number otherwise multisim runs only 1 window as specified by the value of the force gibbs i_window parameter By default this parameter is set to 1 Ensure that gui should_autoset_fep is set to false otherwise multisim auto matically overrides the lambda schedule that you provide By default this parameter is set to true If you use a nondefault number of lambda windows ensure that you set gui selected_lambda_win to include all windows in the list For example if you use 7 windows the gui selected_lambda_win should be set to 0 1 2 3 4 5 6 If you miss some windows in the list simulations will
43. 59 6 2 Running Multiple Simulations 4444n0nnnneenennenennnnennnnnnnnnnnnnnn 62 6 2 1 Examples of Running MUSIM isisisi aiioa 64 6 2 2 Sample MultiSim Job msj File a 2 nennen 64 6 2 3 Treatment of Intermediate Files sanscrit eaaa 67 6 3 Building a Model System 4 424044nsensennnnennennnnennnnnnnnnnnnnnnnnnnnnnnnnnn 67 6 3 1 Reading ne SUCE Siza i A aE 68 6 3 2 Adding Membrane akute 70 6 3 3 Setting the Box Shape and Dimensions mrrserssnnennnnonnnennnennnnnnnn nenne 70 6 3 4 Setting Force Field Informatori en 71 6 3 5 Setting the Number and Location of lons urr24424ssnnnnnnnn nennen nennen 71 6 3 6 Salvaling the System u us s nennen 72 6 3 7 Winnog Ihe UNDUE File acces E E EE E AE 72 Chapter 7 Using VMD for Desmond Trajectories ue 73 7 1 Reading a CMS File and a Desmond Trajectory ennn 73 7 2 Writing a Maestro File u ss un0n0aunananunanaamnannaninar 74 Chapter 8 Using Alternate Force Field Parameters and ONE IN ea 77 8 1 Theviparr VUY nenne 77 8 2 The build_constraints Utility 22044404200nnnnnnnnnnnnnnennnnnnennnnnn 79 8 3 Input and OUMU Files aien R EE NNj 80 8 4 Specifying Multiple Force Fields 0ennnennenennennnnennnnennnnn 81 8 5 User Defined Force Fields 00 0 0 cceeeceeccecesseeseeeeceeeeseeaeceecseeseeseeeaeeaet
44. 6 Relax the system either by minimization or by selecting the panel option to relax the model system before simulation 7 Set the simulation parameters in one of the general Desmond panels for molecular dynamics simulated annealing or replica exchange 8 Run the simulation 9 Analyze your results using the Trajectory Viewer and other analysis tools 1 4 Citing Desmond in Publications The use of this product should be acknowledged in publications as Desmond Molecular Dynamics System version 2 2 D E Shaw Research New York NY 2009 Maestro Desmond Interoperability Tools version 2 2 Schr dinger New York NY 2009 Please also include a reference to the following paper Kevin J Bowers Edmond Chow Huafeng Xu Ron O Dror Michael P Eastwood Brent A Gregersen John L Klepeis Istvan Kolossvary Mark A Moraes Federico D Sacerdoti John K Salmon Yibing Shan and David E Shaw Scalable Algorithms for Molecular Dynamics Simulations on Commodity Clusters Proceedings of the ACM IEEE Conference on Super computing SC06 Tampa Florida November 11 17 2006 Desmond 2 2 User Manual 6 Desmond 2 2 User Manual Chapter 2 Building a Model System Performing simulations on aqueous biological systems requires the preparation of biological molecules such as proteins and ligands addition of counter ions to neutralize the system selec tion of simulation box size solvation of the solutes using explicit s
45. 7 2 of the Maestro User Manual You can also modify the residue using the Build toolbar or the Build panel for example to replace sulfur with selenium or to phosphorylate the residue Since the quality of the results goes down as you increase the size of the perturbation it is not advisable to add too much to the residue You can revert to the original residue orientation and structure by clicking the button in the Reset column You should not make modifications to the ligand core or other mole cules in the system In the Plan Calculation tab choose the FEP protocol you want to use for each calculation type from the FEP protocol option menu You should choose the same ensemble type for both the complex and pure solvent calculations Click Start set the job parameters in the Start dialog box and click Start in the dialog box to run the job 4 5 Total Solvation Free Energy Calculation Calculating the absolute solvation free energy for a molecule involves running an annihila tion FEP simulation in which the selected molecule is removed from the system To run an annihilation job L Include in the Maestro Workspace the system that contains the molecule to be annihi lated This step can be performed prior to opening the panel Select Pick the molecule then pick the molecule in the Workspace When the molecule is picked it is colored with green carbons Once focus is returned to the panel this option is deselect
46. Charges u sinne 11 2 5 are lo 1 fl 0 11 SESSRERREBERERIESANEREL EIDNEFEREEREFEELLERRERSSFERETSTRREL SFEEETETIEBRREREEGFEEILELTERFFERIEFEFFEGES 11 2 5 1 Defining an Excluded Region soriant innen 12 2 5 2 Jon Placement lassen lie erde 12 25 3 Adding a Salt ie iioi ea 14 2 6 Bunning ME JOD T Eee Eee 14 2 7 Quick Setup Instructions 4snnnennennenennennenennnnnnnnnnnnnnnnnnnnnnnnnnn 14 Chapter 3 Running a Desmond Simulation from Maestro 17 3 1 Overview of the General Desmond Panels ennnnennnnnnennnn 17 3 2 Selecting a Model System 4244440n240nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn 18 3 3 MINIMIZatlonS erste eaa aaa eia E eaa AAi 19 3 4 Molecular Dynamics Simulations ennnneenennnnenennennnnnnnennnnnnn 20 3 5 Simulated Annealing Simulations ennnenennneenennennennnnnnnnnnnn 22 3 6 Replica Exchange Simulations 4nnennnnnnenennenennnnennnnnnnnnnnnnn 24 3 7 Simulations on Systems with Membranes nnnneenennnnennnn 26 Desmond 2 2 User Manual Contents 3 8 Setting Options for Desmond Simulations ennennennennn 27 3 8 1 The Integration Tab aa nn 28 3 8 2 Mhe Ensemble VAD 2 sceinsezevartcne encesaeeiste ine A O AO 29 3 8 3 The Minimization Tab ui ana oaa a EAA 31 3 8 4 The Imeraction aD state 32 3 8 5 The Restrai
47. Desmond 2 2 User Manual O Schr dinger Press Desmond User Manual Copyright 2009 Schr dinger LLC All rights reserved While care has been taken in the preparation of this publication Schr dinger assumes no responsibility for errors or omissions or for damages resulting from the use of the information contained herein Canvas CombiGlide ConfGen Epik Glide Impact Jaguar Liaison LigPrep Maestro Phase Prime PrimeX QikProp QikFit QikSim QSite SiteMap Strike and WaterMap are trademarks of Schr dinger LLC Schr dinger and MacroModel are registered trademarks of Schr dinger LLC MCPRO is a trademark of William L Jorgensen Desmond is a trademark of D E Shaw Research Desmond is used with the permission of D E Shaw Research All rights reserved This publication may contain the trademarks of other companies Schr dinger software includes software and libraries provided by third parties For details of the copyrights and terms and conditions associated with such included third party software see the Legal Notices for Third Party Software in your product installation at SSCHRODINGER docs htmi third_party_legal htmi 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 to s
48. P simulations global_forces Only available as BiasingForce Table C 4 Keywords for the force nonbonded section Keyword Description elec Functional form of the electrostatic interactions Allowed values ewald cutoff Must be set to cutoff if force nonbonded far type is none Default ewald type Functional form for pairwise nonbonded interaction Allowed values vdw elec none r_lazy Pair list assembly cutoff radius r_cut Pairwise interaction cutoff distance n_zone Number of interpolation zones points in tabular versions of the potentials Default 1024 far Section describing implementation of far field interaction 114 Desmond 2 2 User Manual Appendix C The Desmond Configuration File Table C 5 Keywords for the force nonbonded far section Keyword Description type Far field interaction type Example pme sigma Ewald sigma coefficient n_k FFT grid size The value on each axis may only have 2 3 and 5 as factors and is related to the partition setting in the global_cell section Table C 8 Example 64 64 64 order PME interpolation order 4 7 sigma_s sigma if type gse r_spread spread oftype gse Table C 6 Keywords for the force gibbs section Keyword Description fec_type Free energy calculation type Allowed values are none alchemical use for relative FEP ligand_binding use for absolute FEP alpha_vdw Alpha parameter in the soft core potential i_window FEP window index la
49. PA integrator section Specify the time steps in fs for bonded near and far by entering values in the text boxes or using the arrow buttons to change the value in increments of the bonded time step Because the bonded near and far time steps must maintain a certain ratio when a new value is set for the bonded time step the other two time steps are automatically updated according the current ratio Changing the near or far time steps adjusts this ratio Selecting Set time step automatically based on constraint setting couples the RESPA time step settings with those in the Constraint section The time steps will be automatically set based on the settings in the Constraint section and are not available for editing Constraint section In this section you can choose to apply constraints to covalent bonds between hydrogen and other atoms and set tolerances and iteration limits for the Shake algorithm Desmond 2 2 User Manual Chapter 3 Running a Desmond Simulation from Maestro Constrain heavy atom hydrogen covalent bonds option Select this option to constrain all bonds that are formed by a heavy atom and a hydrogen atom using the Shake algorithm Deselect this option to use bond potentials as defined in your model system for these bonds Choice of this option affects the settings of the time steps when Set time steps automatically based on constraint setting is selected With the constraint option selected the bonded near and far
50. Predefined and choosing the membrane from the option menu The temperature at Desmond 2 2 User Manual Chapter 2 Building a Model System 10 which the membrane patch was preequilibrated is given in parentheses after the membrane name Because DPPC has a gel transition temperature around 313 K the recommended minimum simulation temperature is also 325 K If you want to position a custom membrane select Custom and enter the name of the Maestro file containing the membrane model in the text box or click Browse and navigate to the file If you have an existing membrane in a project entry that you want to use for the current model system you can load it by selecting the entry and clicking Load Membrane Position from Selected Entry The membrane from this entry is then used for the model system you are building When you click Place Automatically the membrane position is determined according to the information available as follows e If you have a protein from the OPM database http opm phar umich edu the membrane is placed using the information provided with the protein e Otherwise the surface of the membrane is placed perpendicular to the longest axis of the protein If transmembrane atoms are defined they are placed inside the membrane Placement of transmembrane atoms inside the membrane takes precedence over placement perpendicu lar to the longest axis To define the transmembrane atoms click Select and use
51. Replicate system a E b a a Trajectory smoothing Pick atoms to superimpose ASL mol num 1 x All Selection Previous Select Pick Atoms v Structure Image Movie Close Help Figure 5 1 The Trajectory panel You can control the selection of frames and the speed of play in the Frame control section of the panel The Start and End text boxes define the frames at which play starts and ends Frames are numbered from 0 The Frame slider and frame text box can be used to select the frame to view The current frame number is displayed in the text box below the slider The total number of frames is also displayed in a noneditable text box e The Step text box sets the number of frames to step when playing through frames This value does not affect the Frame slider The frames that are selected for play can be exported as a selection of frames using the output buttons Desmond 2 2 User Manual Chapter 5 Analyzing Simulations e The Time text boxes display the time for the current frame and the total time for the tra jectory You can enter a time in the text box to select a frame The Speed slider sets the speed at which the frames are played In addition to controlling which frames are displayed and how fast you can modify the appear ance and content of the Workspace during display of frames To select
52. Section 5 3 of the Maestro User Manual If the property you chose has values only for some of the atoms e g the ligand you can select these atoms by specifying the entire range of values Atoms that do not have a value for the property will not be selected 2 5 Adding lons It is usually desirable to have an electrically neutral system for simulation though not strictly necessary as Desmond applies a uniform background charge distribution to neutralize the system in the Ewald summation You can choose to add ions to neutralize the system in the lon placement section of the lons tab The system can also be set up in a salt solution rather than a pure solvent in the Add salt section of the lons tab To limit the locations in which ions can be placed you can define regions from which ions are excluded in the Exclude region section of the lons tab Desmond 2 2 User Manual Chapter 2 Building a Model System 12 _ System Builder Llo Solvation tons m Excluded region Exclude ion and salt placement within 7 0 A of E ces Ion placement C None Neutralize C Add cl Advanced ion placement mW Add salt Salt concentration 0 15 M Salt positive ion Na Salt negative ion cl Figure 2 3 The lons tab of the System Builder panel 2 5 1 Defining an Excluded Region To define an excluded region click Select in the Excluded region section of the lons tab and
53. ader block contains the information on the energy and log files and has the following format Version version Energy_File enefile Log_File logfile The job details block contains the information from the log file about the simulation such as the status of the simulation number of atoms ensemble and so on An example block is shown below Block Job_Details Status Normal Temperature 300 0 Job_name rin Degrees_of_freedom 103139 Molecules 3 Desmond 2 2 User Manual Appendix D Analyzing a Simulation from the Command Line Duration 1 2 Atoms 50274 Ensemble MTK_NPT End_Block Subsequent data blocks printed in the sba file are block averages enclosed between Block and End_Block lines A sample data block is shown below Block E Time ps E kcal mol 5 0 5 0 10 0 4 9 End_Block The first row is a heading that indicates what quantities are listed below and it is followed by rows of values This block indicates that block average for E for data points up to the first 5 ps was 5 0 kcal mol and for the next 5 ps Sps to 10ps it was 4 9 kcal mol D 4 Simulation Block Test sbt File Syntax Simulation block test sbt files are used to test the data in sba files and determine the stability of the simulation These files contain the test parameters for various properties A sample test set is as follows E sd 5 0 slope 4 3 average 435320 2 average_tol 4000
54. ain atoms ion_location atoml atom2 The keyword ion_location is followed by the list of solute atom indexes Ions are placed near the listed atoms For each ion the atom index is given inside braces Extra atom index specifications are ignored If there are fewer atom index specifications than there are ions the remaining ion locations are determined randomly In order to exclude ions near certain atoms the exclude_ion_from keyword can be used exclude_ion_from atom list distance The keyword exclude_ion_from has two arguments The first argument is a list of atom indices of solute atoms in braces The second argument is the distance value No ion whether a single ion or from a salt is placed within the given distance in angstroms from the listed atoms The salt concentration is determined using the add_salt keyword add_salt conc The keyword add_salt adds the positive and negative salt ions to the system defined above The argument specifies the salt concentration for the molecular system Based on the volume Desmond 2 2 User Manual 71 Chapter 6 Running Desmond Simulations from the Command Line 72 of the solvent and the concentration the number of salt ions is calculated and rounded to an integer value The coordinates of salt ions are determined randomly The following command can be used to neutralize the system neutralize The net charge of the current solute structures is calculated and the nu
55. alize the velocities using the seed specified in the Random number seed text box and the target temperature specified in the Target temperature text box in kelvin In the Atom group section you can specify atom groups Atom groups are used for various special treatments of atoms in the simulation For example if you define the frozen atom group the atoms in this group will be frozen in the simulation You can define multiple groups with the same name but a different index by setting the index in the Value column If you use multiple thermostats for example you can define the atoms in each thermostat group by naming the group thermostat and setting the index to the thermo stat group number in the Ensemble tab Group 0 is the default group to which all unassigned atoms automatically belong The atom groups are listed in the table The Atoms column is filled in automatically when you click Select and use the Atom Selection dialog box to specify the atoms Otherwise you can edit this column to specify the ASL expression for the atoms in the group The number of atoms defined by the ASL expression is shown in the No of Atoms column Desmond 2 2 User Manual 35 Chapter 3 Running a Desmond Simulation from Maestro 36 Beside the table are the following buttons e Select Opens the Atom Selection dialog box to specify the atoms for the selected group Only available if a single row is selected in the table e Add Adds an atom g
56. ame_trj is the trajectory directory produced during the simulation The optional argument data_dir can be used to designate the name for the directory in which to look for the for the data files If this argument is missing the default directory name is jobname This program reviews the trajectory and calculates the correction The final correction is printed to standard output During the process the program writes out several files jobname_correctl cfg jobname_correctl log and jobname_correct1 dat Depending on your system it may also write out the analogous files Jobname_correct2 cfg jobname_correct2 log and jobname_correct2 dat You need not be concerned with the content of these files 4 8 Customizing and Restarting FEP Simulations FEP jobs perform a series of MD simulations for the calculation of the free energy difference between two systems These simulations are set up in the specialized FEP panels described earlier in this chapter The FEP panel allows you to adjust FEP protocols set up in these panels and to rerun lambda windows for FEP jobs that failed To open the FEP panel choose Applica tions gt Desmond gt FEP in the main window The settings for the simulation time recording interval ensemble class temperature pressure and model system relaxation are the same as for a molecular dynamics simulation and are described in Section 3 4 on page 20 There are two options for the type of FEP that can be performed that
57. ances This approach will not give the exact box size for the input structure However it will work reasonably well particularly when the exact box size is not known Click Start Enter a job name and click Start The output CMS file is named jobname out cms To create a CMS file from the command line 1 2 Edit the Maestro file and add the properties that specify the box shape with the appropri ate values The properties are r_chorus_box_ax r_chorus_box_ay r_chorus_box_az r_chorus_box_bx r_chorus_box_by r_chorus_box_bz r_chorus_box_cx r_chorus_box_cy r_chorus_box_cz Create a CSB file my build csb that has the following content read_solute_structure input file mae Desmond 2 2 User Manual 93 Appendix A Creating a CMS File from a Full System Maestro File 94 create_boundary_conditions cubic 0 000000 write_maeff_file output file cms 3 Run the System Builder with the following command SCHRODINGER utilities system_builder my build csb The CMS file that is generated is named output file cms Desmond 2 2 User Manual Appendix B The multisim Utility The multisim utility is useful for running tasks that consist of a sequence of steps such as relaxation of a system followed by a production simulation Maestro runs multisim for jobs that include multiple stages This appendix provides detailed information on how to run multisim and the format of multisim msj files
58. ane cms m desmond_membrane_relax msj o protein membrane out cms This process may take hours to days since it equilbrates the system in stages for about 1 2 ns The file protein membrane out cms should be reasonably well equilibrated and can be used as input for the production simulation for your study 3 8 Setting Options for Desmond Simulations The default settings used in the Desmond panels were selected to produce good results in the majority of cases At times you may want greater control over the parameters of the calcula tion The Advanced Options dialog box provides access to advanced options for control of the simulation or the minimization such as the frequency of data output integration time step sizes thermostat and barostat parameters restraints cutoff radii and so on To open the Advanced Options dialog box click Advanced Options in the Desmond panel that you have open This panel has several tabs which are described in the following subsections e Integration tab Ensemble tab e Minimization tab e Interaction tab e Restraint tab e Output tab e Misc tab The selection of tabs that is displayed depends on the task For minimizations only the Minimi zation Interaction Restraints and Misc tabs are displayed For MD simulations all but the Mini mization tab are displayed The settings in this dialog box and the settings in the Desmond panels are not entirely indepen dent and can affect each other
