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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. https://doi.org/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. 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. 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 referenced in this record:

Efficient Drug Lead Discovery and Optimization
journal, June 2009

  • Jorgensen, William L.
  • Accounts of Chemical Research, Vol. 42, Issue 6
  • DOI: 10.1021/ar800236t

The Many Roles of Computation in Drug Discovery
journal, March 2004


The statistical-thermodynamic basis for computation of binding affinities: a critical review
journal, March 1997


Calculation of Protein-Ligand Binding Affinities
journal, June 2007


Binding of Small-Molecule Ligands to Proteins: “What You See” Is Not Always “What You Get”
journal, April 2009


Alchemical free energy methods for drug discovery: progress and challenges
journal, April 2011

  • Chodera, John D.; Mobley, David L.; Shirts, Michael R.
  • Current Opinion in Structural Biology, Vol. 21, Issue 2
  • DOI: 10.1016/j.sbi.2011.01.011

Extension to the weighted histogram analysis method: combining umbrella sampling with free energy calculations
journal, March 2001


Calculation of Standard Binding Free Energies:  Aromatic Molecules in the T4 Lysozyme L99A Mutant
journal, July 2006

  • Deng, Yuqing; Roux, Benoît
  • Journal of Chemical Theory and Computation, Vol. 2, Issue 5
  • DOI: 10.1021/ct060037v

Predicting Absolute Ligand Binding Free Energies to a Simple Model Site
journal, August 2007

  • Mobley, David L.; Graves, Alan P.; Chodera, John D.
  • Journal of Molecular Biology, Vol. 371, Issue 4
  • DOI: 10.1016/j.jmb.2007.06.002

Confine-and-Release Method:  Obtaining Correct Binding Free Energies in the Presence of Protein Conformational Change
journal, May 2007

  • Mobley, David L.; Chodera, John D.; Dill, Ken A.
  • Journal of Chemical Theory and Computation, Vol. 3, Issue 4
  • DOI: 10.1021/ct700032n

Accurate and Reliable Prediction of Relative Ligand Binding Potency in Prospective Drug Discovery by Way of a Modern Free-Energy Calculation Protocol and Force Field
journal, February 2015

  • Wang, Lingle; Wu, Yujie; Deng, Yuqing
  • Journal of the American Chemical Society, Vol. 137, Issue 7
  • DOI: 10.1021/ja512751q

On achieving high accuracy and reliability in the calculation of relative protein-ligand binding affinities
journal, January 2012

  • Wang, L.; Berne, B. J.; Friesner, R. A.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 6
  • DOI: 10.1073/pnas.1114017109

Advancing Drug Discovery through Enhanced Free Energy Calculations
journal, July 2017


Glycoside Hydrolase Processivity Is Directly Related to Oligosaccharide Binding Free Energy
journal, December 2013

  • Payne, Christina M.; Jiang, Wei; Shirts, Michael R.
  • Journal of the American Chemical Society, Vol. 135, Issue 50
  • DOI: 10.1021/ja407287f

Nanoparticle–Protein Interactions: A Thermodynamic and Kinetic Study of the Adsorption of Bovine Serum Albumin to Gold Nanoparticle Surfaces
journal, November 2013

  • Boulos, Stefano P.; Davis, Tyler A.; Yang, Jie An
  • Langmuir, Vol. 29, Issue 48
  • DOI: 10.1021/la402920f

Predicting Adsorption Affinities of Small Molecules on Carbon Nanotubes Using Molecular Dynamics Simulation
journal, October 2015


The lag between the Hamiltonian and the system configuration in free energy perturbation calculations
journal, December 1989

  • Pearlman, David A.; Kollman, Peter A.
  • The Journal of Chemical Physics, Vol. 91, Issue 12
  • DOI: 10.1063/1.457251

Calculation of absolute protein-ligand binding free energy from computer simulations
journal, May 2005

  • Woo, H. -J.; Roux, B.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 19
  • DOI: 10.1073/pnas.0409005102

Absolute Binding Free Energy Calculations Using Molecular Dynamics Simulations with Restraining Potentials
journal, October 2006


