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Comparison of Receptor–Ligand Restraint Schemes for Alchemical Absolute Binding Free Energy Calculations

[Image: see text] Alchemical absolute binding free energy calculations are of increasing interest in drug discovery. These calculations require restraints between the receptor and ligand to restrict their relative positions and, optionally, orientations. Boresch restraints are commonly used, but the...

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Autores principales: Clark, Finlay, Robb, Graeme, Cole, Daniel J., Michel, Julien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10308817/
https://www.ncbi.nlm.nih.gov/pubmed/37285579
http://dx.doi.org/10.1021/acs.jctc.3c00139
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author Clark, Finlay
Robb, Graeme
Cole, Daniel J.
Michel, Julien
author_facet Clark, Finlay
Robb, Graeme
Cole, Daniel J.
Michel, Julien
author_sort Clark, Finlay
collection PubMed
description [Image: see text] Alchemical absolute binding free energy calculations are of increasing interest in drug discovery. These calculations require restraints between the receptor and ligand to restrict their relative positions and, optionally, orientations. Boresch restraints are commonly used, but they must be carefully selected in order to sufficiently restrain the ligand and to avoid inherent instabilities. Applying multiple distance restraints between anchor points in the receptor and ligand provides an alternative framework without inherent instabilities which may provide convergence benefits by more strongly restricting the relative movements of the receptor and ligand. However, there is no simple method to calculate the free energy of releasing these restraints due to the coupling of the internal and external degrees of freedom of the receptor and ligand. Here, a method to rigorously calculate free energies of binding with multiple distance restraints by imposing intramolecular restraints on the anchor points is proposed. Absolute binding free energies for the human macrophage migration inhibitory factor/MIF180, system obtained using a variety of Boresch restraints and rigorous and nonrigorous implementations of multiple distance restraints are compared. It is shown that several multiple distance restraint schemes produce estimates in good agreement with Boresch restraints. In contrast, calculations without orientational restraints produce erroneously favorable free energies of binding by up to approximately 4 kcal mol(–1). These approaches offer new options for the deployment of alchemical absolute binding free energy calculations.
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spelling pubmed-103088172023-06-30 Comparison of Receptor–Ligand Restraint Schemes for Alchemical Absolute Binding Free Energy Calculations Clark, Finlay Robb, Graeme Cole, Daniel J. Michel, Julien J Chem Theory Comput [Image: see text] Alchemical absolute binding free energy calculations are of increasing interest in drug discovery. These calculations require restraints between the receptor and ligand to restrict their relative positions and, optionally, orientations. Boresch restraints are commonly used, but they must be carefully selected in order to sufficiently restrain the ligand and to avoid inherent instabilities. Applying multiple distance restraints between anchor points in the receptor and ligand provides an alternative framework without inherent instabilities which may provide convergence benefits by more strongly restricting the relative movements of the receptor and ligand. However, there is no simple method to calculate the free energy of releasing these restraints due to the coupling of the internal and external degrees of freedom of the receptor and ligand. Here, a method to rigorously calculate free energies of binding with multiple distance restraints by imposing intramolecular restraints on the anchor points is proposed. Absolute binding free energies for the human macrophage migration inhibitory factor/MIF180, system obtained using a variety of Boresch restraints and rigorous and nonrigorous implementations of multiple distance restraints are compared. It is shown that several multiple distance restraint schemes produce estimates in good agreement with Boresch restraints. In contrast, calculations without orientational restraints produce erroneously favorable free energies of binding by up to approximately 4 kcal mol(–1). These approaches offer new options for the deployment of alchemical absolute binding free energy calculations. American Chemical Society 2023-06-07 /pmc/articles/PMC10308817/ /pubmed/37285579 http://dx.doi.org/10.1021/acs.jctc.3c00139 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Clark, Finlay
Robb, Graeme
Cole, Daniel J.
Michel, Julien
Comparison of Receptor–Ligand Restraint Schemes for Alchemical Absolute Binding Free Energy Calculations
title Comparison of Receptor–Ligand Restraint Schemes for Alchemical Absolute Binding Free Energy Calculations
title_full Comparison of Receptor–Ligand Restraint Schemes for Alchemical Absolute Binding Free Energy Calculations
title_fullStr Comparison of Receptor–Ligand Restraint Schemes for Alchemical Absolute Binding Free Energy Calculations
title_full_unstemmed Comparison of Receptor–Ligand Restraint Schemes for Alchemical Absolute Binding Free Energy Calculations
title_short Comparison of Receptor–Ligand Restraint Schemes for Alchemical Absolute Binding Free Energy Calculations
title_sort comparison of receptor–ligand restraint schemes for alchemical absolute binding free energy calculations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10308817/
https://www.ncbi.nlm.nih.gov/pubmed/37285579
http://dx.doi.org/10.1021/acs.jctc.3c00139
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