Nonadiabatic force matching for alchemical free-energy estimation

Abstract

We propose a method to compute free-energy differences from nonadiabatic alchemical transformations 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 negligible loss of accuracy when compared with thermodynamic integration.

Final version of the article, published by ACS in the Journal of Chemical Theory and Computation

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