59. are handled To define the short range region choose a method from the Short range method option menu The controls below this menu depend on the method chosen which can be one of the following e Cutoff Enter a value in the Cutoff radius text box The default is 9 0 A Force tapering or Potential tapering Specify the range in angstroms over which the force or the potential is tapered off in the two Tapering range text boxes There are two choices for handling the long range Coulombic interactions e Smooth particle mesh Ewald use the smooth particle mesh Ewald method This method requires a tolerance to be set in the Ewald tolerance text box This tolerance affects the accuracy of the long range Coulombic interactions The smaller the tolerance is the more accurate the computation of the long range Coulombic interactions is but the simulation will be correspondingly slower None use the unmodified Coulomb interaction Desmond 2 2 User Manual Chapter 3 Running a Desmond Simulation from Maestro Molecular Dynamics Advanced Options Integration Ensemble Interaction Restraints Output Misc m Position restraint Force Constant At T jeee ey 100 atom entrynum 1 Aad 2 Delete H J P Reset Reset OK Apply Cancel Help Figure 3 9 The Restraints tab of the Advanced Options dialog box 3 8 5 The Restraints Tab In this tab yo
60. ast completed stage with the d option The d option is usually necessary because the subsequent stages need access to the data produced by the last successfully completed stage For example if stage 5 is partially done some subjobs finished some did not then you would also have to include myjob_4 out tgz and the command to use would be SCHRODINGER utilities multisim r myjob multisim_checkpoint d myjob_5 out tgz d myjob_4 out tgz JOBNAME myjob This command restarts the job on the same compute hosts as before Unless the HOST option is given the master job runs on the local host The subjobs will run using the same number of CPUs as before If you want to use different hosts to restart a job you can use the HOST and host options The number of CPUs used by the subjobs can also be changed using the cpu option for example SCHRODINGER utilities multisim HOST another_master_host host another_subjob_host r myjob multisim_checkpoint d myjob_5 out tgz JOBNAME myjob cpu 1 Desmond 2 2 User Manual Appendix B The multisim Utility You can also modify the characteristics of some stages when you restart a job by using the set option For example if you use the command SCHRODINGER utilities multisim r myjob multisim_checkpoint d myjob_4 out tgz JOBNAME myjob set stage 5 time 1200 0 stage 5 cutoff_radius 16 0 then stage 5 is modified so that its subjobs run with the time set to 1200 0 and
61. ata Reading the negative ion data Adding a membrane Solvating Neutralizing Writing out a composite molecular system CMS file The order of the keywords in a CSB file matters Lines beginning with are considered to be comments and are ignored An example CSB file is shown below read_solute_structure mysolute_setup in mae solute file name solvent_desmond_oplsaa_typer input_file_name spc box mae run positive_ion_desmond_oplsaa_typer input_file_name Na mae run negative_ion_desmond_oplsaa_typer input_file_name Cl mae run membranize POPE mae gz 10 000000 10 000000 create_boundary_conditions orthorhombic 0 000000 0 000000 10 000000 exclude_ion_from 1 2 10 0 solvate neutralize write_maeff_file chorus_setup out cms The various sections of the file are described in the following subsections 6 3 1 Reading the Structures The first five sections read in all the structural information for the solute solvent and ions To locate the files that contain this information the current directory is searched first then the directory SCHRODINGER mmshare vversion data system_builder The first section reads the solute and solvent structure read_solute_structure mysolute_setup in mae solute file name solvent_desmond_oplsaa_typer input_file_name spc box mae Desmond 2 2 User Manual Chapter 6 Running Desmond Simulations from the Command Line run The keywor
62. ates Default 3 118 Desmond 2 2 User Manual Appendix C The Desmond Configuration File Table C 12 Keywords for the integrator temperature section Keyword Description T_ref Reference temperature Default 300 0 K groups List of temperature groups assigned to thermostat Default 0 meaning the entire system Several of the integrators have common thermostat and barostat sections The keywords for these sections are listed in Table C 13 and Table C 14 Keywords for other integrator sections are listed in the remaining tables of this section Table C 13 Keywords for the common thermostat section Keyword Description mts Time steps within chain Default 2 tau Relaxation time for chain members Example 1 1 1 Table C 14 Keywords for the common barostat section Keyword Description tau Barostat relaxation time Default 2 0 T_ref Barostat temperature Default 300 0 K thermostat Thermostat section for the barostat This is the section described in Table C 17 for the L_NPT barostat and is the common section described in Table C 13 for other barostats Not used for the Piston_NPH integrator Table C 15 Keywords for the Ber_NPT and Ber_NVT sections Keyword Description barostat Barostat section Ber_NPT only tau Temperature relaxation time one per thermostat Default 1 0 min_velocity_scaling Lower bound for velocity scaling Default 0 85 max_velocity_scaling Upper bound for velocity sca
63. ault the far time step size is 0 006 ps and thus the increments are 0 3 ps Values entered in this text box are rounded to an integer multiple of the far time step size This time step size is set in the Integra tion tab of the Advanced Options dialog box in the RESPA integrator section The controls in the lower part of the Simulation section allow you to choose the ensemble class from NVE NVT NPT NPAT and NPYT to set the temperature except for NVE and the pres Desmond 2 2 User Manual Chapter 3 Running a Desmond Simulation from Maestro sure except for NVE and NVT and set the surface tension NPYT only It also allows you to relax the model system before performing the simulation and choose the protocol for the relaxation When Relax model system before simulation is selected a series of minimizations and short molecular dynamics simulations are performed to relax the model system before performing the simulation you set up This option is selected by default and a default protocol is used Usually if the model system was just created from the System Builder panel it needs to be relaxed if the model system has been relaxed before it does not need to be relaxed again Alternatively you can run a minimization prior to performing the molecular dynamics calcula tion The stages in the default relaxation process for the NPT ensemble are 1 Minimize with the solute restrained 2 Minimize without restraints 3 Simulate
64. ax for this section is same as for the positive and negative ion sections Desmond 2 2 User Manual 69 Chapter 6 Running Desmond Simulations from the Command Line 70 6 3 2 Adding a Membrane The keyword membranize instructs the system builder to create a membrane patch around the current solute structure membranize filename x buf y buf The first input parameter is the name of the file that includes the membrane template and its equilibrating solvent The other two parameters x buf and y buf specify the minimum distance between the solute and the box boundary in the plane of the membrane 6 3 3 Setting the Box Shape and Dimensions The box shape and dimensions can be specified either in terms of an absolute size or in terms of a buffer distance The keyword boundary_conditions is used to define a box with specified absolute dimen sions The command using this keyword can be one of the following boundary_conditions cubic a boundary_conditions orthorhombic a b c boundary_conditions triclinic a b c alpha beta gamma The box shape is the first parameter and can be cubic orthorhombic or triclinic It is followed by the absolute size of the box defined by a or by a b and c For a triclinic box shape the angles alpha beta and gamma must also be given Alternatively the keyword create_boundary_conditions can be used to specify a box in terms of the distance between solute atoms and box edges he command using this keyw
65. ber of passes specified by num_passes has been completed The simulation portions will run for at least twice this duration before early termination occurs Default 100000 Limits of the orthorhombic box in which the water molecules will be sam pled For WaterMap jobs this box should enclose the binding site This box should be completely enclosed by atoms after it is centered in the input periodic cell The closest acceptable approach for any two atoms in angstroms Required Recommended 1 0 A The temperature used in the Monte Carlo simualtion Required Desmond 2 2 User Manual Chapter 9 Utilities 88 Table 9 1 Keywords for the solvate_pocket utility Continued Keyword Description term_std_slope Threshold for the standard deviation of the number of water molecules The calculation is terminated if the standard deviation falls below this value Default 0 00001 update_frequency The number of passes between updates in the log file Default 10 Below is an example solvate pocket command file name solvate_pocket example command file temperature 298 15 init_num_passes 10000 num_passes 100000 update_frequency 10 pass_term_window 10000 term_std_slope 0 00001 num_trans_rot 20 num_delete 5 num_insert 5 max_disp 0 105 max_dpsi 0 318 max_dctheta 0 0654 sample_xmin 8 sample_xmax 8 sample_ymin 8 sample_ymax 8 sample_zmin 8 sample_zmax 8 oO OOOO oO cut_off 9 0
66. calculation of block averages Default 10 ps s simboxfile Simbox dat file name This is the file that Desmond writes out to track how the shape of the simulation box evolves during the simulation Desmond 2 2 User Manual 129 Appendix D Analyzing a Simulation from the Command Line 130 D 2 simulation_block_test py This command evaluates the results in an input sba file using tests specified in an sbt file The output file is a plain text file that prints the job details block from the sba file and then provides information on whether block averages are within the tests specified in the sbt file The syntax is as follows simulation_block_test py d i sbafile t sbtfile o outfile The output file has the following information for each test in the sbt file Test Pass or Fail e Testing criteria from input sbt file e Corresponding block values from input sba file An example output file has the following information besides the job details block from the sba file Test for E Fail Testing criteria SD 5 000 Slope 4 300 kcal mol ps Average 435320 200 4000 000 kcal mol Block data SD 44 941 Slope 0 034 kcal mol ps Average 128666 563 kcal mol D 3 Simulation Block Analysis sba File Syntax The sba file contains properties obtained from the 1og file and block averages from the ene file It has a header block followed by the job details block and then by data blocks The he
67. cel Help Figure 2 2 The Membrane Setup panel When you have chosen the box shape you can choose whether to specify the size of the box in terms of a buffer distance or as an absolute size by selecting one of the Box size calculation method options e Buffer The simulation box size is calculated by using the given buffer distance between the solute structures and the simulation box boundary e Absolute size Specify the lengths of the sides of the simulation box size and angles if necessary Having chosen a method you can specify the distances and angles in the Distances and Angles text boxes The text boxes that are available depend on the box shape For all choices except a truncated octahedron the box can be displayed in the Workspace by selecting Show boundary box If you want to calculate the volume of the box that encompasses the solutes click Calculate The volume is displayed in the Box volume text box To minimize the volume of the box click Minimize Volume The solutes are reoriented so that the box volume is minimized 2 3 Adding a Membrane A membrane can be added to the system using the Set Up Membrane dialog box which you open by clicking Set Up Membrane in the Solvation tab This dialog box allows you to select and position the membrane the actual membrane is added when the system builder job is run There are three predefined membranes DPPC POPC and POPE which you can choose by selecting
68. change tun a replica exchange MD simulation on the system e solvate_pocket add or remove water molecules in buried pockets e fep_analysis analyze FEP calculations e extern custom Python stage The keywords supported for each of these stages and their default values are described in the sections that follow B 2 1 General Keywords The keywords that can be used in any stage of the multisim job are listed in Table B 1 Table B 1 General keywords that can be used in any stage Keyword Description compress File name pattern of the stage data file If it is set to an empty string then the data of this stage is not packaged and compressed Default SJOBNAME_SSTAGENO out tgz dir Pattern for the names of the directories used by subjobs of this stage Default JOBPREFIX PREFIX JOBNAME_ STAGENO _lambda LAMBDA jobname Jobname pattern for subjobs of this stage Default SJOBNAME_SSTAGENO _lambda LAMBDA prefix Value of the PREFIX macro which by default is used to specify the sub direc should_skip should_sync struct_output title tory name of subjobs see the dir keyword Default is an empty string Skip this stage Allowed values true false Default false Do not start this stage until all subjobs of the previous stage finish successfully Allowed values true false If it is set to false this stage is started as soon as any subjob of the previous stage finishes successfully For FEP
69. cien kenn 102 B 2 5 The task Stage nu 103 B 2 6 The System builder Stag Eein nase 103 B 2 7 The simulate and replica_exchange Stages ursuur00unnnnnnnnnnennnnnnnnnnnn 104 B 2 8 The minimize Stage u n u u anne aaa 105 B 2 9 The solvate pocket Stage energie 106 B 2 10 The extern Stage nenne ernten 107 B 2 11 Thetep analysis Stage use ea aan 109 Desmond 2 2 User Manual Contents Appendix C The Desmond Configuration File 111 C 1 General Structure caristes enan Ea AAE AA AE 111 C2 UMIS fer rent anti a ae ae en Ne ik a S me 112 C 3 Configuration File Sections 424240nnnnnennnnnnenennnnnnnnennnnnnn na 112 C 3 1 The boot Section acer ann 113 C 3 2 The constraint Sectionin anere cea lin 113 C 3 3 The Desmond Secon s anadene ee 113 C3 4 Ihe Orce SOCOM 5 525 54 Satis cay aA E 114 C 3 5 The global Cell SSC ON isani e ae Ea E A 116 C 3 6 The integrator SOCHON u een sasacssusieascaszergusesteastaasaabisdsansaicesecaseasa 117 C3 7 Themdsim Section nennen 120 C 3 8 The minimize SEektli n uusnsaeeensenensnseeueeenignneesen 121 63 9 The remd SOCOM nti scciaiece rin ccs ee en E RSE 121 C3110 The ARUN SO CUO Mia samen eine ine 122 C 4 Plugin Descriptions un 122 C5 EXaMPIES nn Mensano naire ean ae 125 G 5 1 FEP Galeulationss an sssn nee 125 G 5 2 Replica Exchange users en uneaankaennd 127 C 5 3simulated Annealnd insert E E E 127 C 5 4 Instructing De
70. class NVT M Relax model system before simulation Relaxation protocol Use default protocol Browse Advanced Options Desmond Developed by D E Shaw Research Start Read Write 1 Reset Close Help Figure 3 4 The Replica Exchange panel 3 6 Replica Exchange Simulations Many molecular systems have conformations that are separated by significant free energy barriers It can be difficult to sample such conformations if they differ by concerted or collec tive shifts of many atoms This commonly occurs in protein ligand complexes Random methods such as Monte Carlo conformational searches have trouble generating such collective changes while thermal methods such as molecular dynamics have trouble surmounting the free energy barriers Replica exchange simulations 39 attempt to tackle this problem by allowing the system to spend some time at elevated temperatures in addition to the temperature of interest Time spent at elevated temperatures permits the system to evolve faster in part by more readily crossing free energy barriers Desmond supports replica exchange simulations in which multiple copies of the system are simulated at different temperatures which usually range from the temperature of interest up to 700 K or more Periodically during the simulation attempts are made to exchange the coordi Desmond 2 2 User Manual Chapter 3 Running a Desmond Simulation from Maestro nat
71. cription first First energy_groups output Default 0 0 interval Interval between energy_groups output Default 1 2 name File name for energy groups output Default jobname_enegrp dat verbose Verbosity Allowed values true false Default false pressure_tensor corr_energy Show pressure tensor Allowed values true false Default false Show correction energy Allowed values true false Default true Table C 25 Keywords for the eneseq plugin Keyword Description name Energy file name Example eneseq ene first First energy store time Example 0 10 interval Simulation time between storing energy values Default 1 2 Table C 26 Keywords for the maeff_output plugin Keyword name full_system_only first interval write_last_step periodicfix Optional trjidx Description Output CMS file name Default jobname out cms Output only full system Allowed values true false Default false First maeff output time Default 0 0 Interval between maeff output Default 12 0 Force output on last step Allowed values true false Default false Keep bonded atoms together Allowed values true false Default true Name of trajectory index file name Default jobname_trj idx Desmond 2 2 User Manual 123 Appendix C The Desmond Configuration File Table C 27 Keywords for the maeff_snapshot plugin Keyword Description name Maeff_snapshot file name jobname mon maegz first First snaps
72. ctories examine individual frames and export trajectory data in a variety of forms in the Trajectory panel To open the Trajectory panel click the T button in the Aux column of the Project Table for the entry whose trajectory you want to view The toolbar in the Trajectory panel contains a standard set of controls for playing through the trajectory frames which are listed below The menu bar has one menu Play which contains items that correspond to the toolbar buttons Go to start E 4 Display the first frame Previous E Display the previous frame Play backward 4 Display the frames in sequence moving toward the first Stop E Stop playing through the frames Play forward p Display the frames in sequence moving toward the last Next Display the next frame Go to end b rl Display the last frame Loop t Choose an option for repeating the display of the frames Single direction displays frames in a single direction then repeats Oscillate reverses direction each time the beginning or end of the frame set is reached Desmond 2 2 User Manual Chapter 5 Analyzing Simulations 54 Trajectory EES Md dd fm gt ODL DDL at Frame control Start 0 End 250 Frame fe of 250 Step 2 Time 0 000000 of 99 000000 ps Slower Faster Speed g Display L Use lower quality drawing to speed up play Show simulation box Show axes
73. cumentation 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 there Auto Help contains a single line of information For more detailed information use the online help e If you want information about a GUI element such as a button or option there may be Balloon Help for the item Pause the cursor over the element If the Balloon Help does not appear check that Show Balloon Help is selected in the Maestro menu of the main window If there is Balloon Help for the element it appears within a few seconds e For information about a panel or the tab that is displayed in a panel click the Help button in the panel or press F1 The help topic is displayed in your browser e For other information in the online help open the default help topic by choosing Online Help from the Help menu on the main menu bar or by pressing CTRL H This topic is dis played
74. cus is returned to the panel this option is deselected In the Mutation targets table select the targets that you want to use to replace the original ring atom by selecting their table rows Use shift click and control click to select multiple table rows You can view the mutated ligand by clicking in the View column If you want to add a functional group as well as mutate the ring atom you can use the build tools to add to the mutated structure In the Plan Calculation tab select the calculation types e For binding free energy calculations select In complex and In pure solvent e For solvation free energy calculations select In pure solvent and In vacuum Choose the FEP protocol you want to use for each calculation type from the FEP protocol option menu Desmond 2 2 User Manual 43 Chapter 4 Running FEP Simulations 44 Protein Residue Mutation by FEP Lali Define Perturbation Plan Calculation Step 1 Display the protein and ligand in the Workspace Step 2 Pick atom to identify a ligand molecule This step can be Be skipped if you do not want to calculate ligand binding free F Pick atom to identify ligand Step 3 Pick amino acid residues in the Workspace and specify what Use they are mutated to r Define mutations M Pick residue Mutation Site Substitutes m H Glu97 A _ Asp v I F Step 4 Generate and select mutants for which FEP calculations will
