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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).
Free energies play a central role in characterizing the behavior of chemical systems and are among the most important quantities that can be calculated by molecular dynamics simulations. Solvation free energies in various organic solvents, in particular, are well-studied physicochemical properties of drug-like molecules and are commonly used to assess and optimize the accuracy of nonbonded parameters in empirical force fields and also as a fast-to-compute surrogate of performance for protein–ligand binding free energy estimation. Machine learned potentials (MLPs) show great promise as more accurate alternatives to empirical force fields but are not readily decomposed into physically motivated functional forms, which has thus far rendered them incompatible with standard alchemical free energy methods that manipulate individual pairwise interaction terms. However, since the accuracy of free energy calculations is highly sensitive to the force field, this is a key area in which MLPs have the potential to address the shortcomings of empirical force fields. In this work, we introduce an efficient alchemical free energy protocol that enables calculations of rigorous free energy differences in condensed phase systems modeled entirely by MLPs. Using a pretrained, transferable, alchemically equipped MLP model, we demonstrate subchemical accuracy for the solvation free energies of a wide range of organic molecules.
Author(s): Moore JH, Cole DJ, Csányi G
Publication type: Article
Publication status: Published
Journal: Journal of the American Chemical Society
Year: 2026
Volume: 148
Issue: 5
Pages: 4928–4937
Print publication date: 11/02/2026
Online publication date: 27/01/2026
Acceptance date: 15/01/2026
Date deposited: 06/02/2026
ISSN (print): 0002-7863
ISSN (electronic): 1520-5126
Publisher: American Chemical Society
URL: https://doi.org/10.1021/jacs.5c10940
DOI: 10.1021/jacs.5c10940
Data Access Statement: An example script to reproduce the replica exchange calculations is provided in the SI. The mace-md package used to run the simulations is available at https://github.com/ jharrymoore/mace-md/tree/master. Calculated solvation free energy values for all force fields are available in the Supporting Information.
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