Free Energy Perturbation Hamiltonian Replica-Exchange Molecular Dynamics (FEP/H-REMD) for Absolute Ligand Binding Free Energy Calculations
journal, July 2010

  • Jiang, Wei; Roux, Benoît
  • Journal of Chemical Theory and Computation, Vol. 6, Issue 9
  • DOI: 10.1021/ct1001768

Binding Energy Distribution Analysis Method: Hamiltonian Replica Exchange with Torsional Flattening for Binding Mode Prediction and Binding Free Energy Estimation
journal, April 2016

  • Mentes, Ahmet; Deng, Nan-Jie; Vijayan, R. S. K.
  • Journal of Chemical Theory and Computation, Vol. 12, Issue 5
  • DOI: 10.1021/acs.jctc.6b00134

Generalized scalable multiple copy algorithms for molecular dynamics simulations in NAMD
journal, March 2014

  • Jiang, Wei; Phillips, James C.; Huang, Lei
  • Computer Physics Communications, Vol. 185, Issue 3
  • DOI: 10.1016/j.cpc.2013.12.014

Sensitivity in Binding Free Energies Due to Protein Reorganization
journal, August 2016

  • Lim, Nathan M.; Wang, Lingle; Abel, Robert
  • Journal of Chemical Theory and Computation, Vol. 12, Issue 9
  • DOI: 10.1021/acs.jctc.6b00532

Specificity of ligand binding in a buried nonpolar cavity of T4 lysozyme: Linkage of dynamics and structural plasticity
journal, July 1995


On the use of orientational restraints and symmetry corrections in alchemical free energy calculations
journal, August 2006

  • Mobley, David L.; Chodera, John D.; Dill, Ken A.
  • The Journal of Chemical Physics, Vol. 125, Issue 8
  • DOI: 10.1063/1.2221683

Computation of Absolute Hydration and Binding Free Energy with Free Energy Perturbation Distributed Replica-Exchange Molecular Dynamics
journal, August 2009

  • Jiang, Wei; Hodoscek, Milan; Roux, Benoît
  • Journal of Chemical Theory and Computation, Vol. 5, Issue 10
  • DOI: 10.1021/ct900223z

Free energy calculations for DNA base stacking by replica-exchange umbrella sampling
journal, February 2004


Enhanced sampling of peptide and protein conformations using replica exchange simulations with a peptide backbone biasing-potential
journal, November 2006

  • Kannan, Srinivasaraghavan; Zacharias, Martin
  • Proteins: Structure, Function, and Bioinformatics, Vol. 66, Issue 3
  • DOI: 10.1002/prot.21258

Accelerated molecular dynamics: A promising and efficient simulation method for biomolecules
journal, June 2004

  • Hamelberg, Donald; Mongan, John; McCammon, J. Andrew
  • The Journal of Chemical Physics, Vol. 120, Issue 24
  • DOI: 10.1063/1.1755656

Accelerated molecular dynamics simulations of protein folding
journal, June 2015

  • Miao, Yinglong; Feixas, Ferran; Eun, Changsun
  • Journal of Computational Chemistry, Vol. 36, Issue 20
  • DOI: 10.1002/jcc.23964

Replica Exchange with Solute Scaling: A More Efficient Version of Replica Exchange with Solute Tempering (REST2)
journal, August 2011

  • Wang, Lingle; Friesner, Richard A.; Berne, B. J.
  • The Journal of Physical Chemistry B, Vol. 115, Issue 30
  • DOI: 10.1021/jp204407d

Replica-Exchange Accelerated Molecular Dynamics (REXAMD) Applied to Thermodynamic Integration
journal, September 2008

  • Fajer, Mikolai; Hamelberg, Donald; McCammon, J. Andrew
  • Journal of Chemical Theory and Computation, Vol. 4, Issue 10
  • DOI: 10.1021/ct800250m

Improved Reweighting of Accelerated Molecular Dynamics Simulations for Free Energy Calculation
journal, May 2014

  • Miao, Yinglong; Sinko, William; Pierce, Levi
  • Journal of Chemical Theory and Computation, Vol. 10, Issue 7
  • DOI: 10.1021/ct500090q