75. cutive reports To change the size of the box enter a value in the Box length for averaging text box When you have the desired box length click Analyze to perform the analysis The analysis can take a few minutes When it finishes the Simulation summary and Properties sections are filled in with the results of the analysis If you want to view a plot of the thermodynamic properties as a function of simulation time click Plot A panel is displayed with the results plotted You can also use the Simulation Event Analysis panel which is not provided with the software distribution but is available from the Script Center This panel can be used to investigate what happened during a simulation Desmond 2 2 User Manual 57 58 Desmond 2 2 User Manual Chapter 6 Running Desmond Simulations from the Command Line Desmond jobs may be started from Maestro or from the command line The mechanisms for running jobs from the command line are described in this chapter You might wish to run Desmond from the command line for any of the following reasons To exercise greater control over Desmond behavior To debug an aberrant run e For convenience To transfer the job to a remote location The Desmond panels can be used to write out using the Write button cfg files for a simula tion Those cfg files can then be run elsewhere routinely from a batch script or customized prior to use More information on the contents of cfg files is
76. d read_solute_structure reads the solute structure from the specified file If the file is given as a relative path it is copied to the temporary directory for the job If it is given as an absolute path the file must exist at that location on the execution host The struc tures can be a solute structure structures for different stages of FEP simulations or a completely solvated system The force field information is obtained by either reading from an existing fi0_ff block in the input file or running the force field server The solvent_desmond_oplsaa_typer section describes the solvent system that is used to solvate the structure The keyword input_file_name specifies the file to be used to read the solvent model The next two sections determine the data to be used for counter ions to neutralize or in some cases charge the system positive_ion_desmond_oplsaa_typer input_file_name Na mae run negative_ion_desmond_oplsaa_typer input_file_name Cl mae run These two sections describe the ion systems to neutralize or to add ions to the current struc tures In each section one input_file_name keyword is provided to determine the file to be used The next two sections not used in the example file above similarly determine the ion systems to add salts to the system salt_positive_ion_desmond_oplsaa_typer input_file_name Na mae run salt_negative_ion_desmond_oplsaa_typer input_file_name Cl mae run The synt
77. dded e AHn where n is a count of the number of hydrogen atoms 1 2 3 in a group com posed of a heavy atom and the hydrogen atoms directly bonded to it HOH oxygen bonded to two hydrogen atoms and no other atoms Table 8 3 Options for the build_constraints utility Option Description a angles Constrain AH2 and AH3 angles h help Show usage message and exit k keep Keep bonded terms that coincide with constraints r revert Remove constraints and restore built terms v verbose Print constraint terms x exclude Don t use the specified type of constraint HOH AHl AH2 exclude exclude Desmond 2 2 User Manual 79 Chapter 8 Using Alternate Force Field Parameters and Constraints 80 8 3 Input and Output Files The input structure file should contain all the atoms in the chemical system that are to be simu lated including hydrogen atoms water molecules ions and so on The chemical system may contain a number of structures also called connection tables or CTs Residues including water molecules and ions in the chemical system are matched to templates in the force fields The CTs should also contain the following CT level properties r_chorus_box_ax r_chorus_box_ay r_chorus_box_bx r_chorus_box_cz that specify the size and shape of the simulation box The output from the system_builder utility meets these conditions Residue Matching Atomic numbers and th
78. de as the master job host is ignored and maxjob is set to 1 Output cms or mae file This file can be incorporated into Maestro Probe a checkpoint file and quit Light log information default Specify parameters that take precedence over those in the msj file Print the multisim version and exit Heavy log information Desmond 2 2 User Manual 63 Chapter 6 Running Desmond Simulations from the Command Line 64 6 2 1 Examples of Running MultiSim A simple multisim command can take the form SSCHRODINGER utilities multisim i input cms m input msj host mycluster JOBNAME multistage which runs the multisim utility with the starting structure from input cms The instruc tions for different stages of multisim are provided in input msj The job is run on the host labeled mycluster in the schrodinger hosts file The job name is multistage The following command uses a different host for the master job and the subjobs SSCHRODINGER utilities multisim i input mae m input_fep msj HOST localhost host kyla_para JOBNAME example_fep_job maxjob 6 cpu 2 2 2 The HOST option specifies the host of the master job whereas host specifies the compute host for the subjobs The keyword maxjob 6 means that at most 6 subjobs are simulta neously in the queue of the compute host When one of the subjobs finishes the next subjob is launched on the compute host At any time the number of the subjobs launched fr
79. ded that the force fields are compatible This flexibility makes it possible to do some things that may be useful in force field development including e Using one force field for one part of the chemical system and another force field for another part this allows you for example to easily switch between water models e Using one or more components from one force field e g the dihedral parameters and the remaining components from another force field e Overriding some of the parameters e g some but not all of the angle parameters with those from another force field Some classes of constraints are often used with and in some cases required by various force field representations of molecules The utility build_constraints may be used to add the constraints to a structure file 8 1 The viparr Utility To run viparr use the following command SCHRODINGER run FROM desmond viparr py options input file output file where input file and output file are the input and output structure CMS files respectively This utility does not run under Job Control It does not take much time so it can be run locally The basic options are given in Table 8 1 The force field data files are located in the directory SCHRODINGER desmond vversion data viparr Desmond 2 2 User Manual 77 Chapter 8 Using Alternate Force Field Parameters and Constraints 78 Table 8 1 Options for the viparr utility Option Description
80. dom placement is performed to place any remaining ions that are needed to neutralized the system or complete the number of ions selected for placement in the Add text box Desmond 2 2 User Manual Chapter 2 Building a Model System 14 2 5 3 Adding a Salt Adding a salt is relatively simple To do so first select the Add salt option The controls in the Add salt section are then activated and you can enter the salt concentration in mol dm and select the desired ions If you select multiply charged ions the concentration is taken from the empirical formula for the salt For example for MgCl the concentration of Mg would be the specified concentration and the concentration of CI would be twice the specified concentra tion A value of 0 15M is approximately the physiological concentration of monovalent ions When the salt ions are placed they are randomly distributed in the solvent and replace solvent molecules Salt ions are not placed in the excluded region defined in the Exclude region section 2 6 Running the Job When you have finished making settings you can set up and start the job immediately or write out the input file and run the job from the command line To set up and run the job click Start The Start dialog box opens allowing you to name the job choose the host and set the user name if necessary System Builder jobs do not usually take more than a few minutes so you can run the job locally You can
81. dow sample_xmin sample_xmax sample_ymin sample_ymax sample_zmin sample_zmax short_dist temperature The number of Monte Carlo passes to perform in the equilibration prior to the production Monte Carlo run Recommended 10000 The maximum change used for the cosine of theta Euler angle for a com bined translation rotation move in radians Required Recommended 0 0654 The maximum change used in each of the x y and z directions for a com bined translation rotation move Required Recommended 0 105 A The maximum change used for phi and psi Euler angles in radians for a combined translation rotation move Required Recommended 0 318 A descriptive name for the simulation The number of attempts to delete a single water molecule per pass Required Recommended half the number of water molecules expected The number of attempts to insert a single water molecule per pass Required Recommended half the number of water molecules expected The number of Monte Carlo passes to perform in the production Monte Carlo run Required Recommended at least 20000 The number of water molecule translations to attempt per pass Required Recommended approximately the number of water molecules expected to reside in the region being sampled The number of passes over which the slope of the standard deviation of the the number of water molecules is calculated This keyword may be used to terminate the calculations before the num
82. e System Builder panel choose Applications gt Desmond gt System Builder in the main window Before you start working in this panel display the solutes in the Workspace 2 1 Adding Solvent The solvation model is selected in the Solvation tab You can choose from a set of predefined solvent models or specify a custom solvent model e None Do not use a solvent This option allows you to run a simulation on a pure liquid for example or in vacuum with a sufficiently large box e Predefined Use one of the predefined solvent models which you can select from the option menu The models include four water models SPC TIP3P TIP4P and TIP4PEW and three organic solvents methanol octanol and dimethyl sulfoxide DMSO Desmond 2 2 User Manual Chapter 2 Building a Model System System Builder lex Solvation tons Set Up Membrane Solvent model None Predefined SPC _ Custom Browse Boundary conditions Box shape Triclinic Box size calculation method Buffer Absolute size Distances a 10 0 b 10 0 c 10 0 Angles alpha 90 0 beta 90 0 gamma 90 0 Box volume 191116 a Calculate Minimize Volume Show boundary box except truncated octahedron M Use custom charges None C Predefined r_m_chargel C Custom Apply to _ Select Start Write Reset Close Help Figure 2 1 The Solvati
83. e bonding pattern graph isomorphism are used to match residues to templates This methodology supports nonstandard atom or residue PDB names without modi fication Atom and residue names in a force field need not be edited In particular viparr will identifies the N and C terminus versions of the residues correctly as well as protonated and deprotonated versions of a residue even if they are not explicitly mentioned as such in the input file Modification of atom and residue names for clarity is allowed Residue and Atom Ordering The atom ordering in the input file is retained in the output structure file The residue numbering which also remains unaltered can begin with any integer including negative inte gers and does not need to be contiguous viparr constructs a contiguous set of indices that it uses internally Residues with different chain names can have the same residue number To aid in diagnosing problems with the input structure file messages involving residues have the form lt chain name residue number gt residue name and are usually preceded by a structure number Output Format A compressed force field representation is written when all the residues in a CT are the same For a CT that only contains water molecules this means that force field parameters are written only for a single water molecule A version number which is associated with a particular version of viparr along with the versions of the built in
84. e files are listed below with any extra controls The intervals for the energy sequence file and for the trajectory can be set in the Desmond panel e Status message file This file contains general information about the current status of the simulation Energy sequence file This file contains a sequence of various energies of the system e Trajectory directory This directory is used by Desmond to periodically write out files that record coordinates and velocities optional of all particles in the system at a particu lar point in the simulation You can provide a title for the trajectory and you can select Record velocities if you want the velocities to be recorded along with the coordinates To ensure that associated solutes appear together in the trajectory rather than on opposite sides of the simulation box you can select Glue close solute molecules together This option only affects the way the trajectory is displayed e Checkpoint file This file contains information that can be used to restart an interrupted simulation Checkpoint files permit bitwise continuation of simulations so they can be large and should be saved infrequently if at all e Monitoring file This file contains the coordinates of all particles in the system This file is in Maestro format and is used to monitor the progress of the simulation in Maestro Molecular Dynamics Advanced Options Integration Ensemble Interactio
85. e number of history vectors used by the LBFGS minimizer for the update of the Hessian The maximum is 6 e Minimum SD steps Specify the minimum number of steepest descent steps to be used before switching to the LBFGS minimizer e Maximum step size Specify the maximum step size in angstroms Gradient threshold Specify the gradient value in kcal mol A at which the minimiza tion method switches from steepest descent to LBFGS The gradient is checked only after the minimum number of steps is performed In the Output section you can specify the name of the structure output file You can use JOBNAME as a variable representing the job name that you will set when you start the job or write out the input files You can also select Monitor structural change in minimization if you want results returned to the Workspace during the course of the minimization Desmond 2 2 User Manual 31 Chapter 3 Running a Desmond Simulation from Maestro 32 7 Molecular Dynamics Advanced Options Integration Ensemble Interaction Restraints Output Misc Coulombic Short range method Cutoff Cutoff radius A 9 0 Long range method Smooth particle mesh Ewald Ewald tolerance 1e 9 OK Apply Cancel Help Figure 3 8 The Interaction tab of the Advanced Options dialog box 3 8 4 The Interaction Tab In this tab you can specify how the short range and long range Coulombic interactions
86. e shift click and control click to select multiple table rows You can view the mutated ligand by clicking in the View column Desmond 2 2 User Manual Chapter 4 Running FEP Simulations X H Ligand Functional Group Mutation by FEP EENE Define Perturbation Plan Calculation Display the ligand and its receptor if any in the Step 1 Workspace Pick the attachment bond to define the core and the substitution group M Pick the attachment bond Select fragments that will replace the substitution group Step 2 Step 3 Fragment library 9 items 1 item selected Fragment Name methyl D ethyl hydroxy 3 amino ammonio E carboxy fluoro chloro voelo lalun e w in irm hydro X Desmond Developed by D E Shaw Research Start Write Reset Close Help Figure 4 1 The Ligand Functional Group Mutation by FEP panel Define Perturbation tab Since each FEP mutation requires a large amount of CPU time and space we recommend performing only one mutation in a given calculation 4 Optional Display the mutated ligand and make adjustments to the fragment The adjusted fragment is used as the starting point in the FEP simulations It is possible that the fragment may have clashes with the protein in its default orientation or be in an in appropriate conformation The barriers between local minima in the potential energy sur face can
87. e simulation time recording interval ensemble class and model system relaxation are the same as for a molecular dynamics simulation and are described in Section 3 4 on page 20 The main specific task for simulated annealing is to provide information on the stages by providing a schedule of reference temperature changes The number of stages is set in the Number of stages text box When a value has been entered the table below is adjusted to display text boxes for each stage The stages are indexed from 0 For each stage you can specify a starting time in the Time text box and a starting temperature in the Temperature text box The temperature is linearly interpolated between adjacent time points The last stage runs until the specified total simulation time Desmond 2 2 User Manual 23 Chapter 3 Running a Desmond Simulation from Maestro 24 Replica exchange ENTE r Model system Load from Workspace Load The system is not specified r Simulation Number of replicas 8 Exchange scheme nearest neighbor random Exchange attempt ps starting time 120 0 interval 12 0 Temperature range K low 300 0 high 800 0 Temperature profile quadratic linear manually set Replica index 0 1 2 3 4 5 Temperature K 300 0 310 2 340 82 391 84 463 27 555 1 H z Simulation time ns total 1 2 elapsed 0 0 Recording interval ps energy 1 2 trajectory 4 8 E Ensemble
88. e utility of both Examples of such synergies include e The Protein Preparation Wizard LigPrep ligand structure and Epik ligand protonation state preparation tools can be used to ensure that the structures provided to Desmond are chemically correct Such careful system preparation often represents a crucial step prior to initiating a molecular dynamics simulation Prime can be used to create homology models for use in simulations and to repair protein structures e Glide can be used to generate relevant poses within protein binding sites for use in simu lations Desmond in turn can be used to thermally relax refine and sample conforma tions related to the docked poses e Strike can be used to generate statistical models from the results of simulations e Desmond can be used to sample protein structures prior to performing docking calcula tions with Glide e SiteMap can be used to identify potential binding sites from simulation results e WaterMap analyses specially designed Desmond simulations to characterize the thermo dynamics of water in protein binding sites 1 1 Installation and Configuration Desmond is supported on x86 hardware under Linux and is available in both 32 bit and 64 bit versions Detailed requirements and installation and configuration instructions are given in the Installation Guide Although Desmond can run serially for most purposes you will want to make use of the parallel execution capabilities
89. ealing is to perform an effective minimization with some relaxation of the system by slowly decreasing the temperature down to very low temper atures This slow cooling should permit at least some shifts from higher energy minima to lower minima in the energy landscape Desmond 2 2 User Manual Chapter 3 Running a Desmond Simulation from Maestro Simulated Annealing EES r Model system Load from Workspace Load The system is not specified Simulation Schedule of reference temperature change Number of stages 5 Stage index 0 1 2 3 4 Time ps 10 0 30 0 60 0 90 0 600 0 Temperature K 0 0 300 0 600 0 900 0 300 0 Temperature is linearly interpolated between two adjacent time points in the am _ J Simulation time ns total 1 2 elapsed 0 0 Recording interval ps energy 1 2 trajectory 4 8 Ensemble class NVT M Relax model system before simulation Relaxation protocol Use default protocol Browse Advanced Options Desmond Developed by D E Shaw Research Start Read Write Reset Close Help Figure 3 3 The Simulated Annealing panel Simulated annealing calculations can be set up and run from the Simulated Annealing panel which you open by choosing Applications gt Desmond gt Simulated Annealing in the main window In the Simulation section you can make settings for the simulated annealing job The settings for th
90. ed In the Plan Calculation tab ensure that In pure solvent is selected Choose the FEP protocol you want to use for each calculation type from the FEP protocol option menu and make any related settings The default simulation time is 2 ns which is recommended for accurate results Click Start set the job parameters in the Start dialog box and click Start in the dialog box to run the job Desmond 2 2 User Manual Chapter 4 Running FEP Simulations 7 Total Free Energy by FEP Lloi Define Perturbation Plan Calculation Display the system in the Step 1 Workspace Step 2 Pick atom to choose a molecule to annihilate M Pick the molecule Desmond Developed by D E Shaw Research Start Write Reset Close Help Figure 4 4 The Total Free Energy by FEP panel Define Perturbation tab 4 6 Selecting the Environment and FEP Protocol The selection of the ligand environment and FEP protocol is made in the Plan Calculation tab The FEP simulations can be performed in three ligand environments in the protein ligand complex with solvent in pure solvent and in vacuum This permits the calculation of binding free energies by selecting In complex and In pure solvent and of solvation free energies by selecting In pure solvent and In vacuum The FEP protocol defines in detail how system is solvated relaxed and simulated Four main protocols are provided in the FEP protocol option menu for
