Alchemical Free-Energy Calculations at Quantum-Chemical Precision

Abstract

In the past decade, machine-learned potentials (MLP) have demonstrated the capability to predict various QM properties learned from a set of reference QM calculations. Accordingly, hybrid QM/MM simulations can be accelerated by replacement of expensive QM calculations with efficient MLP energy predictions. At the same time, alchemical free-energy perturbations (FEP) remain unachievable at the QM level of theory. In this work, we extend the capabilities of the Buffer Region Neural Network (BuRNN) QM/MM scheme toward FEP. BuRNN introduces a buffer region that experiences full electronic polarization by the QM region to minimize artifacts at the QM/MM interface. An MLP is used to predict the energies for the QM region and its interactions with the buffer region. Furthermore, BuRNN allows us to implement FEP directly into the MLP Hamiltonian. Here, we describe the alchemical change from methanol to methane in water at the MLP/MM level as a proof of concept.