Nonadiabatic Force Matching for Alchemical Free-Energy Estimation

Journal Article · Tue Nov 25 00:00:00 EST 2025 · Journal of Chemical Theory and Computation

DOI:https://doi.org/10.1021/acs.jctc.5c01478· OSTI ID:3009043

Rosa-Raíces, Jorge L; Limmer, David T

We propose a method to compute free-energy differences from nonadiabatic alchemical transformations by using flow-based generative models. The method, nonadiabatic force matching, hinges on estimating the dissipation along an alchemical switching process in terms of a nonadiabatic force field that can be learned through stochastic flow matching. The learned field can be used in conjunction with short-time trajectory data to evaluate upper and lower bounds on the alchemical free energy that variationally converge to the exact value if the field is optimal. Applying the method to evaluate the alchemical free energy of atomistic models shows that it can substantially reduce the simulation cost of a free-energy estimate at a negligible loss of accuracy when compared with thermodynamic integration.

• Research Organization: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
• Sponsoring Organization: US Department of Energy; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
• Grant/Contract Number: AC02-05CH11231
• OSTI ID: 3009043
• Journal Information: Journal of Chemical Theory and Computation, Journal Name: Journal of Chemical Theory and Computation Journal Issue: 22 Vol. 21
• Country of Publication: United States
• Language: English

Related Subjects

Computational chemistry
Diffusion
Equilibrium
Thermodynamic properties
Thermodynamics