91. ed from well prepared structures For proteins it is recommended that the protein be prepared with the Protein Preparation Wizard see the Protein Preparation Guide for details For other types of molecules such as ligands the molecule should have a fairly good Lewis structure although there are some built in capabilities for adjusting incor rect or non optimal Lewis structures If you have MacroModel you can perform a quick check on the structure by performing a Current Energy calculation available from the MacroModel submenu of the Applications menu using the OPLS_2005 force field with the Solvent set to None If that calculation succeeds it is almost certain that Desmond and its associated tools will be able to work with this structure as well If the structure is problematic Maestro and MacroModel often provide useful diagnostics for what might be wrong Performing a study based on a Desmond molecular dynamics simulation usually involves a number of stages including simulation setup relaxing the system this could just be a minimi zation running the simulation viewing trajectories and analyzing the results Simulation setup is described in Chapter 2 the basic Desmond minimization molecular dynamics simu lated annealing and replica exchange tasks are described in Chapter 3 Simplified FEP setup for relative binding and solvation free energies and absolute solvation free energies is described in Chapter 4 along with restarting and c
92. es of copies that are at different temperatues The exchange is processed in a Monte Carlo like process select the systems to attempt to exchange and then use a Metropolis like criterion to decide whether to accept the change 39 The exchange acceptance ratio satisfies the detailed balance or balance condition so that each replica remains in equilibrium after the exchange When many such exchanges are accepted over the course of an extended simulation multiple systems with very different histories can visit the temperature of interest While systems spend time at higher temperatures they explore conformational space signficantly more rapidly than if they remained at the target temperature Thus the composite trajectory at the temperature of interest may contain a more diverse collection of conformations than if multiple simulations were performed at the target temperature As with a regular molecular dynamics simulation each replica may be run on multiple proces sors Since the simulations of each replica proceeds independently between exchange attempts the additional level of parallelization achieved by running multiple replicas is highly efficient Replica exchange simulations can be set up and run from the Replica Exchange panel which you open by choosing Applications gt Desmond gt Replica Exchange in the main window In the Simulation section you can make settings for the replica exchange job The settings for the simulation time recordi
93. esmond P 4 restore x cpt exec remd 6 2 Running Multiple Simulations Molecular dynamics studies usually involve performing a series of calculations For example a sequence of minimization thermalization and relaxation calculations followed by the produc tion simulation itself is usually undertaken for molecular dynamics study The MultiSim utility multisim facilitates the task of running multiple Desmond related or MCPRO related calculations in a sequential manner The Desmond general and FEP panels can be used to write out msj files for those tasks These msj files can then be run elsewhere for example from a batch script or customized prior to use More information on the contents of msj files is available in the Maestro online help see the list of Desmond topics The syntax for the multisim utility is as follows SCHRODINGER utilities multisim options i structure file m msj file SCHRODINGER utilities multisim options r checkpoint file The first syntax should be used for new jobs and the second for restarting jobs The structure file can be either a Maestro mae file or a CMS cms file The options are described in Table 6 2 including job options The standard Job Control options are also supported as are the options LOCAL WAIT and NOJOBID see Section 2 3 of the Job Control Guide Desmond 2 2 User Manual Chapter 6 Running Desmond Simulations from the Command Line Table 6 2 Options for the m
94. ess interval Minimum chemical time between frames max_margin_contraction Used to maintain integrity of PME calculation C 4 Plugin Descriptions The plugins that can be used within the mdsim minimze remd and vrun sections are listed in Table C 23 The plugins themselves are described in the following tables Table C 23 Plugins that can be used in the mdsim minimze and vrun sections Plugin Name Plugin Description energy_groups eneseq maeff_output maeff_snapshot anneal randomize_velocities simbox_output status trajectory Desmond 2 2 User Manual Plugin to control reporting on energy groups Energy output plugin Controls writing to the jobname ene file Maestro file output plugin Controls writing to the jobname out cms file Maestro monitoring file plugin Controls writing to jobname_mon mae Simulated annealing plugin Must be included in the mdsim plugins section to turn on simulated annealing Reassign velocities based on temperature Write out simulation box vectors The default file name is jobname_simbox dat Status output plugin Output goes to the main log file Trajectory plugin A Desmond trajectory is in the form of a group of files one per frame with names framenine digit number These files are written to a directory with the default name jobname_trj Appendix C The Desmond Configuration File Table C 24 Keywords for the energy_groups plugin Keyword Des
95. f you want to modify the protocol you can copy these files and edit them To make use of the modified protocol click Browse and navi gate to the new protocol file which has a msj extension The file name is then listed in the Relaxation protocol text box When the simulation finishes the output structure file cms is written to disk and incorpo rated into the Maestro project In addition a new trajectory directory is created called Jobname_trj by default Checkpoint files are written during the simulation but are not written during the relaxation process 3 5 Simulated Annealing Simulations Simulated annealing methods use a temperature program rather than a single temperature for the simulation A temperature program is a series of times and target temperatures The temperature is linearly interpolated as a function of time between adjacent target temperatures and is controlled by a thermostat One of the predominant strategies used is to raise the temperature to a high value one or more times before relaxing the system to the desired temperature The goal is to permit the system to relax out of an initial state that corresponds to a high energy potential minimum into a lower state by crossing barriers in the free energy landscape which is achieved more effectively during the periods of elavated temperatures The default temperature program in the Simulated Annealing panel falls into this catagory Another common use for simulated ann
96. for the minimize stage Keyword Description max_steps Maximum iterations Default 200 convergence Convergence threshold in kcal mol A Default 1 0 kcal mol A steepest_descent_steps Number of steepest descent steps performed before switching to the LBFGS algorithm Default 10 Desmond 2 2 User Manual 105 Appendix B The multisim Utility 106 B 2 9 The solvate_pocket Stage The keywords for the solvate_pocket stage are listed in Table B 8 This stage runs the solvate_pocket utitlity which is described in Section 9 1 on page 85 Table B 8 Keywords for the solvate_pocket stage Keyword Description spd_file spd_overwrite ligand_file name temperature init_num_passes num_passes update_frequency pass_term_window term_std_slope num_trans_rot num_delete num_insert The name of the solvate_pocket command file If omitted the default settings are used Block that provides settings in Ark syntax to overwrite specific commands in the command file All keywords other than spd_file and ligand_file must be inside this block The name of the ligand file used to define the region sampled If the name is set to an empty string or omitted the name jobname ligand mae is used A ligand must be used to define the region A descriptive name for the simulation Default name of standard solvate_pocket command file The temperature used in the Monte Carlo simualtion Default 300 K The n
97. grate p_ref pressure remove_com_motion respa temperature type Optional anneal tension_ref Keep frozen atoms centered Allowed values true false Default true Innermost RESPA time step in fs Type of global cell changes permitted Allowed values isotropic semi_isotropic anisotropic constant_area Used to maintain the integrity of PNE calculation Section describing migration Reference pressure Barostat section Remove center of mass motion of the whole system Allowed val ues true false You should set this keyword to true for Ber_NVT and Ber_NPT and to false otherwise Default false Section describing updates for RESPA Thermostat section one list per thermostat Example temperature T_ref 300 groups 1 T_ref 100 groups 2 Type of integrator and associated ensemble Allowed values V_NVE NH_NVT MTK_NPT Ber_NVT Ber_NPT L_NVT L_NPT Piston_NPH and anneal For each integrator type there is an associated section that provides additional information Simulated annealing section This section has the same keywords as its parent integrator except that the type cannot be set to anneal and it cannot contain an anneal section Specifiy the surface tension for constant surface tension simula tions Default 0 Constant energy dynamics no available options Desmond 2 2 User Manual 117 Appendix C The Desmond Configuration File Table C 9 Keywords for t
98. hanism of Na H Antiporting Science 2007 317 799 Humphrey W Dalke A Schulten K VMD Visual Molecular Dynamics J Molec Graphics 1996 14 33 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 Kollmann P A J Am Chem Soc 1995 117 5179 Parameters converted from those at http amber scripps edu amber9 ffparms tar gz Kollman P A Acc Chem Res 1996 29 461 Parameters converted from those at http amber scripps edu amber9 ffparms tar gz Wang J Cieplak P Kollman P J Comput Chem 2000 21 1049 Parameters converted from those at http amber scripps edu amber9 ffparms tar gz Hornak et al Proteins Structure Function amp Genetics 2006 3 712 Desmond 2 2 User Manual 133 References 134 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Duan Y Wu C Chowdhury S Lee M C Xiong G Zhang W Yang R Cieplak P Luo R Lee T Caldwell J Wang J Kollman P J Comput Chem 2003 24 1999 Parameters converted from those at _ http amber scripps edu amber9 ffparms tar gz Bugfix from http amber scripps edu bugfixes 9 0 bugix 5 applied to correct torsional assignments Parameters generated from http mackerell umaryland edu CHARMM_ff_params_files toppar toppar_c35b2_c36a2 tar gz Beglov D Roux B J Chem Phys 1994 10
99. he integrator section Continued Keyword Description NH_NVT Nose Hoover NVT dynamics section Contains only the thermostat section described in Table C 13 MTK_NPT Martyna Tobias Klein NPT dynamics section Contains only the thermostat section described in Table C 13 and the barostat section described in Table C 14 Ber_NVT Berendsen NVT dynamics section Contains only the thermostat section described in Table C 15 Ber_NPT Berendsen NPT dynamics section Contains only the thermostat section described in Table C 15 and the barostat section described in Table C 16 L_NVT Langevin NVT dynamics section Contains only the thermostat section described in Table C 17 L_NPT Langevin NPT dynamics section Contains only the thermostat section described in Table C 17 and the barostat section described in Table C 14 Piston_NPH Constant enthalpy dynamics section Contains only the barostat section described in Table C 14 Table C 10 Keywords for the integrator migrate section Keyword Description first First migration time May be overridden automatically Default 0 0 interval Time between migrations May be overridden automatically Default 0 012 Table C 11 Keywords for the integrator respa section Keyword Description bonded_interval Steps between bonded force updates Default 1 nonbonded_near_interval Steps between nonbonded force updates Default 1 nonbonded_far_interval Steps between far field force upd
100. hich has a msj extension in the text box or navigate to it in the file selector that opens when you click Browse The default protocol is as follows The original system is solvated by adding SPC water mole cules with a buffer distance of 5 A for complexes and 10 A for pure solvent The vacuum simu lation uses a buffer distance of 100 A The system goes through a relaxation process that includes two minimizations followed by 4 short molecular dynamics simulations The produc tion simulation is run for 0 6 ns for each lambda window and 12 windows are used for each perturbation You can change the buffer size and the production simulation time for each envi ronment in the Buffer size and Production simulation time text boxes After the production simulations the results are collected and analyzed using the Bennett method The final result free energy for each perturbation is recorded as an entry level prop erty in the final Maestro output file Desmond 2 2 User Manual Chapter 4 Running FEP Simulations 4 7 FEP Results The results of FEP calculations usually need some further processing to produce the quantities of interest The most common of these are discussed in the sections below 4 7 1 Relative Free Energy Differences The estimated changes in free energy for FEP calculations are recorded as structure level prop erties in the mutated structures rather than in the original structures in the output structure file For liga
101. his command summarizes the contents of the checkpoint file without submitting a job to continue the calculation Below is an example of the output from a successful relative solvation free energy calculation Probing checkpoint file Benzene to Pyridine_solvent multisim_checkpoint multisim version 3 2 Desmond 2 2 User Manual 97 Appendix B The multisim Utility 98 mmshare version 18104 Jobname Benzene to Pyridine_solvent Username me Master job host tabitha schrodinger com Subjob host myhost CPUs per subjob 1 Original start time Checkpoint time Master job ID Structure input file Original msj file Sat May 2 00 26 20 2009 Sat May 2 02 34 16 2009 tabitha 0 49fbcb67 scr me Benzene to Pyridine_lig mae scr me Benzene to Pyridine_solvent msj Stages Stage 1 completed Stage 2 completed Stage 3 completed Stage 4 completed Stage 5 completed Stage 6 completed If the job had failed in Stage 5 you would see something like Stage 5 partially completed 1 subjobs failed 11 subjobs done Jobname of failed subjobs Benzene to Pyridine_5_lambda2 Stage 6 not run To resume the job as described earlier this output tells you that you need to provide the tgz file from stage 4 and that you might want to provide the tgz file from the partially completed stage 5 In this case only one subjob failed in stage 5 so rerunning just that subjob might require significantly less computer time than rerunning the
102. his file is usually named jobname out cms Viewing trajecto ries from Desmond FEP simulations is not currently supported To read in a CMS file 1 Choose New Molecule from the File menu of the VMD Main window The Molecule File Browser panel opens 2 Click Browse A file selector opens 3 Navigate to and select the output cms file from a Desmond simulation and click OK The file selector closes Desmond 2 2 User Manual 73 Chapter 7 Using VMD for Desmond Trajectories 74 4 In the Molecule File Browser panel set the file type to Maestro File no timesteps 5 Click Load You have just created a Molecule listing in VMD which should appear as a new a line in the VMD Main window corresponding to the CMS file that you just read in To read in a trajectory for this system 1 Ensure that the line for the CMS file that you just read in is the only one that is high lighted 2 Choose Load Data into Molecule from the File menu in the VMD Main window The Molecule File Browser panel opens 3 Click Browse A file selector opens 4 Navigate into the trajectory directory from a Desmond simulation 5 Select the file clickme dtr and click OK The file selector closes In the Molecule File Browser the file type should now be listed as Desmond trajectory 6 Click Load The trajectory should load into VMD and automatically start playing 7 2 Writing a Maestro File You can export individual configurations
103. hot time Default 0 0 interval Interval between writing snapshots Default 1 2 Table C 28 Keywords for the mdsim anneal plugin Keyword Description first Starting time to reset the reference temperature Default 0 0 interval Time interval of resetting the reference temperature Default 0 03 schedule time Set the series of time points for the simulation Default 0 0 30 0 60 0 90 0 600 0 schedule value Set the list of temperatures for the simulation Default 0 0 300 0 600 0 900 0 300 0 Table C 29 Keywords for the randomize_velocities plugin Keyword Description first First randomization Default 0 0 interval Interval between randomizations Default inf remove_com_motion Remove center of mass motion of the whole system after reassigning velocities Allowed values true false Default true seed Random seed Default 2007 temperature Target temperature Default 300 K Table C 30 Keywords for the simbox_output plugin Keyword Description name Simulation box vector output file name Default jobname_simbox dat first Starting time for recording of the simulation box vector Default 0 0 interval Time interval of recordings Default 1 2 124 Desmond 2 2 User Manual Appendix C The Desmond Configuration File Table C 31 Keywords for the status plugin Keyword Description first First status report time written to log file Example 0 10 interval Simulation time between reporting status
104. in the NVT ensemble using a Berendsen thermostat with e asimulation time of 12ps e a temperature of 10K e a fast temperature relaxation constant e velocity resampling every Ips e non hydrogen solute atoms restrained 4 Simulate in the NPT ensemble using a Berendsen thermostat and a Berendsen barostat with e asimulation time of 12ps e atemperature of 10K and a pressure of 1 atm e a fast temperature relaxation constant e aslow pressure relaxation constant e velocity resampling every Ips e non hydrogen solute atoms restrained 5 Simulate in the NPT ensemble using a Berendsen thermostat and a Berendsen barostat with e a simulation time of 24ps e a temperature of 300K and a pressure of 1 atm e a fast temperature relaxation constant e aslow pressure relaxation constant e velocity resampling every Ips e non hydrogen solute atoms restrained Desmond 2 2 User Manual 21 Chapter 3 Running a Desmond Simulation from Maestro 22 6 Simulate in the NPT ensemble using a Berendsen thermostat and a Berendsen barostat with e a simulation time of 24ps e a temperature of 300K and a pressure of 1 atm e a fast temperature relaxation constant e anormal pressure relaxation constant This protocol is used for the NPAT and NPyT ensembles as well A similar protocol is used for the NVT ensemble The protocol files can be found in SCHRODINGER mmshare vversion data desmond The procedure follows a similar pattern as for NPT I
105. in your browser You can navigate to topics in the navigation bar The Help menu also provides access to the manuals including a full text search the FAQ pages the New Features pages and several other topics If you do not find the information you need in the Maestro help system check the following sources e Maestro User Manual for detailed information on using Maestro e Maestro Command Reference Manual for information on Maestro commands Maestro Overview for an overview of the main features of Maestro Maestro Tutorial for a tutorial introduction to basic Maestro features e Desmond Quick Start Guide for a tutorial introduction to Desmond e Desmond User s Guide from D E Shaw Research for details of command line opera tion file formats and technical background Desmond 2 2 User Manual 137 Getting Help 138 e Desmond Frequently Asked Questions pages at https www schrodinger com Desmond_FAQ html e Known Issues pages available on the Support Center The manuals are also available in PDF format from the Schr dinger Support Center Local copies of the FAQs and Known Issues pages can be viewed by opening the file Suite_2009_Index html which is in the docs directory of the software installation and following the links to the relevant index pages Information on available scripts can be found on the Script Center Information on available software updates can be obtained by choosing Check for Upda
106. ional Group Mutation In ligand mutation a group on the ligand molecule called the substitution group is replaced with selected fragments These fragments are chosen from a list of small predefined frag ments The fragments can be adjusted to reduce steric clashes and can be modified by using the tools on the Build toolbar or in the Build panel The FEP calculations for ligand mutation are set up in the Ligand Functional Group Mutation by FEP panel which you open by choosing Desmond from the Applications menu then choosing Ligand Functional Group Mutation by FEP To run a ligand mutation job 1 Include in the Maestro Workspace the system that contains the ligand to be mutated the receptor protein optional and any other key molecules of the system This step can be performed prior to opening the panel 2 Select Pick the attachment bond then pick the attachment bond in the Workspace at the end toward the substitution group This bond is the bond at which the substitution will take place When the bond is picked a green arrow is drawn over the bond pointing to the substitution group and the ligand core is colored with green carbons If you clicked on the wrong end of the bond click again to correct the error Once focus is returned to the panel this option is deselected 3 In the Fragment library table select the fragments that you want to use to replace the orig inal substitution group by selecting their table rows Us
