Nonadiabatic force matching for alchemical free-energy estimation

Abstract: We propose a method to compute free energies from nonadiabatic alchemical transformations using diffusion-denoising generative models. The method, nonadiabatic force matching, hinges on estimating -- rather than minimizing -- the dissipation along an alchemical transition as the functional of a nonadiabatic potential, which plays the role of a diffusion-denoising protocol. Applying the algorithm to compute alchemical free energies of simple atomistic models shows it can significantly cut the simulation cost of a free-energy estimate at no loss of accuracy compared with thermodynamic integration.