Scalable molecular dynamics with NAMD
journal, January 2005

  • Phillips, James C.; Braun, Rosemary; Wang, Wei
  • Journal of Computational Chemistry, Vol. 26, Issue 16, p. 1781-1802
  • DOI: 10.1002/jcc.20289

CHARMM-GUI Ligand Binder for Absolute Binding Free Energy Calculations and Its Application
journal, December 2012

  • Jo, Sunhwan; Jiang, Wei; Lee, Hui Sun
  • Journal of Chemical Information and Modeling, Vol. 53, Issue 1
  • DOI: 10.1021/ci300505n

CHARMM-GUI 10 years for biomolecular modeling and simulation: Biomolecular Modeling and Simulation
journal, November 2016

  • Jo, Sunhwan; Cheng, Xi; Lee, Jumin
  • Journal of Computational Chemistry, Vol. 38, Issue 15
  • DOI: 10.1002/jcc.24660

Constant pressure molecular dynamics simulation: The Langevin piston method
journal, September 1995

  • Feller, Scott E.; Zhang, Yuhong; Pastor, Richard W.
  • The Journal of Chemical Physics, Vol. 103, Issue 11
  • DOI: 10.1063/1.470648

CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields
journal, January 2009

  • Vanommeslaeghe, K.; Hatcher, E.; Acharya, C.
  • Journal of Computational Chemistry
  • DOI: 10.1002/jcc.21367

Avoiding singularities and numerical instabilities in free energy calculations based on molecular simulations
journal, June 1994


Separation‐shifted scaling, a new scaling method for Lennard‐Jones interactions in thermodynamic integration
journal, June 1994

  • Zacharias, M.; Straatsma, T. P.; McCammon, J. A.
  • The Journal of Chemical Physics, Vol. 100, Issue 12
  • DOI: 10.1063/1.466707

Improving the efficiency and reliability of free energy perturbation calculations using overlap sampling methods
journal, January 2003

  • Lu, Nandou; Kofke, David A.; Woolf, Thomas B.
  • Journal of Computational Chemistry, Vol. 25, Issue 1
  • DOI: 10.1002/jcc.10369

THE weighted histogram analysis method for free-energy calculations on biomolecules. I. The method
journal, October 1992

  • Kumar, Shankar; Rosenberg, John M.; Bouzida, Djamal
  • Journal of Computational Chemistry, Vol. 13, Issue 8
  • DOI: 10.1002/jcc.540130812

Generalized solvent boundary potential for computer simulations
journal, February 2001

  • Im, Wonpil; Bernèche, Simon; Roux, Benoı̂t
  • The Journal of Chemical Physics, Vol. 114, Issue 7
  • DOI: 10.1063/1.1336570

    Works referencing / citing this record:

    Ligand binding free energy and kinetics calculation in 2020
    journal, January 2020

    • Limongelli, Vittorio
    • WIREs Computational Molecular Science, Vol. 10, Issue 4
    • DOI: 10.1002/wcms.1455

    Oversampling Free Energy Perturbation Simulation in Determination of the Ligand‐Binding Free Energy
    journal, December 2019

    • Ngo, Son Tung; Nguyen, Trung Hai; Tung, Nguyen Thanh
    • Journal of Computational Chemistry, Vol. 41, Issue 7
    • DOI: 10.1002/jcc.26130

    Conformational flexibility correlates with glucose tolerance for point mutations in β-glucosidases – a computational study
    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

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

    • Menzer, William M.; Xie, Bing; Minh, David D. L.
    • Journal of Computational Chemistry, Vol. 41, Issue 6
    • DOI: 10.1002/jcc.26119

    Deciphering molecular mechanism behind conformational change of the São Paolo metallo-β-lactamase 1 by using enhanced sampling
    journal, December 2019


    Conformational flexibility correlates with glucose tolerance for point mutations in β-glucosidases – a computational study
    text, January 2020

    • Lima, Leonardo Henrique Franca De; Fernandez-Quintéro, Monica Lisa; Rocha, Rafael Eduardo Oliveira
    • Taylor & Francis
    • DOI: 10.6084/m9.figshare.11913315.v2

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