107. jobs setting this keyword to false can result in earlier completion of the job Default true File name of the final output structure file This keyword is only effective when set in the last stage and the setting can be overwritten by the o option of multisim The title for the stage Default no title B 2 2 Desmond Specific Common Keywords The stages that run Desmond directly minimize replica_exchange and simulate accept a common set of keywords in addition to keywords specific to the Desmond task Desmond 2 2 User Manual Appendix B The multisim Utility Keywords for the config file the interaction and setting the number of CPUs are listed in Table B 2 Table B 2 Keywords for Desmond specific stages Keyword Description cfg_file Config file cfg that provides the default values for simulation This option is not required and is usually used to customize simulations beyond the keywords supported by multisim cfg_overwrite Settings to override the values given in the config file Specifies a block in Ark syntax that contains the desired settings cutoff_radius Cutoff radius for the short range interactions in angstroms Default 9 A coulomb_method Long range Coulomb interaction treatment Allowed values are pme use smooth particle mesh Ewald cutoff use cutoff only Default pme cpu Number of processors to use and optional topology If given as a single integer the topology is determined automaticall
108. lated using the real space part of the Ewald sum only approximation that still gives reasonable energetics For instance the chemical potential of bulk TIP4P water using this approach is around 7 17 kcal mol The solvate_pocket utility uses the concept of a pass which is roughly 1 translation rota tion move for each molecule being sampled This can be useful because 1 pass is very roughly Desmond 2 2 User Manual 85 Chapter 9 Utilities 86 equivalent to a MD time step in terms of the amount of sampling for small molecules like water The passes can include insertion and deletion moves as well Both types of moves are required in order to equilibrate the number of water molecules in the system 9 1 2 Command Syntax The syntax of the solvate_pocket command is as follows SCHRODINGER utilities solvate_pocket spd command file icms input cms file ocms output cms file 1mae ligand file Here command file is the name of the command file for solvate_pocket which has the extension spd and is described in Section 9 1 3 input cms file and output cms file are the input and output CMS composite model system files and usually have a cms extension The optional ligand file is a file containing the ligand If it is present it is used to define the subre gion for solvation By default the maximum and minimum x y and z values in the command file are used The solvate_pocket utility is run under Job Control by defa
109. ling Default 1 20 Desmond 2 2 User Manual 119 Appendix C The Desmond Configuration File 120 Table C 16 Keywords for the Ber_NPT barostat section Keyword Description tau Pressure relaxation time Default 2 0 kappa Compressibility Default 4 5e 5 min_contraction_per_step Lower bound for home box rescaling Default 0 95 max_contraction_per_step Upper bound for home box rescaling Default 1 10 Table C 17 Keywords for the L_NVT and L_NPT thermostat sections Keyword Description tau Velocity relaxation time Default 0 016129 seed Random seed Default 2007 C 3 7 The mdsim Section The keywords for the mdsim section are listed in Table C 18 This section has one subsection whose keywords are listed in Table C 19 Table C 18 Keywords for the mdsim section Keyword Description title Title required for plugins Default Desmond Simulation last_time End time for simulation Default 1200 0 plugins List of plugins used Default status randomize_velocities eneseq trajectory maeff_output maeff_snapshot simbox_output checkpt Checkpoint configuration section Table C 19 Keywords for the mdsim checkpt section Keyword Description name Checkpoint file name Default jobname cpt first First checkpoint time Default 0 0 interval Simulation time between checkpoints Default 240 0 Desmond 2 2 User Manual Appendix C The Desmond Configuration File C 3 8 The minimize Section
110. llowing statement section name section contents In general section contents consists of a number of keyword value statements The concept of values includes not only a number or a string but also a block or a list A block is one or more settings within a pair of braces For example a b 3 ce 4 where a is set to the block value b 3 c 4 that contains two settings A list is a sequence of values that is enclosed by a pair of square brackets For example a 35 where a is set toalist 3 5 that contains two values Elements of a list do not have to be of the same type Here are some examples of valid lists 1 string 5 a list consisting of an integer a string and an integer lta 1 35 a list consisting of an integer the block a 1 and another integer LP 2 2 1 3 a list consisting of the list 1 2 followed by two integers Hierarchical expressions involving blocks and lists help elucidate the relationships within the data You can also set the values of variables within a hierarchy without reference to the whole data structure For example a b 3 40 can be written as aip 3 ase 4 Desmond 2 2 User Manual 111 Appendix C The Desmond Configuration File 112 The Ark standard specifies that if the same parameter is assigned two different values the second one will be used If the value is a block the blocks are merged and parameters present in each block are a
111. lue feature that can signifi cantly reduce this problem by wrapping associated molecules together This feature is on by default and can be turned off by including the following at the end of the config file gui should_glue false Desmond 2 2 User Manual 127 128 Desmond 2 2 User Manual Appendix D Analyzing a Simulation from the Command Line This appendix documents the command line usage of two related Python scripts and the syntax of two file formats used for analysis of a simulation The two Python scripts are simulation_block_data py and simulation_block_test py and are located in the directory SCHRODINGER mmshare vversion 1lib Linux x86 lib python2 6 site packages schrodinger application desmond These scripts can be run with the SCHRODINGER run command D 1 simulation_block_data py This command determines simulation properties from the input 1og file and block averages from the input ene file and writes the results to the output sba file The syntax is as follows simulation_block_data py n block length s simboxfile e enefile 1 logfile c sbafile The options are described in Table D 1 Table D 1 Options for the simulation_block_data py command Option Description e enefile Input ene file name from a simulation No default 1 logfile Input 1log file name from a simulation No default c sbafile Output sba file name No default n block length Input block length in ps for
112. m the trajectory to a file or create project entries from the structures Opens the Export Structure dialog box in which you can specify where the structures will go and which structures to export e Image Create an image of the Workspace with the current frame displayed Opens the Save Image panel e Movie Save a movie of the trajectory in MPEG format Opens the Export Movie panel in which you can select the frames to be exported the speed and the resolution Desmond 2 2 User Manual 55 Chapter 5 Analyzing Simulations 56 _ 7 Simulation Quality Analysis Job base name scr dyall 4q21_md 2 4q21_md 2 Browse Analyze Plot Block length for averaging 100 ps m Simulation summary Properties Job name liscr dyali 4q21_ Job progress Normal Average Std Dev Slope ps 1 Duration ns ass Total energy kcal mol 71990 43 jaza r06 joz Degrees of freedom j5 ooo Potential energy kcal mol 81018 85 72 297 ooo Molecules Bf Temperature K 300 040 joe76 jaooo Atoms ZA Pressure bar 1 067 jegsz2 0 003 Target temp K 3000 Volume Ar 243435 3 286 031 0 005 Ensemble type MTK_NPT Close Help Figure 5 2 The Simulation Quality Analysis panel If you want to view a trajectory while a simulation is running you can do so by importing the jobname out cms file for the simulation from the host on which the simulation is running
113. mbda Section for setting up lambda schedule For the force gibbs lambda section the schedules are lists of lambda values e g 0 0 0 14 0 28 0 42 0 57 0 71 0 85 1 0 1 0 1 0 1 0 1 0 All lists in this section must be of the same length or empty Table C 7 Keywords for the force gibbs lambda section Keyword Description vdw Van der waals schedule for absolute FEP Must be set to for relative FEP coulomb Coulomb schedule for absolute FEP Must be set to for relative FEP vdwA Vdw schedule of initial structure for relative free energy Must be set to for absolute FEP vdwB Vdw schedule of final structure for relative free energy Must be set to for absolute FEP Desmond 2 2 User Manual 115 Appendix C The Desmond Configuration File 116 Table C 7 Keywords for the force gibbs lambda section Keyword Description chargeA Charge schedule of initial structure for relative free energy Must be set to for absolute FEP chargeB Charge schedule of final structure for relative free energy Must be set to for absolute FEP bondedA Bonded terms schedule of initial structure for relative free energy Must be set to for absolute FEP bondedB Bonded terms schedule of final structure for relative free energy Must be set output name output first output interval to for absolute FEP Name of the FEP data file Example fep dE Simulation time to start writing FEP data Simulation
114. mber of counter ions necessary to neutralize the system is added 6 3 6 Solvating the System This command is used to initiate the solvation of the current solute structure which includes the ions and the membrane solvate The keyword solvate is used to solvate the current solute structures using the solvent system defined in the solvent_desmond_oplsaa_typer section The solvent system is extended to be consistent with the boundary condition defined by the boundary_conditions or create_boundary_conditions section Any solvent molecules that overlap the solute structures are removed 6 3 7 Writing the Output File This command is used to write the output to a maeff Maestro force field file otherwise known as a composite model system CMS file which has the extension cms write_maeff_file filename The keyword write_maeff_file writes the current composite structures and their force field parameters into a file in CMS format The first structure contains all of the molecules in the system and is usually referred to as the full system CT The structures or CTs that follow it contain different components of the system For instance there usually is a solute structure a solvent structure containing all of the solvent molecules and structures for different types of ions There may also be a structure that contains solvent molecules that are extracted from the solute The force field parameters are inserted as ffio_ff block
115. mmon scenarios e Mutation of ligand functional groups a group attached to a ligand by a single bond is mutated to some other group e Aromatic ring atom substitution an atom with its attached hydrogens is mutated into another atom usually a heteroatom Protein residue mutation the side chain of a protein residue is mutated into that of another residue In these three scenarios the binding free energy of the ligand can be calculated For the first two the solvation free energy of the ligand relative to the original ligand can be calculated Total absolute solvation free energies can also be calculated for a ligand or a molecule which is done by annihilating the chosen molecule in the FEP simulation Free energy perturbation calculations are resource intensive While it is possible with the FEP panels to set up multiple mutations in a single calculation we recommend that only one muta tion be performed per calculation due to the resource requirements 4 1 FEP Panels The FEP panels are designed to make setting up FEP jobs as easy as possible most of the computational details such as setting the force field parameters solvation relaxation of the system and simulation time are taken care of automatically These predetermined parameters for the FEP calculations should work for most systems but you can also write out the input files and then modify the simulation parameters in the FEP panel see Section 4 8 on page 50 No
116. n Restraints output Misc Trajectory directory JOBNAME_trj Trajectory title Desmond Simulation OBNAME Recording starting time ps 0 0 M Record velocities Glue close solute molecules together Gluing affects only display of trajectory and has no effect on physics of the simulation Checkpoint file JOBNAME cpt Recording starting time ps 0 0 interval ps 240 0 M Monitor structural change in simulation Monitoring file JOBNAME mon maegz aj Monitoring starting time ps 0 0 interval ps 1 2 Eir Apply Cancel Help Figure 3 10 The Output tab of the Advanced Options dialog box Desmond 2 2 User Manual Chapter 3 Running a Desmond Simulation from Maestro Molecular Dynamics Advanced Options Integration Ensemble Interaction Restraints Output Misc r M Randomize velocities Random number seed 2007 Target temperature K 300 Randomize starting time ps 0 0 interval ps Inf r Atom group OK Apply Cancel Help Figure 3 11 The Misc tab of the Advanced Options dialog box 3 8 7 The Misc Tab This tab provides access to various options that do not fit into the other categories In this tab you can initialize the velocities using a random number and a target temperature and specify atom groups for special treatment in the simulation Select Initialize velocities to initi
117. nd functional group mutation protein residue mutation and ring atom mutation these values are displayed in Maestro as dG jobname and recorded in the file as s_des_dG_jobname where jobname is the name for the multisim job and usually ends in _vacuum _solvent or _complex for the corresponding environments vacuum pure solvent and complex These values are strings rather than real numbers because they include the estimated uncertainty To obtain a relative solvation free energy subtract the vacuum result from the solvent result Similarly relative binding free energies are calculated by subtracting the solvent result from the complex result You can use the script calculate_ddg py to take the difference between the values in two different environments to provide a AAG value To run this script use the following command SSCHRODINGER run FROM desmond calculate_ddg py jobnamel out mae Jobname2 out mae output file mae where jobnamel out mae and jobname2 out mae are the Maestro output structure files from the two FEP calculations The output file output file mae is optional the default name is ddG mae This file is in Maestro format and contains the AG value from both input files The final AAG value is recorded for each mutant as an entry property s_des_ddG_jobnamel Jobname2 which is displayed in the Project Table as ddG jobnamel jobname2 The atom coor dinates in the output file are copied from the first input structure file 4 7 2 T
118. ne 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 Desmond 2 2 User Manual x Desmond 2 2 User Manual Chapter 1 Introduction Desmond is a new explicit solvent molecular dynamics program developed by D E Shaw Research Desmond was created from scratch with an emphasis on accuracy speed and scal ability It supports many of the most sought after features in a modern molecular dynamics program including Highly scalable parallel execution Explicit solvent simulations with periodic boundary conditions using cubic orthorhom bic and triclinic simulation boxes Truncated octahedron and rhombic dodecahedron are supported via their triclinic analogues Support for isotropic semi isotropic and anisotropic pressure coupling Smooth particle mesh Ewald method for accurate and efficien
119. ng interval ensemble class and model system relaxation are the same as for a molecular dynamics simulation and are described in Section 3 4 on page 20 The default ensemble for replica exchange is NVT The main specific task for replica exchange is to provide information on the exchange scheme temperature range and temperature profile There are two exchange scheme options e nearest neighbor allow exchange only between replicas that are adjacent in tempera ture e random allow exchange between randomly chosen replicas In the Exchange attempt text boxes you can set the starting time and the interval for making exchanges in ps The first exchange occurs at the specified starting time and thereafter at the specified interval The temperature range is set in the Temperature range text boxes The defaults are 300 K for the low temperature and 800 K for the high temperature There are three options for the temperature profile e quadratic Set the temperatures by quadratic interpolation between the minimum and maximum with the high temperature at the maximum of the quadratic curve e linear Set the temperatures by linear interpolation between the maximum and the mini mum Desmond 2 2 User Manual 25 Chapter 3 Running a Desmond Simulation from Maestro 26 e manual Set the temperatures manually by editing the temperatures in the replica table When you select this option the table becomes editable Information
120. nge tpp n Specify the number of threads per processor Some examples of running desmond from command line are shown below 1 Running a 4 processor job on a queuing system or a particular machine myhost SSCHRODINGER desmond HOST myhost P 4 c x cfg in x cms 2 Running a 4 processor job on two different machines host and host2 SSCHRODINGER desmond HOST host1 2 host2 2 P 4 c x cfg in x cms 3 Continuing a 4 processor simulation from a checkpoint file x cpt SSCHRODINGER desmond HOST myhost P 4 restore x cpt 4 Running a minimization job on a queuing system or a particular machine ahost SSCHRODINGER desmond HOST ahost c x cfg in x cms exec minimize 5 Running an energy calculation with an existing trajectory on a queuing system or a par ticular machine myhost SSCHRODINGER desmond HOST myhost c x cfg in x cms exec vrun 6 Running a replica exchange simulation in which each replica uses 2 processors with the same input cms file Desmond 2 2 User Manual 61 Chapter 6 Running Desmond Simulations from the Command Line 62 desmond P 4 c x cfg t 300 t 310 in x cms exec remd 7 Running a replica exchange simulation in which each replica uses 2 processors with dif ferent input cms files desmond P 4 c x cfg t 300 in x300 cms t 310 in x310 cms exec remd 8 Restarting a replica exchange simulation from a checkpoint file x cpt d
121. nge the total simulation time and then start the job 3 3 Minimizations Minimization jobs relax the system into a local energy minimum The minimization task performs minimization of the model system using a hybrid method of the steepest decent and the limited memory Broyden Fletcher Goldfarb Shanno LBFGS algorithms This task is set up in the Minimization panel which you open by choosing Applications gt Desmond gt Minimiza tion in the main window There are only two parameters that can be set for this task e Maximum iterations Enter the maximum number of iterations in this text box or use the arrow buttons to change the maximum number of iterations in steps of 10 e Convergence Threshold Enter the convergence threshold for the gradient in units of kcal mol AT _ Minimization r Model system Load from Workspace Load The system contains 1496 atoms and was set up for non FEP simulations r Simulation Maximum iterations 200 Convergence threshold kcal mol A 11 0 Advanced Options Desmond Developed by D E Shaw Research Start Read Write Reset Close Help Figure 3 1 The Minimization panel Desmond 2 2 User Manual 19 Chapter 3 Running a Desmond Simulation from Maestro 20 a Molecular Dynamics ES r Model system Load from Workspace Load The system contains 1496 atoms and was set up for non FEP simulations
122. not be run for them By default the number of lambda windows is 12 and gui selected_lambda_winissetto 0 1 2 3 4567891011 Ensure that you set force gibbs fec_type to alchemical for relative free energy calculations or ligand_binding for absolute free energy calculations Running an FEP job with N windows using an automatically generated schedule is much simpler You can create a config file that has the following contents force gibbs n_windows N force gibbs fec_type alchemical gui selected_lambda_win 0 123 N 1 Desmond 2 2 User Manual Appendix C The Desmond Configuration File and use the cfg option of multisim to specify this cfg file C 5 2 Replica Exchange To customize REMD you will need to provide a remd top level section In addition you should add the following at the end of the cfg file gui remd temperature 300 0 350 0 400 0 450 0 500 0 600 0 700 0 800 0 global_cell n_replica 8 C 5 3 Simulated Annealing You will need to provide a config file for simulated annealing that contains the mdsim anneal and integrator anneal sections In addition you should include anneal in the list of plugins assigned to the mdsim plugins parameter and set integrator type to anneal C 5 4 Instructing Desmond to Glue Close Solute Molecules Together Periodic boundary conditions can wrap associated solute moleucles separately such that they appear on opposite sites of the simulation box Desmond has a g
