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Lookup NU author(s): Dr Daniel ColeORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Alchemical absolute binding free energy (ABFE) calculations have substantial potential in drug discovery, but are often prohibitively computationally expensive. To unlock their potential, efficient automated ABFE workflows are required to reduce both computational cost and human intervention. We present a fully automated ABFE workflow based on the automated selection of λ windows, the ensemble-based detection of equilibration, and the adaptive allocation of sampling time based on inter-replicate statistics. We find that the automated selection of intermediate states with consistent overlap is rapid, robust, and simple to implement. Robust detection of equilibration is achieved with a paired t-test between the free energy estimates at initial and final portions of a an ensemble of runs. We determine reasonable default parameters for all algorithms and show that the full workflow produces equivalent results to a nonadaptive scheme over a variety of test systems, while often accelerating equilibration. Our complete workflow is implemented in the open-source package A3FE (https://github.com/michellab/a3fe).
Author(s): Clark F, Robb GR, Cole DJ, Michel J
Publication type: Article
Publication status: Published
Journal: Journal of Chemical Theory and Computation
Year: 2024
Volume: 20
Issue: 18
Pages: 7806–7828
Print publication date: 24/09/2024
Online publication date: 10/09/2024
Acceptance date: 26/08/2024
Date deposited: 14/09/2024
ISSN (print): 1549-9618
ISSN (electronic): 1549-9626
Publisher: American Chemical Society
URL: https://doi.org/10.1021/acs.jctc.4c00806
DOI: 10.1021/acs.jctc.4c00806
Data Access Statement: The A3FE package is available on GitHub at https://github.com/michellab/a3fe. Example input files, all data analyzed, and analysis code is available at https://github.com/michellab/Automated-ABFE-Paper.
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