Generalized Ensemble Sampling of Enzyme Reaction Free Energy Pathways

Abstract

Free energy path sampling plays an essential role in computational understanding of chemical reactions, particularly those occurring in enzymatic environments. Among a variety of molecular dynamics simulation approaches, the generalized ensemble sampling strategy is uniquely attractive for the fact that it not only can enhance the sampling of rare chemical events but also can naturally ensure consistent exploration of environmental degrees of freedom. In this review, we plan to provide a tutorial-like tour on an emerging topic: generalized ensemble sampling of enzyme reaction free energy path. The discussion is largely focused on our own studies, particularly ones based on the metadynamics free energy sampling method and the on-the-path random walk path sampling method. We hope that this mini presentation will provide interested practitioners some meaningful guidance for future algorithm formulation and application study.

Calculation of Conformational Free Energies with the Focused Confinement Method

“…It is often not possible to calculate conformational free energy differences from unbiased simulations due to limited sampling. Instead, free energy differences are generally obtained from enhanced sampling simulations, in which the Hamiltonian and/or temperature is modified in order to enforce multiple transitions between states. − Since this biasing can be accounted for by reweighting techniques, such as the multistate Bennett acceptance ratio estimator (MBAR), accurate free energy differences can be computed from these simulations.…”

“…While many enhanced sampling techniques exist, − the confinement method (CM) − seems particularly appealing for the calculation of conformational free energy differences. Rather than connecting the conformations of interest by a geometrical path, CM connects them to harmonic oscillator (HO) states for which the free energies are known analytically.…”