123. nts Tabuan tale ink 33 3 8 6 The Output Tab mairinn aka eae ai nee 33 3 87 The Mise Talia scunig pneu Maas 35 3 9 Running a Simulation Job 240snnensenennnnenennnnnnnnennnnnnnnnnnnnnnnnnnnn 36 Chapter 4 Running FEP Simulati ons ana a a a 39 4 1 FEP Panels 2 u 2 2 anne nee el 39 4 2 Ligand Functional Group Mutation 04nnnnennnennennennennnnnnnnnnn 40 4 3 Ring Atom Mutation een ETE ra AE ETE 42 4 4 Protein Residue Mutation 00 cee eeeseesesseeseeeeeeeeeaeeeesaecseeseeseeeaeeaesaeeaeeeetens 44 4 5 Total Solvation Free Energy Calculation ennennnnnennn 46 4 6 Selecting the Environment and FEP Protocol 47 4 7 FEP Results esi signs annie cane i eneinia nade nici ale Ran 49 4 7 1 Relative Free Energy Differences 0 0 eee eeseeeceeseeeeeeseeesneeeeeseeseeeseneeneeeeees 49 4 7 2 Total SolWationsFree Energie S wisi anni enge 49 4 8 Customizing and Restarting FEP Simulations en 50 Chapter 5 Analyzing Simblalions nes 53 5 1 Viewing Trajeto S eia e eE E E ERTER 53 5 2 Simulation Quality Analysis 04u0nenenennnnenennennnnnnnnnennnnnnnnnnnnnnnnn 56 Desmond 2 2 User Manual Contents Chapter 6 Running Desmond Simulations from the Command See eer Dn CMe ton et ee ena even Ss eer nombre Onna cee Oneonta ae ney 59 6 1 The desmond Command 4nnrsenennennenennnnennnnnennnnnnnnnnnnnnnnennnnnnn
124. number of steps minimization remd Sets parameters for replica exchange molecular dynamics REMD simula REMD simulations tion vrun Sets parameters for analysis runs analysis C 3 1 The boot Section The boot section contains a single keyword file which specifies the name of the input cms file This keyword is overwritten by the Desmond driver script C 3 2 The constraint Section The keywords for the constraint section are listed in Table C 2 Table C 2 Keywords for the constraint section Keyword Description tol Convergence tolerance Default 1e 8 maxit Maximum number of iterations Default 8 C 3 3 The Desmond Section The Desmond section contains a single keyword config_version which gives the config file format version Desmond 2 2 User Manual 113 Appendix C The Desmond Configuration File C 3 4 The force Section The keywords for the force section are listed in Table C 3 This section contains subsections whose keywords are described in Table C 4 Table C 7 Table C 3 Keywords for the force section Keyword Description Required type Type of routine for calculating forces Allowed values desmond gibbs Use gibbs for FEP simulations nonbonded Section for nonbonded settings Optional average_dispersion Used to calculate energy and virial corrections due to cutoff Example 69 5 bonded_terms The set of bonded terms stretch angle dihedral improper pair cmap gibbs Section for setting up FE
125. o our knowledge Desmond 2 2 User Manual References 30 31 32 33 34 35 36 37 38 39 40 Jensen K P Jorgensen W L J Chem Theory Comput 2006 2 1499 Jacobson M P Kaminski G A Friesner R A Rapp C S J Phys Chem B 2002 106 11673 Berendsen H J C et al in Intermolecular Forces edited by B Pullman Reidel Dordrecht 1981 p 331 Berendsen H J C Grigera J R Straatsma T P J Phys Chem 1987 91 6269 Jorgensen W L Chandrasekhar J Madura J D Impey R W Klein M L J Chem Phys 1983 79 926 Parameters as tabulated in Mahoney M W Jorgensen W L J Chem Phys 2000 112 8910 Neria E Fischer S Karplus M J Chem Phys 1996 105 1902 Jorgensen W L Madura J D Mol Phys 1985 56 1381 Parameters as tabulated in Mahoney M W Jorgensen W L J Chem Phys 2000 112 8910 Horn H W Swope W C Pitera J W Madura J D Dick T J Hura G L J Chem Phys 2004 120 9665 Mahoney M W Jorgensen W L J Chem Phys 2000 112 8910 Earl D J Deem M W Phys Chem Chem Phys 2005 7 3910 Patriksson A van der Spoel D A temperature predictor for parallel tempering simula tions Phys Chem Chem Phys 2008 10 2073 Desmond 2 2 User Manual 135 136 Desmond 2 2 User Manual Getting Help Schr dinger software is distributed with documentation in PDF format If the do
126. olvent molecules and align ment of proteins to a membrane bilayer if used This procedure is often tedious if it has to be performed manually Tools for all these tasks are provided with Maestro Protein and ligand structures used in a Desmond simulation must be complete all atom 3D structures with a reasonable geometry The preparation of protein and ligand structures for use in a simulation can be done with the Protein Preparation Wizard and LigPrep The Protein Preparation Wizard corrects structural defects adds hydrogen atoms assigns bond orders and can selectively assign tautomerization and ionization states and optimize the hydrogen bonding network For more information see the Protein Preparation Guide LigPrep performs 2D to 3D conversion if necessary adds hydrogen atoms generates tautomers ionization states ring conformations and stereoisomers as requested and produces minimized 3D struc tures For more information see the LigPrep User Manual Once you have prepared the protein and ligand structures you can proceed to the remaining tasks in building a model system that can include proteins ligands explicit solvent a membrane and counter ions The System Builder automates this process and significantly reduces the effort required You can set up and run a System Builder job from the System Builder panel or from the command line See Chapter 9 for information on running the System Builder from the command line To open th
127. om the master job does not exceed 6 on the compute host 6 2 2 Sample MultiSim Job msj File An example msj file is given below The file syntax is described in full in Appendix B The file is modular consisting of a series of stages each of which contains a list of keywords and value settings enclosed within braces Lines beginning with are comments and hence are ignored Desmond standard NPT relaxation protocol All times are in the unit of ps Energy is in the unit of kcal mol task task desmond auto minimize max_steps 2000 steepest_descent_steps 10 convergence 50 0 cfg_overwrite minimize maeff_snapshot interval inf restrain atom solute force_constant 50 0 Desmond 2 2 User Manual Chapter 6 Running Desmond Simulations from the Command Line minimize max_steps steepest_descent_steps convergence cfg_overwrite minimize maeff_snapshot simulate 2000 10 interval inf time S012 timestep 0 001 0 001 0 003 ensemble NVT_Ber NPT NPT_Ber NVT NVT_Ber NVE temperature 10 0 thermostat_relaxation Si resampling period 12 0 cfg_overwrite integrator remove_com_motion true mdsim maeff_snapshot interval inf mdsim checkpt first inf mdsim eneseq interval 0 3 restrain atom solute_heavy_atom force_constant 50 0 simulate time 12 ensemble NPT_Ber NPT NPT_Ber NVT NVT_Ber NVE temperature 10 0 the
128. on tab of the System Builder panel e Custom Import a custom solvent system from file Enter the solvent system file name in the text box or click Browse and navigate to the solvent system file in the file selector that is displayed The solvent is placed by replicating boxes of solvent molecules and deleting molecules whose center of mass lies outside the periodic box boundary and molecules that are inside or have significant overlap with the solute or the membrane if one is used 2 2 Setting Up the Boundary Box The periodic boundary conditions are set up by specifying the shape and size of the repeating unit or box which you can do in the Solvation tab To set up the box first choose the shape from the Box shape option menu Three basic shapes are provided Cubic Orthorhombic and Triclinic As special cases of the triclinic box shape three other shapes are supported Truncated octahedron Rhombic dodecahedron xy square and Rhombic dodecahedron xy hexagon Desmond 2 2 User Manual Chapter 2 Building a Model System _ Desmond Set Up Membrane Membrane model Predefined DPPC 325K 2 Custom Transmembrane atoms ASL optional res num 209 554 AND res sec strand _ Select Place Automatically Place on Prealigned Structure Adjust membrane position Save Membrane Position to Selected Entries Load Membrane Position from Selected Entry OK Can
129. on type from the option menu 2 3 4 If the solvent is intended to be a salt solution select Add salt 5 Enter the desired salt concentration in the Salt concentration text box 6 Choose positive and negative ion types from the Salt positive ion and Salt negative ion option menus To add a membrane 1 Click Add Membrane in the Solvation tab 2 Inthe Membrane tab select Predefined for the membrane model and choose a membrane type from the option menu 3 Click Place Automatically 4 Select Adjust membrane position and adjust the orientation of the membrane in the Work space 5 Click OK Click Start to run the job or click Write to write the input file Desmond 2 2 User Manual 15 16 Desmond 2 2 User Manual Chapter 3 Running a Desmond Simulation from Maestro The general Desmond panels enable you to set up and run the main tasks available with Desmond molecular dynamics minimization simulated annealing and replica exchange jobs The panels are designed to make setting up these types of jobs as easy as possible and provide the most common simulation controls The default values provided in the panels repre sent a good balance between accuracy and performance and are adequate for most jobs without change For more control over the simulation parameters you can make settings in the Advanced Options dialog box which is described in Section 3 8 on page 27 A much more automated approach is provided f
130. ond stage is a minimization of the system over a maximum of 2000 steps Of the 2000 steps the first 10 steps are be steepest descent The convergence criterion is set rather loosely to 50 0 kcal mol t The solute is restrained with a force constant of 50 0 kcal mol The monitor file is not updated The third stage is similar except that nothing is restrained Desmond 2 2 User Manual Chapter 6 Running Desmond Simulations from the Command Line The fourth stage sets up a 12 ps Berendsen NVT simulation For this simulation the tempera ture is set to 10 0 K and the thermostat relaxation is set to 0 1 ps Resampling is done every 1 ps The solute atoms are restrained Checkpointing and structure monitoring are turned off Center of mass motion is removed and the ene file is updated more frequently at intervals of 0 3 ps Subsequent simulation stages follow with progressively more freedom until the second last stage when conditions resemble the production run The last stage is the production dynamics simulation The simulation parameters could have been explicitly listed here as in the preceding stages In this example this stage simply refers to a Desmond cfg file The last line gives an example of how this msj file could be run You would need to change the options for the job More examples can be found in the SCHRODINGER mmshare vversion data desmond directory Detailed information on the syntax of msj files is available
131. or FEP simulations of binding and solvation free energies in four specialized panels Ligand Functional Group Mutation by FEP Ring Atom Mutation by FEP Protein Residue Mutation by FEP and Total Free Energy by FEP for which a model system and the additional parameters are set up automatically These panels and the FEP panel for restarting and customizing these jobs are described in Chapter 4 In addition to setting up simulations you can use the general panels to restart a simulation from a checkpoint file as generated by a previously interrupted simulation All jobs run from these panels require a model system to be built first in the System Builder panel see Chapter 2 for details Desmond simulations can also be run from the command line see Chapter 6 3 1 Overview of the General Desmond Panels The general Desmond panels have two main sections Model system in which the model system is chosen and Simulation in which the parameters for the task are set up The controls in the Simulation section depend on the panel Specifying a model system is described in Section 3 2 on page 18 and the various tasks are described in the subsequent sections At the bottom of the panel are the action buttons for the job e Start Start the job Opens the Start dialog box to set job parameters and submit the job for execution See Section 3 9 on page 36 for details A general description of this dialog box and its features is given in Section 2 2
132. or the type of calculation requested If the first stage is not a task stage Multisim inserts a task stage and issues a warning The inserted task stage has the task parameter set to desmond auto or mcpro auto The task stage has only one keyword task whose allowed values are listed in Table B 4 Table B 4 Values of the task keyword Value Description desmond regular Non FEP Desmond job desmond fep Desmond absolute or relative free energy FEP job desmond afep Desmond absolute free energy FEP job desmond auto Desmond job whose type is determined from the input structure file mcpro auto MCPRO job whose type is determined from the input structure file mcpro fep MCPRO FEP job B 2 6 The system_builder Stage Keywords for the system_builder stage are listed in Table B 5 The keywords restrain Section B 2 3 on page 101 and atom_group Section B 2 4 on page 102 can also be used in this stage When they are used the settings are persistent they apply to all subsequent stages unless explicitly overridden by another system_builder stage Desmond 2 2 User Manual 103 Appendix B The multisim Utility 104 Table B 5 Keywords for the system_builder stage Keyword Description csb_file distil_solute solvate_system neutralize_system buffer_width rezero_system box_shape solvent Input composite system builder csb file This option is not required and is usually used to customize sys
133. ord can be one of the following create_boundary_conditions cubic a create_boundary_conditions orthorhombic a bc create_boundary_conditions triclinic a b c alpha beta gamma The parameters are similar to those for the absolute box size but the distances are the minimum distance any solute atom and the box boundary in the given direction The distance between two images of the solute structures is therefore twice the specified values If a membrane is used the box shape must be orthorhombic and the a and b values must be set to zero so that solvent molecules are not placed within the membrane layers Desmond 2 2 User Manual Chapter 6 Running Desmond Simulations from the Command Line 6 3 4 Setting Force Field Information The command set_oplsaa_version can be used to specify OPLSAA version Currently only OPLS_2005 value 2005 is supported set_oplsaa_version 2005 6 3 5 Setting the Number and Location of lons The addition of ions to the system is governed by several keywords add_ion ion_location exclude_ion_from add_salt and neutralize Two commands using the keyword add_ion can be used to add specific numbers of positive and negative ions add_ion positive 5 add_ion negative 5 The keyword add_ion adds positive or negative ions to the system The number of ions to be added is specified as the second argument of this keyword The ion_location keyword can be used to specify the proximity of ions with reference to cert
134. ord Description auxiliary_file List of files containing extra modlues to be transferred to the runtime direc tory command Command to execute once for each subjob of the previous stage The com mand specifies Python code that can span multiple lines command_once Command to execute once for the previous stage The command specifies Python code that can span multiple lines B 2 11 The fep_analysis Stage Keywords for the fep_analysis stage are listed in Table B 10 Table B 10 Keywords for the fep_analysis stage Keywords Description bennett random_seed Random seed for the Bennett method Default 2111839 correct_vdw Calculate the long range dispersion correction for absolute free energy jobs This keyword has no effect for relative free energy jobs Default true correct_restr Calculate the enthalpic correction for position restraints This parameter does no harm if the production simulations have no restraints Default true Desmond 2 2 User Manual 109 110 Desmond 2 2 User Manual Appendix C The Desmond Configuration File C 1 General Structure Desmond configuration files config files for short adhere to the Ark format from D E Shaw Research and have the extension cfg The definitive description of this format is avail able in the Desmond User s Guide This format is also used by multisim msj files Config files are composed of a number of sections that are usually delimited with the fo
135. otal Solvation Free Energies The total absolute free energies calculated by Desmond are recorded in the output structure file as structure level properties for the solute structures The property names are s_des_dg_jobname_transfer and s_des_dg_jobname_solvation The former the transfer free energy uses the same concentration in both the vacuum and solution phases while the latter the solvation free energy uses standard state concentrations in the two phases 1 bar in vacuum and 1 Molal or 1 mole of solute per kg of solvent in solution When charged molecules are deleted or created in absolute free energy calculations finite size effects can be significant particularly for the pure solvent FEP calculations A script Desmond 2 2 User Manual 49 Chapter 4 Running FEP Simulations 50 calculate_correction py has been provided to provide a correction to the free energy once the FEP calculation is complete To run this script use the following command SSCHRODINGER run FROM desmond calculate_correction py jobname data dir where jobname is the name of the A 0 simulation job for the original FEP calculation e g myfepjob_complex_4_lambda0 This program assumes the input and output file names are derived from jobname Specifically this program looks for the following files and directories Jobname in cms jobname in cfg and jobname_trj jobname in cms and jobname in cfg must be the input files of the simulation and jobn
136. over only e Chain length e Update frequency The Barostat method option menu also offers four choices Martyna Tobias Klein Berendsen Langevin and None For each of these methods you can set the relaxation time ps in the Relaxation time text box choose a coupling style from the Coupling style option menu and set a reference pressure in the Reference pressure text box The coupling style choices are Isotropic Semi isotropic and Anisotropic For the Berendsen barostat you can also enter the compressibility in the Compressibility text box Desmond 2 2 User Manual Chapter 3 Running a Desmond Simulation from Maestro Minimization Advanced Options Minimization Interaction Restraints Misc Minimizer The method used is steepest descent SD until the gradient threshold is reached then LBFGS LBFGS vectors 3 Maximum step size A 0 005 Minimum SD steps 10 Gradient threshold kcal mol A 25 0 Output Final structure file JOBNAME out cms Monitor structural change in minimization OK Apply Cancel Help Figure 3 7 The Minimization tab of the Advanced Options dialog box 3 8 3 The Minimization Tab In this tab you can set parameters for the minimization and also specify the output file Mini mization is performed with the LBFGS method with an optional steepest descent initial phase The Minimizer section provides the following controls e LBFGS vectors Specify th
137. p with it are removed to accommodate the solute If you click Place Automatically after adjusting the membrane the membrane is returned to its default position and orientation The membrane position and orientation can be stored in Project Table entries by selecting the entries in the Project Table and clicking Save Membrane Position to Selected Entries This enables the membrane position and orientation to be loaded at a later time by selecting the entry and clicking Load Membrane Position from Selected Entry If you have a related well equilibrated membrane bound protein system you can use the mold_gpcr_membrane py script to replace the protein with a new protein See Section 9 4 on page 90 for details 2 4 Using Custom Charges If you want to use partial charges from a source other than the force field you can do so by selecting Use custom charges in the Solvation tab You can then choose from one of the predefined properties on the Predefined option menu or enter the name of the property that defines the custom charges in the Custom text box The property name is the internal name which should start with r_ i e a real valued property For example the property r_j_ESP_Charges selects Jaguar generated ESP charges When you have selected the property click Select to select the atoms for which these charges are to be used There is no default The selection is made in the Atom Selection dialog box which is described in detail in
138. process As a result adjustment of the surface area of the solute membrane system is often needed This can usually be done using a fairly short semi isotropic simulation of up to about 0 5ns When simulating beyond that time range it is recommended to switch to either a constant surface area constant normal pressure simula tion NPAT or a constant surface tension simulation NPYT If the latter is selected we suggest using a surface tension of 2000 bar A for DPPC and 4000 bar A for POPE and POPC We recommend examining the results of all membrane simulations carefully It can be difficult to relax freshly built protein membrane systems In particular penetration of the water between the protein than the lipids can be problematic and require very lengthy simu lations to correct A relaxation protocol desmond_membrane_relax msj is available from the command line that should reduce or eliminate such problems To use the membrane relaxation protocol 1 Copy desmond_membrane_relax msj to your working directory from the directory SCHRODINGER mmshare vversion data desmond Desmond 2 2 User Manual Chapter 3 Running a Desmond Simulation from Maestro 2 Save your newly built protein membrane system in a CMS file referred to here as pro tein membrane cms 3 Run the membrane relaxation protocol using the command SCHRODINGER utilities multisim JOBNAME protein membrane HOST localhost host myhost cpu cpus i protein membr
