Temperature replica exchange Gaussian accelerated molecular dynamics (T-Rex-GaMD): Improved enhanced sampling and energetic reweighting of biomolecules

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 the various states of a biomolecular system separated by large energy barriers. Previously, GaMD has been combined with replica exchange algorithms, resulting in force constant Rex-GaMD and threshold energy Rex-GaMD. Recently, this approach has been expanded to include parallel tempering, allowing exchanges at various temperatures. This new method, Temperature Rex-GaMD (T-Rex-GaMD), can 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, all while maintaining the accuracy of energetic reweighting to recover the true free energy profile. Successful T-Rex-GaMD simulations on test systems alanine dipeptide, chignolin, and HIV protease showcase its potential for advancing the study of biomolecular free energy profiles and providing profound insights into complex biological molecules.