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Title: Computing Relative Binding Affinity of Ligands to Receptor: An Effective Hybrid Single-Dual-Topology Free-Energy Perturbation Approach in NAMD

Abstract

An effective hybrid single-dual-topology protocol is designed for the calculation of relative binding affinities of small ligands to a receptor. The protocol was developed as an extension of the NAMD molecular dynamics program, which exclusively supports a dual-topology framework for relative alchemical free-energy perturbation (FEP) calculations. Here, the alchemical end states are represented as two separate molecules sharing a common substructure identified through maximum structural mapping. Within the substructure, an atom-to-atom correspondence is established, and each pair of corresponding atoms is holonomically constrained to share identical coordinates at all time throughout the simulation. The forces are projected and combined at each step for propagation. Following this formulation, a set of illustrative calculations of reliable experiment/simulation data, including relative solvation free energies of small molecules and relative binding affinities of drug compounds to proteins, are presented. To enhance sampling of the dual-topology region, the FEP calculations were carried out within a replica-exchange MD scheme supported by the multiple-copy algorithm module of NAMD, with periodically attempted swapping of the thermodynamic coupling parameter lambda between neighboring states. The findings are consistent with experiments and benchmarks reported in the literature, lending support to the validity of the current protocol. In summary, this hybrid single-dual-topologymore » approach combines the conceptual simplicity of the dual-topology paradigm with the advantageous sampling efficiency of the single-topology method, making it an ideal strategy for high-throughput in silico drug design.« less

Authors:
ORCiD logo [1]; ORCiD logo [2]; ORCiD logo [3]
  1. Argonne National Lab. (ANL), Lemont, IL (United States)
  2. Univ. of Lorraine, Nancy (France); Univ. of Illinois, Urbana-Champaign, IL (United States)
  3. Univ. of Chicago, IL (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Institutes of Health (NIH); National Science Foundation (NSF); USDOE Office of Science (SC)
OSTI Identifier:
1570437
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Chemical Information and Modeling
Additional Journal Information:
Journal Volume: 59; Journal Issue: 9; Journal ID: ISSN 1549-9596
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Jiang, Wei, Chipot, Christophe, and Roux, Benoît. Computing Relative Binding Affinity of Ligands to Receptor: An Effective Hybrid Single-Dual-Topology Free-Energy Perturbation Approach in NAMD. United States: N. p., 2019. Web. doi:10.1021/acs.jcim.9b00362.
Jiang, Wei, Chipot, Christophe, & Roux, Benoît. Computing Relative Binding Affinity of Ligands to Receptor: An Effective Hybrid Single-Dual-Topology Free-Energy Perturbation Approach in NAMD. United States. https://doi.org/10.1021/acs.jcim.9b00362
Jiang, Wei, Chipot, Christophe, and Roux, Benoît. Wed . "Computing Relative Binding Affinity of Ligands to Receptor: An Effective Hybrid Single-Dual-Topology Free-Energy Perturbation Approach in NAMD". United States. https://doi.org/10.1021/acs.jcim.9b00362. https://www.osti.gov/servlets/purl/1570437.
@article{osti_1570437,
title = {Computing Relative Binding Affinity of Ligands to Receptor: An Effective Hybrid Single-Dual-Topology Free-Energy Perturbation Approach in NAMD},
author = {Jiang, Wei and Chipot, Christophe and Roux, Benoît},
abstractNote = {An effective hybrid single-dual-topology protocol is designed for the calculation of relative binding affinities of small ligands to a receptor. The protocol was developed as an extension of the NAMD molecular dynamics program, which exclusively supports a dual-topology framework for relative alchemical free-energy perturbation (FEP) calculations. Here, the alchemical end states are represented as two separate molecules sharing a common substructure identified through maximum structural mapping. Within the substructure, an atom-to-atom correspondence is established, and each pair of corresponding atoms is holonomically constrained to share identical coordinates at all time throughout the simulation. The forces are projected and combined at each step for propagation. Following this formulation, a set of illustrative calculations of reliable experiment/simulation data, including relative solvation free energies of small molecules and relative binding affinities of drug compounds to proteins, are presented. To enhance sampling of the dual-topology region, the FEP calculations were carried out within a replica-exchange MD scheme supported by the multiple-copy algorithm module of NAMD, with periodically attempted swapping of the thermodynamic coupling parameter lambda between neighboring states. The findings are consistent with experiments and benchmarks reported in the literature, lending support to the validity of the current protocol. In summary, this hybrid single-dual-topology approach combines the conceptual simplicity of the dual-topology paradigm with the advantageous sampling efficiency of the single-topology method, making it an ideal strategy for high-throughput in silico drug design.},
doi = {10.1021/acs.jcim.9b00362},
journal = {Journal of Chemical Information and Modeling},
number = 9,
volume = 59,
place = {United States},
year = {2019},
month = {8}
}

Journal Article:
Free Publicly Available Full Text
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Cited by: 3 works
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Figures / Tables:

Figure 1 Figure 1: Alchemical transformation between benzene to phenol as an illustrative example for the current hybrid single-dual topology protocol. Panel (a) presents a strict one-to-one correspondence between the two molecules aided with explicit dummy atom; Panel (b) presents a flexible hybrid single-dual topology implementation on the top of a MCSmore » region.« less

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Works referencing / citing this record:

Rigorous Computational and Experimental Investigations on MDM2/MDMX-Targeted Linear and Macrocyclic Peptides
journal, December 2019


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