139. r in the CPUs text box However if you enter a number that is not a power of 2 the actual number of processors used is the largest power of 2 that is smaller than the number you entered The number of processors actually used is displayed in the details section To hide the details click the Details button again It is possible to use a decomposition that is not in powers of 2 when running from the command line see the Desmond User s Guide Before you can run Desmond jobs in parallel you must perform the necessary configuration of the hosts file and any queues that you want to use Details are given in Chapter 6 of the Instal lation Guide Desmond 2 2 User Manual Chapter 3 Running a Desmond Simulation from Maestro 7 Molecular Dynamics Start Output Incorporate Append new entries Master job Multiple simulations to run Each simulation will be run as a subjob Name desmond_job Username dyall Host localhost 1 F Use the subjob host Subjob Host ravanque 16 CPUs subjob 8 Details lt lt The system will be domain decomposed as follows x 2 yl2 z 2 Actually needs 8 CPUs subjob Maximum simultaneous subjobs 0 Start Cancel Figure 3 12 The Start dialog box Desmond 2 2 User Manual 37 38 Desmond 2 2 User Manual Chapter 4 Running FEP Simulations Maestro provides panels for quickly setting up FEP simulations for certain co
140. rmostat_relaxation 0 1 barostat_relaxation 50 0 resampling_period S130 cfg_overwrite integrator remove_com_motion true mdsim maeff_snapshot interval inf mdsim checkpt first inf mdsim eneseq interval 023 restrain retain simulate time 24 Desmond 2 2 User Manual 65 66 ensemble NPT_Ber thermostat_relaxation 0 545 barostat_relaxation 50 0 resampling_period 1 0 cfg_overwrite integrator remove_com_motion mdsim maeff_snapshot interval mdsim checkpt first mdsim eneseq interval restrain retain simulate time 24 ensemble NPT_Ber thermostat_relaxation Scy E barostat_relaxation S250 cfg_overwrite integrator remove_com_motion mdsim maeff_snapshot interval mdsim checkpt first mdsim eneseq interval a simulate cfg_file example cfg jobname SJOBNAME dir nee compress me Job launching command NPT NPT_Ber NVT NVT_Ber NVE true inf inf NPT NPT_Ber NVT NVT_Ber NVE true inf inf SSCHRODINGER utilities multisim JOBNAME example HOST master_job_host host subjob_host maxjob 0 cpu 2 2 2 i example cms m example msj cfg example cfg o example out cms In the above example the first stage task specifies the type of job that is run so that appro priate defaults can be set In this case desmond auto indicates that it is a Desmond job and that the type of job should be detected automatically The sec
141. rom the list that you want to use to replace the original To open the list click the arrow button The arrow changes direction and the list is dis played To close it click the arrow button again Repeat Step 4 and Step 5 for as many mutations as you want to perform You can pick the same residue multiple times to mutate it to different residues If you pick different residues each residue that you pick is mutated Click Generate Mutants The table is filled with the mutations that you have defined For each of the original resi dues that you picked all possible combinations of mutations are added to the table For example if you picked two different residues and for each you specified three substi tutes the table would list nine mutations corresponding to each possible combination In the mutants table select the mutations that you want to use by selecting their table rows Use shift click and control click to select multiple table rows You can view the mutated ligand by clicking in the View column Once the residue is displayed you can reorient the side chain with the adjustment tools which are available from the Adjust toolbar button i or with the local transformation tools which are available from the Local transformation toolbar button G Desmond 2 2 User Manual 45 Chapter 4 Running FEP Simulations 46 10 11 For more information on these tools see Section 4 8 and Section
142. roup Clicking this button adds a row to the table e Delete Deletes the selected groups This operation can only be done on user defined groups e Reset Resets the table to its default state 3 9 Running a Simulation Job Once you have finished making settings you can click Start to set up the job parameters and run the job or you can click Write to write out the input files and run the job from the command line For information on running from the command line see Chapter 6 When you click Start the Start dialog box opens The common features of this dialog box such as the Output section the Name Username and CPUs text boxes and the Host option menu are described in Section 2 2 of the Job Control Guide These features allow you to direct the job to the appropriate host with the desired number of processors and decide how to incor porate the output into the Maestro project For Desmond jobs the choice of the number of processors has some special requirements Desmond uses a Cartesian domain decomposition of the simulation for efficient processing This decomposition is described in the Desmond User s Guide provided by D E Shaw Research The details of the decomposition can be displayed in the Start dialog box by clicking the Details button You can control the decomposition by entering values in the x y and z text boxes The values you enter must be a power of 2 The decomposition is done automatically if you enter a numbe
143. s within each CT block structure except the first The coordinate origin of the structures is by default the center of mass of the solutes Desmond 2 2 User Manual Chapter 7 Using VMD for Desmond Trajectories VMD 7 is a powerful program for visualizing molecular dynamics simulations that is avail able from the Theoretical and Computational Biophysics Group at the University of Illinois at Urbana Champaign A plugin for Desmond is provided as part of VMD that makes it possible for VMD to read and write Maestro files and read Desmond trajectories The output Maestro files are suitable for use in building model systems that can then be used to run Desmond This chapter contains information on reading a CMS file and a Desmond trajectory into VMD and writing a Maestro file from VMD For information on installing VMD see Section 3 9 of the Installation Guide To start VMD enter the command vmd Two windows are opened VMD main and VMD version OpenGL Display The former can be used to control VMD while the latter can be used to display the molecular systems and to view trajectories VMD has extensive documentation which is available from the Help menu in the VMD main window 7 1 Reading a CMS File and a Desmond Trajectory This section describes how to read a Maestro CMS file and a Desmond trajectory into VMD To view a Desmond trajectory in VMD you must first read in the output structure CMS file from a Desmond simulation T
144. se Help Figure 4 6 The FEP panel You can specify the parameter for the soft core potential used to eliminate van der Waals singularities in the Soft core parameter text box It is not normally necessary to change this value The number of lambda windows you want to use can be entered in the Number of windows text box Each window is listed in the table below with values for each of the six lambda parame ters Van der Waals Charge Charge and Bonding for the two systems labeled A and B You can set the lambda values automatically which is the default or you can deselect Set lambda values automatically and edit the values for each window and each type of lambda The lambda values must be within the range 0 1 The background color of the cell is changed to pink if the value is out of range to warn that it must be set within the range Desmond 2 2 User Manual 51 Chapter 4 Running FEP Simulations 52 The windows can be selected or deselected for the simulation using the buttons in the Window index row You can also use the Select All Windows and Deselect All Windows buttons to select all windows or clear the selection For a new FEP job all windows should normally be selected for simulation If a simulation for a particular lambda window needs to be re run select only that window Desmond 2 2 User Manual Chapter 5 Analyzing Simulations 5 1 Viewing Trajectories You can play through traje
145. seeaeteeteaes 82 8 6 KNOWN ISSUCS 4 icine pci ee es ee cn ee 83 Desmond 2 2 User Manual Contents vi Chapter 9 UN Sic nannte etw 85 941 S0lvatezD cket nu na een ne ret rence errr eters try cere 85 9 1 1 Methodology a 4422020 soesnesesancacencvas scenceeesieenesvecneantiusacenmseensbarttencnenstbenecees 85 9 1 2 Command Syn nella el br 86 9 1 3 Command File Syn yasni lese te AAE aiie Aaa A AA eiiiai 86 9 2 manipulate tr PVa sense aenwi AnA 89 9 3 amber pim2emS Py sczc iacsicsaciascsacslecscesaesans edacescesnsastaces sesaaeadeacesopacanadedecheescaaeandassees 90 9 4 mold_gpcer_membrane py uurrsrsnnanesnennnannannnnnnnsonannnannnnannennnonennnannannn 90 9 5 TOCECONNIGIPY ache Rees 91 Appendix A Creating a CMS File from a Full System Maestro File 93 Appendix B The multisim LH sank 95 B 1 Running MultiSim usss NAR 95 B 1 1 Template multisim Commands cs 2 sc2 sa chcicesesccdesteescceisaectecsneedasaestcnenntandeceens 95 B 12 Node LOCKING an ur Re RRMA RHE RR AR 96 B 1 3 Restarting multisim Jobs aka 96 B 1 4 Obtaining Information from multisim Checkpoint Files 4u 97 B 2 Theimultisim Hile Synlax u unruusmesrsnanenenan een 98 Bi2 1 General Keywords u innen 100 B 2 2 Desmond Specific Common Keywords z2224442nrnnnn nn nnnnnnnnnnnennon nennen 100 B 2 3 ThefestrainiKeyW rd unse ek 101 B 2 4 The atom group KeyWord i i ccacsncrn an
146. smond to Glue Close Solute Molecules Together 127 Appendix D Analyzing a Simulation from the Command Line 129 D 1 Sim lation block data Py oaeen perch cceenishiatienyeiniieenehdenandan 129 D 2 simulation block test py orrera onnenn 130 D 3 Simulation Block Analysis sba File Syntax eenn 130 D 4 Simulation Block Test sbt File Syntax eneenenennenen 131 REOLEN O Se ancotsnaniniminncetinnineamnniadaninamineminemaaieiainin 133 Getting Fel een 137 Desmond 2 2 User Manual vii viii Desmond 2 2 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 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 o
147. solvent calculations 7 Click Start set the job parameters in the Start dialog box and click Start in the dialog box to run the job 4 3 Ring Atom Mutation Ring atom mutation changes a selected ring atom to a different atom type while preserving the hybridization of the atom To run a ring atom mutation job 1 Include in the Maestro Workspace the system that contains the ligand to be mutated the receptor protein optional and any other key molecules of the system This step can be performed prior to opening the panel 2 Select Pick the ring atom then pick the ligand atom to be mutated in the Workspace Desmond 2 2 User Manual Chapter 4 Running FEP Simulations gt Ring Atom Mutation by FEP Lol Define Perturbation Plan Calculation Step 1 Display the ligand and its receptor if any in the pa Workspace Step 2 Pick the ring atom on the ligand to mutate Pick the ring atom Step 3 erg the targets which the ring atom will be mutated Mutation targets 4 items 1 item selected Target t N S O NH r Desmond Developed by D E Shaw Research Start Write Reset Close Help Figure 4 2 The Ring Atom Mutation by FEP panel Define Perturbation tab When the atom is picked it is rendered in ball and stick and the ligand is colored with green carbons The Mutation targets table is displayed Once fo
148. ssigned the values from the latter block The symbol can be omitted if the value is a block value This means that a b 1 and a b 1 are equivalent Lines starting with a character are treated as comments C 2 Units The units used in the configuration file are e time ps e distance angstroms e energy kcal mol e pressure bar e surface tension bar angstroms e temperature kelvin Boolean values must be set to either true or false Time can be specified as a positive real number or as the string inf meaning infinity or never C 3 Configuration File Sections Table C 1 lists the supported top level sections for the configuration file These sections are described in the document sections and tables below Table C 1 Top level sections Section Name Description Job Type boot Sets parameters for booting the backend all constraint Sets parameters for contraints all Desmond Provides general information about Desmond all force Sets parameters related to interactions amongst the atoms all Desmond 2 2 User Manual Appendix C The Desmond Configuration File Table C 1 Top level sections Continued Section Name Description Job Type global_cell Provides information for domain decomposition all integrator Sets parameters for integrating the equations of motion simulation incl REMD mdsim Sets parameters for simulations e g duration simulation minimize Sets parameters for minimizations e g
149. t evaluation of long range electrostatics NVE NVT NPT NPAT NPyT ensembles with Berendsen Langevin or Nos Hoover thermostats and Berendsen Langevin or Martyna Tobias Klein barostats Symplectic integration of the equations of motion using a multiple time step approach RESPA Elimination of many sources of numerical error permitting accurate and fast calculations using single precision arithmetic Accurate implementation of constraints to eliminate high frequency motions and thus permit larger time steps Exploitation of modern computer chip features to enhance speed SIMD Efficient calculation of the pressure Accurate checkpointing mechanism for continuing or restoring simulations Template based support for widely used force fields using viparr Viewing of trajectories with VMD using a Desmond plug in A description of Desmond was published along with performance data as part of the confer ence proceedings of the ACM IEEE Conference on SuperComputing 2006 SC06 1 While developing Desmond D E Shaw Research has introduced and extended a number of scientific Desmond 2 2 User Manual Chapter 1 Introduction algorithms including new parallelization strategies and numerical techniques some of which have been published 2 5 Problem solving often involves using a wide range of modelling techniques so integrating Desmond into Schr dinger s premier molecular modelling suite for drug development enhances th
150. t have only the factors 2 3 and 5 Desmond 2 2 User Manual 95 Appendix B The multisim Utility 96 e the value for maxjob which is used to specify how many subjobs can be queued at the same time for FEP jobs The value 0 means all subjobs B 1 2 Node Locking Node locking involves requiring all subjobs to run on the same nodes CPUs as the master job Node locking can be turned on by adding mode umbrella to the command line This feature can be useful on busy computer systems that are controlled by a queuing system because only the master process is submitted to the queuing system All subjobs will then run on the nodes allocated to the master process without being resubmitted to the queuing system When this option is given the host option is ignored Node locking is not supported for FEP jobs B 1 3 Restarting multisim Jobs The multisim job periodically writes out a checkpoint file which records the current state of the workflow The checkpoint file is named jobname multisim_checkpoint This file does not include data produced by subjobs The checkpoint file is copied back to the job launch directory when the master job stops In most cases the multisim job can be restarted with a command similar to the following S SCHRODINGER utilities multisim r myjob multisim checkpoint d myjob_stage out tgz JOBNAME myjob where you specify the checkpoint file with the r option and the out tgz file of the l
151. t 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 If Maestro fails an error report that contains the relevant information is written to the current working directory The report is named maestro_error txt and should be sent to help schrodinger com A message giving the location of this file is written to the terminal window More information on the postmortem command can be found in Appendix A of the Job Control Guide Desmond 2 2 User Manual 139 140 Desmond 2 2 User Manual 120 West 45th Street 17th Floor 101 SW Main Street Suite 1300 8910 University Center Lane Suite 270 New York NY 10036 Portland OR 97204 San Diego CA 92122 Zeppelinstra e 13 Dynamostra e 13 Quatro House Frimley Road 81669 M nchen Germany 68165 Mannheim Germany Camberley GU16 7ER United Kingdom SCHR DINGER
152. t placed in the excluded regions Instead of placing ions automatically at random you can locate and select suitable regions for ions to be placed Usually these regions are near residues that have the same charge as the system charge and are not near the active site You can define these regions in the Advanced lon Placement dialog box which you open by clicking Advanced lon Placement in the lons tab To place the ions you must identify suitable candidate residues When you click Candidates the Candidates table is populated with a list of residues in regions that have not been excluded and have the same charge as the overall charge of the system These residues are colored red and rendered in CPK Ions are placed near the residues that you select in the table replacing the closest solvent molecule to the average position of the atoms in the residue The number of ions placed initially 0 along with the number of ions remaining to be placed and the total number of candidate residues are displayed above the table You can add candidates to the table by clicking New and selecting the residues in the Atom Selection dialog box When you click OK in the dialog box the residues are added to the table and can be selected along with the automatically located residues To clear the table click Reset When the system builder job is run ions that are placed using the Advanced lon Placement dialog box are placed first Once these ions are placed ran
153. te that checkpoint files are not written out for the relaxation stages The panels for these calculation types have a common design Each panel has a Define Pertur bation tab in which you set up the systems to be simulated and a Plan Calculation tab in which you choose the environment complex pure solvent vacuum for the ligand and choose the FEP protocol which includes the ensemble Information on setting up the system is contained in the next few sections followed by a section describing the Plan Calculation tab Desmond 2 2 User Manual 39 Chapter 4 Running FEP Simulations The panels have action buttons at the bottom e Start Opens the Start dialog box in which you can set the job parameters such as job name host number of CPUs and so on and then start the job The general layout of this dialog box is described in Section 2 2 of the Job Control Guide The Desmond specific features of the Start dialog box and the issues in choosing the number of CPUs are described in Section 3 9 on page 36 e Write Writes the input files for the job but does not start the job Opens a dialog box in which you can specify a job name which is used to name the files This capability is use ful if you want to change the FEP protocol e Reset Resets the entire panel to its initial state This includes clearing the Workspace If you want to use the same structures you will have to redisplay them before proceeding 4 2 Ligand Funct
154. tem building beyond the keywords supported by multisim Move water molecules from the solute entry CT to a separate entry CT Allowed values are true false For non aqueous solvents use asl ASL expression to specify the solvent mole cule Default true Solvate the system Allowed values are true false Default true Add counter ions to neutralize the system Allowed values are true false Default true Minimum distance between the box edge and solute in Ang stroms Default 10 0 A Reset the origin of the coordinates to the center of mass of the solutes Allowed values are true false Default true Specifies the box shape Allowed values are cubic orthorhomibic triclinic Default cubic Solvent type Allowed values are SPC TIP3P TIP4P and TIP4PEW Default SPC B 2 7 The simulate and replica_exchange Stages The keywords that are specific to the simulate and the replica_exchange stages are listed in Table B 6 The keywords restrain Section B 2 3 on page 101 and atom_group Section B 2 4 on page 102 can also be used in this stage When they are used the settings are temporary they apply only to the current stage Table B 6 Keywords for the simulate stage Keyword Description barostat_relaxation coulomb_method ensemble Desmond 2 2 User Manual Relaxation time constant for barostat in picoseconds Default 2 0 ps Coulomb interactions Allowed values are pme cutoff Default pme
155. tes from the Maestro menu If you have questions that are not answered from any of the above sources contact Schr dinger using the information below E mail help schrodinger com USPS Schr dinger 101 SW Main Street Suite 1300 Portland OR 97204 Phone 503 299 1150 Fax 503 299 4532 WWW _ http www schrodinger com FTP ftp ftp schrodinger com 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 Desmond purchaser company research institution or individual e Primary Desmond user e Computer platform type e Operating system with version number e Desmond version number e Maestro version number e mmshare version number On UNIX you can obtain the machine and system information listed above by entering the following command at a shell prompt SSCHRODINGER utilities postmortem This command generates a file named username host schrodinger tar gz which you should send to help schrodinger com If you have a job that failed enter the following command SCHRODINGER utilities postmortem jobid Desmond 2 2 User Manual Getting Help where jobid is the job ID of the failed job which you can find in the Monitor panel This command archives job information as well as the machine and system information and includes input and output files bu
