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Alchemical Free Energy Estimators and Molecular Dynamics Engines: Accuracy, Precision, and Reproducibility

Wade, Alexander D; Bhati, Agastya P; Wan, Shunzhou; Coveney, Peter V; (2022) Alchemical Free Energy Estimators and Molecular Dynamics Engines: Accuracy, Precision, and Reproducibility. Journal of Chemical Theory and Computation 10.1021/acs.jctc.2c00114. (In press). Green open access

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Abstract

The binding free energy between a ligand and its target protein is an essential quantity to know at all stages of the drug discovery pipeline. Assessing this value computationally can offer insight into where efforts should be focused in the pursuit of effective therapeutics to treat a myriad of diseases. In this work, we examine the computation of alchemical relative binding free energies with an eye for assessing reproducibility across popular molecular dynamics packages and free energy estimators. The focus of this work is on 54 ligand transformations from a diverse set of protein targets: MCL1, PTP1B, TYK2, CDK2, and thrombin. These targets are studied with three popular molecular dynamics packages: OpenMM, NAMD2, and NAMD3 alpha. Trajectories collected with these packages are used to compare relative binding free energies calculated with thermodynamic integration and free energy perturbation methods. The resulting binding free energies show good agreement between molecular dynamics packages with an average mean unsigned error between them of 0.50 kcal/mol. The correlation between packages is very good, with the lowest Spearman's, Pearson's and Kendall's tau correlation coefficients being 0.92, 0.91, and 0.76, respectively. Agreement between thermodynamic integration and free energy perturbation is shown to be very good when using ensemble averaging.

Type: Article
Title: Alchemical Free Energy Estimators and Molecular Dynamics Engines: Accuracy, Precision, and Reproducibility
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/acs.jctc.2c00114
Publisher version: https://doi.org/10.1021/acs.jctc.2c00114
Language: English
Additional information: © 2022 The Authors. Published by American Chemical Society under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/).
UCL classification: UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10149863
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