Temperature Replica Exchange Gaussian Accelerated Molecular Dynamics: Improved Enhanced Sampling and Energetic Reweighting

Gaussian accelerated molecular dynamics (GaMD) provides enhanced sampling and energy reweighting of biomolecules. GaMD works through adding a harmonic boost potential, defined by a force constant and a threshold energy, to smooth the potential energy surface and accelerate sampling between different states of a biomolecular system separated by large energy barriers. Previously, GaMD has been combined with replica exchange algorithms to improve the acceleration power and energy reweighting of the conventional GaMD simulation. Replica exchange GaMD (Rex-GaMD) comes in two varieties: force constant Rex-GaMD and threshold energy Rex-GaMD, which exchange between replicas of different harmonic force constants and threshold energies, respectively. Recently, Rex-GaMD has been combined with the parallel tempering algorithm that exchanges replicas which vary over a range of temperatures. This new method of temperature Rex-GaMD (T-Rex-GaMD) is able to exchange any combination of replicas defined over a range of different values of the force constant, energy threshold, and temperature. Our hope is that the use of high temperature replicas, in addition to force constant and energy threshold replicas, will lead to accelerated sampling of interesting biomolecular systems with multiple different conformational states separated by large energy barriers. For this new method to be useful we must still be able to perform accurate energetic reweighting, allowing us to recover the true free energy profile of our biomolecular system. To this date, we have performed T-Rex-GaMD simulations on three test systems: alanine dipeptide, chignolin, and HIV protease.