A python workflow to set up BEDAM binding free energy calculations
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README.md
bedam.py
bedam_analyze.py
bedam_analyze_acflat.py
bedam_asyncre.py
bedam_prep.py
bedam_prep_ac.py
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README.md

	        BEDAM WORKFLOW  (v1.0)
	    =============================

	Emilio Gallicchio, emilio.gallicchio@gmail.com
	  	Junchao Xia, junchaoxia@hotmail.com
		  Ronald Levy, ronlevy@temple.edu 

Please acknowledge use of this software citing the following publication:

Gallicchio E, Lapelosa M, Levy RM. Binding energy distribution analysis method (BEDAM) for estimation of protein-ligand binding affinities. J Chem Theory Comput, 6, 2961-2977 (2010).

Copyright and Disclaimers

Copyright (c) 2010-2013

Emilio Gallicchio, emilio.gallicchio@gmail.com

Junchao Xia, junchaoxia@hotmail.com

Ronald Levy, ronlevy@temple.edu

License Agreement and Disclaimers

This software is licensed under GPL v.3.

http://www.gnu.org/licenses/gpl.html

See LICENSE in this directory.

Installation

Unpack the distribution in a directory of your choice. Dependencies includes numpy, and the MBAR python package of Michael Shirts and John Chodera downaloadable from http://simtk.org. These libraries should be installed where python can find them (for example by setting the PYTHONPATH env variable as appropriate)

Introduction

The BEDAM Binding Energy Distribution Analysis Method is an absolute binding free energy estimation and analysis methodology based on a statistical mechanics theory of molecular association and efficient computational strategies built upon parallel Hamiltonian replica exchange, implicit solvation and multi-state statistical inference. The method takes its name from the technique it employs to extract standard binding free energies from the statistical analysis of the probability distributions of the energies of association over a series of conformational ensembles connecting the bound and unbound states. The ability to carry out extensive conformational sampling is one of the main advantages of BEDAM over existing FEP and absolute binding free energies protocols in explicit solvent which suffer from limited exploration of conformational space. The method has been extensively used to estimate protein-ligand and host-guest binding free energies.

This python workflow facilitates the preparation and the analysis of BEDAM binding free energy calculations. It is designed to work with the IMPACT program within the Schrodinger computational environment and also the academic version. The workflow for commercial IMPACT works in three steps:

  1. System Preparation $SCHRODINGER/run bedam_prep.py bedam.cntl

  2. Launch equilibration and productions calculations $SCHRODINGER/impact -i _mintherm.inp -LOCAL $SCHRODINGER/impact -i _remd.inp -LOCAL

  3. Analysis $SCHRODINGER/run bedam_analyze.py bedam.cntl

A control file ('bedam.cntl' above) is used to specify parameters and settings. Examples for some of the main settings are:

 # path to MBAR for binding energy calculations
 MBAR_PATH '/home/tuf29141/software/bedam_workflow/pymbar-1.0d/pymbar'
 #name of receptor .mae file
 RECEPTOR_FILE 'bcy_noprop.maegz'
 #name of ligand .mae file
 LIGAND_FILE 'benzene.maegz'
 #list of lambdas for each replica (16 replicas, in this case). 
 #lambda=0 is the decoupled state, lambda=1 is the coupled state.
 #The binding free energy is the free energy difference between the lambda=1
 #and lambda=0 states plus a standard state correction term.
 LAMBDAS '0.0,0.001,0.002,0.004,0.005,0.006,0.008,0.01,0.02,0.04,0.07,0.1,0.25,0.5,0.75,1.0'
 #the atoms of the receptor and ligand that define their centroids. 
 #These are given in ASL (atom selection language). A flat-bottom
 #harmonic restraint (see below) on the centroid-to-centroid distance defines
 #the binding site region and keeps the ligand and the receptor together at
 #small lambdas.
 REST_LIGAND_CMRECASL '( all) AND NOT (( atom.ele H ) )'
 REST_LIGAND_CMLIGASL '( all) AND NOT (( atom.ele H ) )'
 #parameters of the flat-bottom harmonic restraints between the centroids
 #defined above.
 # force constant in kcal/mol/A^2 of receptor-ligand restraints
 REST_LIGAND_CMKF 3.0
 # equilibrium distance in Angstroms of receptor-ligand restraint
 REST_LIGAND_CMDIST0 0.0
 # distance tolerance in Angstroms of receptor-ligand restraint
 REST_LIGAND_CMTOL 6.0
 #the atoms of the receptor that are harmonically restrained
 REST_RECEPTOR_ASL '(not (atom.num 3, 5, 10, 11, 14, 16, 21, 22, 25, 27, 32, 33, 36, 38, 43, 44, 47, 49, 54, 55, 58, 60,
 65, 66, 69, 71, 76, 77 ) ) AND NOT (( atom.ele H ) )'
 # force constant of receptor atomic restraints in kcal/mol/A^2
 REST_RECEPTOR_KF 0.6
 #Temperature in K
 TEMPERATURE 300
 # number of equilibration MD steps
 EQUILIBRATION_STEPS 10000
 # number of production MD steps.
 PRODUCTION_STEPS 500000
 #Frequency of printing information in output file in number of steps. The number
 #of binding energy samples collected for each replica is
 #PRODUCTION_STEPS/PRNT_FREQUENCY = 500 in this case.
 #500 x 16replicas = 800 samples in total
 PRNT_FREQUENCY 1000
 # Frequency of saving trajectory frames. 500 frames per replica.
 TRJ_FREQUENCY 1000

The workflow takes as input .mae files of receptor and ligand, plus a definition (see above) of the binding site region in terms of a receptor-ligand restraint potential. Analysis of the results produce, among other things, the estimated values of the binding free energy.

See the 'examples' directory for other examples of usage for a host guest system using commercial or academic IMPACT. Similar procedures are used for protein-ligand receptors.