Computing equilibrium free energies through a nonequilibrium quench

TL;DR

This paper introduces a nonequilibrium quench method implemented in LAMMPS for computing free energy surfaces, demonstrating its accuracy and efficiency, especially when combined with umbrella sampling, across molecular systems.

Contribution

The paper provides a new implementation of the nonequilibrium quench approach in LAMMPS and evaluates its effectiveness for free energy calculations, including extensions to solute tempering.

Findings

Exact results for harmonic springs model.

Accurate FES near stable configurations for alanine dipeptide.

Enhanced efficiency when combining quench with umbrella sampling.

Abstract

Many methods to accelerate sampling of molecular configurations are based on the idea that temperature can be used to accelerate rare transitions. These methods typically compute equilibrium properties at a target temperature using reweighting or through Monte Carlo exchanges between replicas at higher temperatures. A recent paper demonstrated that accurate equilibrium densities of states can also be computed through a nonequilibrium "quench" process, where sampling is performed at a higher temperature to encourage rapid mixing and then quenched to lower energy states with dissipative dynamics. Here we provide an implementation of the quench dynamics in LAMMPS and evaluate a new formulation of nonequilibrium estimators for the computation of partition functions or free energy surfaces (FESs) of molecular systems. We show that the method is exact for a minimal model of $N$-independent harmonic springs, and use these analytical results to develop heuristics for the amount of quenching required to obtain accurate sampling.= We then test the quench approach on alanine dipeptide, where we show that it gives an FES that is accurate near the most stable configurations using the quench approach, but disagrees with a reference umbrella sampling calculation in high FE regions. We then show that combining quenching with umbrella sampling allows the efficient calculation of the free energy in all regions. Moreover, by using this combined scheme, we obtain the FES across a range of temperatures at no additional cost, making it much more efficient than standard umbrella sampling if this information is required. Finally, we discuss how this approach can be extended to solute tempering and demonstrate that it is highly accurate for the case of solvated alanine dipeptide without any additional modifications.