156. the Atom Selection dialog box to select the desired atoms For more information on this dialog box see Section 5 3 of the Maestro User Manual If you have a protein that is prealigned you can click Place on Prealigned Structure to place the membrane The membrane is positioned symmetrically about the coordinate origin so that its surfaces are parallel to the xy plane perpendicular to the z axis This means that the protein must be aligned accordingly When you have placed the membrane a representation of the membrane is displayed in the Workspace The representation consists of two red slabs for the surfaces with a yellow line perpendicular to the slab planes After the membrane has been placed you can adjust its orien tation by selecting Adjust membrane position and rotating the membrane The actual membrane molecules are placed when the system builder job is run The molecules are placed by replication of a membrane segment and deletion of molecules whose center of mass lies 1 The PDB files in this database have an invalid positioning of the remark fields for the membrane information and must be fixed before use To fix them you can use the command perl pi e s REMARK 1 2 REMARK 1 2 pdb Here there are two spaces after the first REMARK and five after the second Desmond 2 2 User Manual Chapter 2 Building a Model System outside the periodic box boundaries Molecules that are inside the solute or have significant overla
157. thermodynamically consistent manner solvate_pocket uses a grand canonical Monte Carlo approach to sample both the water molecule positions and the number of water molecules present by attempting to introduce or remove water molecules in a Metropolis like manner 9 1 1 Methodology In grand canonical methods a value of the chemical potential is set and the simulation samples the number of water molecules in a manner consistent with the chemical potential and the specified temperature In principle even the water in buried pockets is in equilibrium with bulk water and so one should conduct the simulation using the excess chemical potential for bulk water for TIP4P this is about 6 95 kcal mol The solvate_pocket utility samples the number and conformation of water molecules within an orthorhombic region of the simulation cell using grand canonical Monte Carlo GCMC in the muVT constant chemical potential volume and temperature ensemble As a short cut it does not use periodic boundary conditions other than to center the orthorhombic cell in the simulation prior to simulating water molecules in the sampled region As such the subregion sampled by solvate_pocket should be surrounded overall by bulk solution even if the sampled region itself is not fully solvated In its current form solvate_pocket expects a CMS file as input and produces a CMS file containing the final conformation of the system from the GCMC simulation Interactions are calcu
158. time interval for writing FEP data C 3 5 The global_cell Section The keywords for the global_cell section are listed in Table C 8 Table C 8 Keywords for the global_cell section Keyword Description Required keywords n_replica partition r_clone reference_time Optional keywords clone_policy Number of replicas Should be set to 1 except for replica exchange Grid dimensions for the home boxes The simulation box is divided into smaller boxes by partitioning the system in the a b and directions for domain decomposition parallelization The number of partitions on each axis must have only 2 3 and 5 as factors and must also divide evenly into the FFT grid size n_k see Table C 5 Example 4 4 4 Clone buffer radius Example 5 3125 Constant offset added to elapsed chemical time during simulation Allowed values rounded unrounded In most situations rounded is preferred est_n_atom_per_voxel Estimated number of atoms per particle array voxel est_p_dens Estimated required size of Desmond communication buffers Desmond 2 2 User Manual Appendix C The Desmond Configuration File C 3 6 The integrator Section The keywords for the integrator section are listed in Table C 9 Keywords for sections within this section are listed in the following tables Table C 9 Keywords for the integrator section Keyword Description center_frozen_group dt isotropy max_margin_contraction mi
159. to the number of processes o order Order of interpolation for particle mesh Ewald calculation in the pme order order range 4 7 Default 5 g gridsize Grid size for particle mesh Ewald calculation If the grid spacing is pme gridsize gridsize outside the range 0 6 3 6 is chosen based on the clamped spacing If cutoff is less than 9 then is chosen to satisfy erfc B r r lt 1e 6 where sqrt 0 5 o and r is the cutoff If cutoff is greater than 12 0 is chosen based on a cutoff of 12 Default 1 2 Desmond 2 2 User Manual Appendix A Creating a CMS File from a Full System Maestro File If you have a Maestro file that contains the entire system including solvent you can generate a CMS file that can be used in Desmond using the System Builder The procedure given below is useful when you have a system that was generated by another application First if the property s_ffio_ct_type is present you must edit the Maestro file and remove it To create a CMS file using the System Builder panel 1 2 3 4 5 Import the system into Maestro From the Applications menu choose Desmond then System Builder Set the Solvent model to None Select the appropriate box shape Specify the box size in one of the following ways e Set the Box size calculation method to Absolute size and type in the box dimensions e Set the Box size calculation method to Buffer and enter 0 0 for the buffer dist
160. u can specify restraints on atom positions A restraint is defined by a set of atoms and a force constant The restraints are listed in the restraints table The Atoms column is filled in automatically when you click Select and use the Atom Selection dialog box to specify the atoms You must enter the force constant in the table manually by editing the table cell To manage the restraints you can use the buttons beside the table e Select Opens the Atom Selection dialog box to specify the atoms for the selected restraint Only available if a single row is selected in the table e Add Adds a row to the restraints table so that a new restraint can be defined e Delete Deletes the selected restraints e Reset Resets the table to its default state 3 8 6 The Output Tab In this tab you can set names for various output files and set the times for which recording in these files begins and the update frequency For each file there is a starting time text box in which you can enter the starting time for recording of information to this file or adjust the starting time in increments of 50 times the far time step except for the checkpoint file where the increment is 5000 times the far time step Some files also have an interval text box in which you can enter or adjust the recording interval in the same increments as the starting Desmond 2 2 User Manual 33 Chapter 3 Running a Desmond Simulation from Maestro 34 time Th
161. uch 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 October 2009 Contents Document Conventions na eek ix Chapter 1 Introducti GN en 1 1 1 Installation and Configuration 24042442nsnnennennnnennennnnnnennnnnnnennnnn 2 1 2 The Maestro Interface to Desmond 4444emesnnnnnnnennennnenen nennen nennen 3 1 3 Desmond Calculations Overview eeeeseeisesieieisirisrsrsisrsrsrsisrsrersrsrersrsrsrsrsrnt 4 1 4 Citing Desmond in Publications 444404snnnnnnnnnnnnnennennennnnennennnnnn 5 Chapter 2 Building a Model System 7 2 1 Adding SOWGNE neren AA nenn 7 2 2 Setting Up the Boundary Box 4444nmnsenennennenennnnennnnnnnennnnnnnnnnnnnnnnan 8 2 3 Adding Membrane iioii nedeninin aiaa a a a 9 2 4 Using Custom
162. ugins The other files namely the templates file parameter files and rules file that specify a given force field are placed in a force field directory The force field directories for the built in force fields are located in the directory given by the environment variable VIPARR_FFDIR which should be set to SCHRODINGER desmond vversion data viparr The d m and p options described in Table 8 1 are provided for working with user defined force fields Desmond 2 2 User Manual Chapter 8 Using Alternate Force Field Parameters and Constraints 8 6 Known Issues Two or more geometrically identical hydrogen atoms such as in CH2 or CH3 are treated identically If the force field needs to treat them differently you must ensure that the residue name exactly matches the force field template name When you import a structure into Maestro make sure you correct any problems that Maestro detects especially those involving the atomic numbers of ions Desmond 2 2 User Manual 83 84 Desmond 2 2 User Manual Chapter 9 Utilities The Desmond distribution contains a number of utilities for performing a range of specific tasks apart from those described previously These utilities are described in this chapter 9 1 solvate_pocket The solvate_pocket utility is a tool for solvating subregions of a system with water and in particular to solvate buried regions in a protein or protein ligand complex To solvate such regions in a
163. ult A solvate_pocket run on a binding site that can contain around 15 water molecules about 450 can take between 10 minutes and an hour The cost of the simulation increases approx imately as the square of the number of water molecules sampled It is unlikely that solvate_pocket is needed to prepare systems for NPT simulations if there are no buried pockets 9 1 3 Command File Syntax The solvate_pocket utility uses a keyword value syntax that is at least nominally consis tent with Ark syntax This means that you can use the same keywords in both the solvate_pocket command file and in the solvate_pocket stage of the multisim input file Comments are lines that begin with a character Blank lines are ignored Strings are limited to 80 characters and must not contain a new line character The keywords are described in Table 9 1 Table 9 1 Keywords for the solvate_pocket utility Keyword Description chemical_potential The chemical potential of water in kcal mol Required Recommended 7 17 kcal mol for TIP4P cut_off The cutoff distance for calculating electrostatic and Lennard Jones inter actions in angstroms Required Recommended 9 0 A Desmond 2 2 User Manual Chapter 9 Utilities Table 9 1 Keywords for the solvate_pocket utility Continued Keyword Description init_num_passes max_dctheta max_disp max_dpsi name num_delete num_insert num_passes num_trans_rot pass_term_win
164. ultisim utility Option Description ADD_FILE filename cfg cfg file Cpu num cpus d stage file debug DEBUG description string h elp HELP host compute host HOST multisim host JOBNAME jobname max_retries maxretries maxjob maxjob mode mode o output file probe quiet set string v ersion verbose Additional input file to copy to the working directory of the multisim job By default multisim identifies and copies most files needed for the run File that contains the default Desmond config parameters This option is only useful for Desmond subjobs Number of CPUs for each Desmond subjob This can be a string indi cating the CPU topology e g 2 2 2 If this option is not provided a default value set by either the backend or the protocol will be used All CPU counts must be a power of 2 File containing information on the stages from the previous job when restarting a simulation Use one instance for each file Turn on multisim debug mode Turn on both multisim and Job Control debug modes Job description to print to the log file Print usage message and exit Host on which to run the subjobs Host to run the multisim master job Job name of this multisim job Maximum number of times to restart failed subjobs Maximum number of simultaneous subjobs Run in non default job management mode The only allowed value is umbrella for which subjobs run on the same no
165. um change used for phi and psi Euler angles in radians for a combined translation rotation move Default 0 318 max_dctheta The maximum change used for the cosine of theta Euler angle for a com bined translation rotation move in radians Default 0 0654 cut_off The cutoff distance for calculating electrostatic and Lennard Jones inter actions Default 9 0 A short_dist The closest acceptable approach for any two atoms Default 1 0 A chemical_potential The chemical potential of water in kcal mol Default 7 17 kcal mol for TIP4P B 2 10 The extern Stage The extern stage provides an extremely flexible way to include your own Python code in a multisim run The code can be embedded in the msj file as a string value assigned to the command keyword For example extern command import os def main current_stage job os system ls In the embedded Python code you can import and use modules from your Schr dinger Python installation If you need extra modules you can pass their file names to multisim by setting the auxiliary_file parameter and multisim transfers them to the scratch directory of the master job at run time For example extern auxiliary_file modi py mod2 py command import os import modl import mod2 def main current_stage job does something with mod1 and mod2 Desmond 2 2 User Manual 107 Appendix B The multisim Utility 108 os system ls
166. umber of Monte Carlo passes to perform in the equilibration prior to the production Monte Carlo run Default 10000 The number of Monte Carlo passes to perform in the production Monte Carlo run Default 100000 The number of passes between updates in the log file Default 100 The number of passes over which the slope of the standard deviation of the the number of water molecules is calculated This keyword may be used to terminate the calculations before the number of passes specified by num_passes has been completed The simulation portions will run for at least twice this duration before early termination occurs Default 100000 Threshold for the standard deviation of the number of water molecules The calculation is terminated if the standard deviation falls below this value Default 0 00001 The number of water molecule translations to attempt per pass This should be set to approximately the number of water molecules expected to reside in the region being sampled Default 100 The number of attempts to delete a single water molecule per pass Default 25 The number of attempts to insert a single water molecule per pass Default 25 Desmond 2 2 User Manual Appendix B The multisim Utility Table B 8 Keywords for the solvate_pocket stage Keyword Description max_disp The maximum change used in each of the x y and z directions for a com bined translation rotation move Default 0 105 A max_dpsi The maxim
167. ustomizing FEP simulations Examining the results including viewing a trajectory and analysis of results is described in Chapter 5 FEP jobs are handled differently due to the complexity of the calculations and the fact that the overall goal for an FEP job is to produce one number the free energy change FEP jobs are Desmond 2 2 User Manual Chapter 1 Introduction supported for specific types of calculations using automated procedures that differ from those used for individual general purpose Desmond simulations The basic outline of a Desmond simulation as run from Maestro is as follows 1 Import the structure file for the system of interest into Maestro 2 Prepare the structure for simulation with the Protein Preparation Wizard This step involves removing ions and molecules which are artifacts of crystallization setting cor rect bond orders adding hydrogens filling in missing side chains or whole residues as necessary reorienting various groups and varying residue protonation states to optimize the hydrogen bonding network and then checking the structure carefully 3 If your system is a membrane protein embed the protein in the membrane This step and the next two steps are performed in the System Builder panel 4 Generate a solvated system for simulation 5 Distribute positive or negative counter ions to neutralize the system and introduce addi tional ions to set the desired ionic strength when necessary
168. utility programs are provided in the SCHRODINGER utilities directory Desmond 2 2 User Manual 59 Chapter 6 Running Desmond Simulations from the Command Line 60 The syntax for the desmond command is as follows SCHRODINGER desmond options in cms file c config file SCHRODINGER desmond options restore checkpoint file Use the in option for a new job and the restore option for restarting a job The input file for a new job must be a CMS file with extension cms and a configuration file c g must also be specified For restarting a job a checkpoint file with extension cpt must be provided The options for the desmond command are listed in Table 6 1 The standard Job Control options are also supported see Section 2 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 For information on storage of temporary files interacting with running Desmond jobs and so on see the Job Control Guide Table 6 1 Options for the desmond command Option Description Job Options DEBUG Print diagnostic output LOGINTERVAL Interval for copying the log file back to the submission host Default 5s INTERVAL Interval for copying monitor files back to the submission host Default 5s
169. word can be used to define atoms groups within the cms file Atom groups can be frozen restrained or associated with particular thermostats The atom group is defined by the atom level property i_ffio_grp_name This keyword can be set to the following values e none Remove all atom groups e retain Keep all atom groups from the previous stage e atom atoms index i name name atom group block Put the specified Desmond 2 2 User Manual Appendix B The multisim Utility atoms in the atom group i that has the name name The atom keyword accepts the same values for atoms as the atom keyword for restrain described above The index i is the value for the i_ffio_grp_name property Desmond only supports index numbers from 0 to 7 e groupl group2 Specify multiple atom groups Each group can be specified as a block in the above format An atom group set in the system_builder stage is persistent which means that it remains defined in all subsequent stages until the next system_builder stage B 2 5 The task Stage The msj file should start with a task stage to specify the type of job Although Multisim can determine the type of job based on the input structure file provided this can lead to unpredict able behavior if the file was previously used by a different type of job Explicitly stating the job type avoids this problem and also permits Multisim to ensure that the input structure file provided is appropriate f
170. y To specify the topol ogy use the format n n2 n3 or nl n2 n3 For replica exchange this keyword specifies the processors to use for each replica Default 2 2 2 jlaunch_opt Options to add to the command to run Desmond The options are listed in Table 6 1 on page 60 Example dp turns on use of double pre cision B 2 3 The restrain Keyword The restrain keyword specifies the atom sets to be restrained Restraints set in all stages except the system_builder stage apply only to the current stage Restraints set in the system_builder stage are permanent they are inherited by all subsequent stages Perma nent restraints can be overridden in a particular stage but only to increase the restraint force constants They will still be applied in subsequent stages The restrain keyword supports the specific values listed in Table B 3 and also supports a block syntax and a list syntax Restraints can be specified using blocks and ASL expressions can be used to define the atoms that are restrained within restraint blocks The syntax is restrain atom atoms force_constant value reference_position retain reset where atoms can be solute solvent solute_heavy_atom or heavy_atom as before or an ASL expression prefixed by as1 For example Desmond 2 2 User Manual 101 Appendix B The multisim Utility 102 Table B 3 Specific allowed values of the restrain keyword Value Description heavy_atom
171. zation and simulation settings Easy simulation continuation and restoration e Optional automated relaxation and equilibration procedures Ligand Functional Group Mutation by FEP panel Ring Atom Mutation by FEP panel Protein Residue Mutation by FEP panel Total Free Energy by FEP panel Easy to use with a focus on the real problem of interest rather than the details of the cal culation e Support for absolute and relative solvation free energy calculations e Support for relative binding free energy calculations Restarting and customization of FEP jobs via FEP panel Trajectory Viewer panel e Integrated into Maestro e Comprehensive speed controls Desmond 2 2 User Manual 3 Chapter 1 Introduction e Replication of primary simulation box for viewing Easy creation of images and movies Simulation Quality Analysis panel e Intuitive tool for examining certain markers of simulation quality The use of these panels is described in subsequent chapters of this manual In addition the following tool is available from the Script Center Simulation Event Analysis panel e Intuitive tool for investigating what happened during a simulation Most Desmond related tools are available from the Desmond submenu of the Application menu in Maestro The exceptions are the trajectory viewer which is launched from the Project Table using the output entry for a job 1 3 Desmond Calculations Overview Desmond jobs should be start

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