GROMACS Implementation of Free Energy Calculations with Non-Pairwise Variationally Derived Intermediates

TL;DR

This paper implements the novel Variationally derived Intermediates (VI) method, which uses non-pairwise forces for free energy calculations, into GROMACS, enabling more accurate and stable simulations of solvation free energies.

Contribution

The paper introduces the first implementation of non-pairwise VI intermediates in GROMACS, including a variant to improve numerical stability in free energy calculations.

Findings

Successful implementation in GROMACS 2020.

Enhanced accuracy in solvation free energy calculations.

Improved numerical stability for vanishing particles.

Abstract

Gradients in free energies are the driving forces of physical and biochemical systems. To predict free energy differences with high accuracy, Molecular Dynamics (MD) and other methods based on atomistic Hamiltonians conduct sampling simulations in intermediate thermodynamic states that bridge the configuration space densities between two states of interest ('alchemical transformations'). For uncorrelated sampling, the recent Variationally derived Intermediates (VI) method yields optimal accuracy. The form of the VI intermediates differs fundamentally from conventional ones in that they are non-pairwise, i.e., the total force on a particle in an intermediate states cannot be split into additive contributions from the surrounding particles. In this work, we describe the implementation of VI into the widely used GROMACS MD software package (2020, version 1). Furthermore, a variant of VI is developed that avoids numerical instabilities for vanishing particles. The implementation allows the use of previous non-pairwise potential forms in the literature, which have so far not been available in GROMACS. Example cases on the calculation of solvation free energies, and accuracy assessments thereof, are provided.