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Title: Free Energy Perturbation Hamiltonian Replica-Exchange Molecular Dynamics (FEP\H-REMD) for absolute ligand binding free energy calculations.

Abstract

Free Energy Perturbation with Replica Exchange Molecular Dynamics (FEP/REMD) offers a powerful strategy to improve the convergence of free energy computations. In particular, it has been shown previously that a FEP/REMD scheme allowing random moves within an extended replica ensemble of thermodynamic coupling parameters '{lambda}' can improve the statistical convergence in calculations of absolute binding free energy of ligands to proteins [J. Chem. Theory Comput. 2009, 5, 2583]. In the present study, FEP/REMD is extended and combined with an accelerated MD simulations method based on Hamiltonian replica-exchange MD (H-REMD) to overcome the additional problems arising from the existence of kinetically trapped conformations within the protein receptor. In the combined strategy, each system with a given thermodynamic coupling factor {lambda} in the extended ensemble is further coupled with a set of replicas evolving on a biased energy surface with boosting potentials used to accelerate the interconversion among different rotameric states of the side chains in the neighborhood of the binding site. Exchanges are allowed to occur alternatively along the axes corresponding to the thermodynamic coupling parameter {lambda} and the boosting potential, in an extended dual array of coupled {lambda}- and H-REMD simulations. The method is implemented on the basis of newmore » extensions to the REPDSTR module of the biomolecular simulation program CHARMM. As an illustrative example, the absolute binding free energy of p-xylene to the nonpolar cavity of the L99A mutant of the T4 lysozyme was calculated. The tests demonstrate that the dual {lambda}-REMD and H-REMD simulation scheme greatly accelerates the configurational sampling of the rotameric states of the side chains around the binding pocket, thereby improving the convergence of the FEP computations.« less

Authors:
;  [1]
  1. Biosciences Division
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Science Foundation (NSF)
OSTI Identifier:
1018895
Report Number(s):
ANL/BIO/JA-67686
Journal ID: 1549-9618; TRN: US201114%%400
DOE Contract Number:  
DE-AC02-06CH11357
Resource Type:
Journal Article
Journal Name:
J. Chem. Theory Comput.
Additional Journal Information:
Journal Volume: 6; Journal Issue: 9 ; Sep. 2010
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; CONVERGENCE; FREE ENERGY; HAMILTONIANS; LYSOZYME; MUTANTS; PROTEINS; REPLICAS; SAMPLING; SIMULATION; THERMODYNAMICS

Citation Formats

Jiang, W, Roux, B, and Univ. of Chicago). Free Energy Perturbation Hamiltonian Replica-Exchange Molecular Dynamics (FEP\H-REMD) for absolute ligand binding free energy calculations.. United States: N. p., 2010. Web. doi:10.1021/ct1001768.
Jiang, W, Roux, B, & Univ. of Chicago). Free Energy Perturbation Hamiltonian Replica-Exchange Molecular Dynamics (FEP\H-REMD) for absolute ligand binding free energy calculations.. United States. doi:10.1021/ct1001768.
Jiang, W, Roux, B, and Univ. of Chicago). Wed . "Free Energy Perturbation Hamiltonian Replica-Exchange Molecular Dynamics (FEP\H-REMD) for absolute ligand binding free energy calculations.". United States. doi:10.1021/ct1001768.
@article{osti_1018895,
title = {Free Energy Perturbation Hamiltonian Replica-Exchange Molecular Dynamics (FEP\H-REMD) for absolute ligand binding free energy calculations.},
author = {Jiang, W and Roux, B and Univ. of Chicago)},
abstractNote = {Free Energy Perturbation with Replica Exchange Molecular Dynamics (FEP/REMD) offers a powerful strategy to improve the convergence of free energy computations. In particular, it has been shown previously that a FEP/REMD scheme allowing random moves within an extended replica ensemble of thermodynamic coupling parameters '{lambda}' can improve the statistical convergence in calculations of absolute binding free energy of ligands to proteins [J. Chem. Theory Comput. 2009, 5, 2583]. In the present study, FEP/REMD is extended and combined with an accelerated MD simulations method based on Hamiltonian replica-exchange MD (H-REMD) to overcome the additional problems arising from the existence of kinetically trapped conformations within the protein receptor. In the combined strategy, each system with a given thermodynamic coupling factor {lambda} in the extended ensemble is further coupled with a set of replicas evolving on a biased energy surface with boosting potentials used to accelerate the interconversion among different rotameric states of the side chains in the neighborhood of the binding site. Exchanges are allowed to occur alternatively along the axes corresponding to the thermodynamic coupling parameter {lambda} and the boosting potential, in an extended dual array of coupled {lambda}- and H-REMD simulations. The method is implemented on the basis of new extensions to the REPDSTR module of the biomolecular simulation program CHARMM. As an illustrative example, the absolute binding free energy of p-xylene to the nonpolar cavity of the L99A mutant of the T4 lysozyme was calculated. The tests demonstrate that the dual {lambda}-REMD and H-REMD simulation scheme greatly accelerates the configurational sampling of the rotameric states of the side chains around the binding pocket, thereby improving the convergence of the FEP computations.},
doi = {10.1021/ct1001768},
journal = {J. Chem. Theory Comput.},
number = 9 ; Sep. 2010,
volume = 6,
place = {United States},
year = {2010},
month = {9}
}