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:

Jiang, Wei  ^[1];

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• Search DOE PAGES for ORCID "0000-0001-7707-6247"
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Thirman, Jonathan ^[1]; Jo, Sunhwan ^[1]; Roux, Benoît  ^[2]

• Search DOE PAGES for author "Roux, Benoît"
• Search DOE PAGES for ORCID "0000-0002-5254-2712"
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+ Show Author Affiliations

1. Argonne National Lab. (ANL), Argonne, IL (United States)
2. Univ. of Chicago, IL (United States)

Publication Date:

2018-09-25

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