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Title: Reduced Free Energy Perturbation/Hamiltonian Replica Exchange Molecular Dynamics Method with Unbiased Alchemical Thermodynamic Axis

Abstract

We report that replica-exchange molecular dynamics (REMD) has been proven to efficiently improve the convergence of free energy perturbation (FEP) calculations involving considerable reorganization of their surrounding. We previously introduced the FEP/(λ,H)-REMD algorithm for ligand binding, in which replicas along the alchemical thermodynamic coupling axis λ were expanded as a series of Hamiltonian boosted replicas along a second axis to form a two-dimensional (2D) replica-exchange exchange map [Jiang, W.; Roux, B., J. Chem. Theory Comput. 2010, 6 (9), 2559-2565]. Aiming to achieve a similar performance at a lower computational cost, we propose here a modified version of this algorithm in which only the end-states along the alchemical axis are augmented by boosted replicas. The reduced FEP/(λ,H)-REMD method with one-dimensional (1D) unbiased alchemical thermodynamic coupling axis λ is implemented on the basis of generic multiple copy algorithm (MCA) module of the biomolecular simulation program NAMD. The flexible MCA framework of NAMD enables a user to design customized replica-exchange patterns through Tcl scripting in the context of a highly parallelized simulation program without touching the source code. Two Hamiltonian tempering boosting scheme were examined with the new algorithm: a first one based on potential energy rescaling of a pre-identified “solute”, and amore » second one via the introduction of flattening torsional free energy barriers. As two illustrative examples with reliable experiment data, the absolute binding free energies of pxylene and n-butylbenzene to the nonpolar cavity of the L99A mutant of T4 lysozyme were calculated. Lastly, the tests demonstrate that the new protocol efficiently enhances the sampling of torsional motions for backbone and side chains around the binding pocket and accelerates the convergence of the free energy computations.« less

Authors:
ORCiD logo [1];  [1];  [1]; ORCiD logo [2]
  1. Argonne National Lab. (ANL), Argonne, IL (United States)
  2. Univ. of Chicago, IL (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Advanced Scientific Computing Research (ASCR); National Institutes of Health (NIH)
OSTI Identifier:
1488538
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry
Additional Journal Information:
Journal Volume: 122; Journal Issue: 41; Journal ID: ISSN 1520-6106
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Jiang, Wei, Thirman, Jonathan, Jo, Sunhwan, and Roux, Benoît. Reduced Free Energy Perturbation/Hamiltonian Replica Exchange Molecular Dynamics Method with Unbiased Alchemical Thermodynamic Axis. United States: N. p., 2018. Web. doi:10.1021/acs.jpcb.8b03277.
Jiang, Wei, Thirman, Jonathan, Jo, Sunhwan, & Roux, Benoît. Reduced Free Energy Perturbation/Hamiltonian Replica Exchange Molecular Dynamics Method with Unbiased Alchemical Thermodynamic Axis. United States. doi:https://doi.org/10.1021/acs.jpcb.8b03277
Jiang, Wei, Thirman, Jonathan, Jo, Sunhwan, and Roux, Benoît. Tue . "Reduced Free Energy Perturbation/Hamiltonian Replica Exchange Molecular Dynamics Method with Unbiased Alchemical Thermodynamic Axis". United States. doi:https://doi.org/10.1021/acs.jpcb.8b03277. https://www.osti.gov/servlets/purl/1488538.
@article{osti_1488538,
title = {Reduced Free Energy Perturbation/Hamiltonian Replica Exchange Molecular Dynamics Method with Unbiased Alchemical Thermodynamic Axis},
author = {Jiang, Wei and Thirman, Jonathan and Jo, Sunhwan and Roux, Benoît},
abstractNote = {We report that replica-exchange molecular dynamics (REMD) has been proven to efficiently improve the convergence of free energy perturbation (FEP) calculations involving considerable reorganization of their surrounding. We previously introduced the FEP/(λ,H)-REMD algorithm for ligand binding, in which replicas along the alchemical thermodynamic coupling axis λ were expanded as a series of Hamiltonian boosted replicas along a second axis to form a two-dimensional (2D) replica-exchange exchange map [Jiang, W.; Roux, B., J. Chem. Theory Comput. 2010, 6 (9), 2559-2565]. Aiming to achieve a similar performance at a lower computational cost, we propose here a modified version of this algorithm in which only the end-states along the alchemical axis are augmented by boosted replicas. The reduced FEP/(λ,H)-REMD method with one-dimensional (1D) unbiased alchemical thermodynamic coupling axis λ is implemented on the basis of generic multiple copy algorithm (MCA) module of the biomolecular simulation program NAMD. The flexible MCA framework of NAMD enables a user to design customized replica-exchange patterns through Tcl scripting in the context of a highly parallelized simulation program without touching the source code. Two Hamiltonian tempering boosting scheme were examined with the new algorithm: a first one based on potential energy rescaling of a pre-identified “solute”, and a second one via the introduction of flattening torsional free energy barriers. As two illustrative examples with reliable experiment data, the absolute binding free energies of pxylene and n-butylbenzene to the nonpolar cavity of the L99A mutant of T4 lysozyme were calculated. Lastly, the tests demonstrate that the new protocol efficiently enhances the sampling of torsional motions for backbone and side chains around the binding pocket and accelerates the convergence of the free energy computations.},
doi = {10.1021/acs.jpcb.8b03277},
journal = {Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry},
number = 41,
volume = 122,
place = {United States},
year = {2018},
month = {9}
}

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Cited by: 15 works
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Figures / Tables:

Figure 1 Figure 1: Implementation of the reduced FEP/($λ$,H)-REMD method with 1D unbiased alchemical thermodynamic coupling implemented within the charm++ multiple partition module. Each square box represents an FEP/MD simulation with its own trajectory. A branch of four boosting-biasing replica (red) is attached to each of the two end FEP windows alongmore » the reversible work process, forming an extended thermodynamic axis. The biasing strength of boosting replicas linearly increases outward along the thermodynamic axis, illustrated with varying chroma of red color. The possible attempted moves, indicated by the dashed-line arrows, are only allowed between neighboring replicas. It needs to be noted that during the postprocessing phase only the outputs generated from the normal FEP windows (blue) are processed.« less

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Works referencing / citing this record:

On Restraints in End‐Point Protein–Ligand Binding Free Energy Calculations
journal, December 2019

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  • Ngo, Son Tung; Nguyen, Trung Hai; Tung, Nguyen Thanh
  • Journal of Computational Chemistry, Vol. 41, Issue 7
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journal, March 2020

  • Lima, Leonardo Henrique Franca de; Fernandez-Quintéro, Monica Lisa; Rocha, Rafael Eduardo Oliveira
  • Journal of Biomolecular Structure and Dynamics
  • DOI: 10.1080/07391102.2020.1734484

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