An interoperable implementation of collective‐variable based enhanced sampling methods in extended phase space within the OpenMM package

Abstract

AbstractCollective variable (CV)‐based enhanced sampling techniques are widely used today for accelerating barrier‐crossing events in molecular simulations. A class of these methods, which includes temperature accelerated molecular dynamics (TAMD)/driven‐adiabatic free energy dynamics (d‐AFED), unified free energy dynamics (UFED), and temperature accelerated sliced sampling (TASS), uses an extended variable formalism to achieve quick exploration of conformational space. These techniques are powerful, as they enhance the sampling of a large number of CVs simultaneously compared to other techniques. Extended variables are kept at a much higher temperature than the physical temperature by ensuring adiabatic separation between the extended and physical subsystems and employing rigorous thermostatting. In this work, we present a computational platform to perform extended phase space enhanced sampling simulations using the open‐source molecular dynamics engine OpenMM. The implementation allows users to have interoperability of sampling techniques, as well as employ state‐of‐the‐art thermostats and multiple time‐stepping. This work also presents protocols for determining the critical parameters and procedures for reconstructing high‐dimensional free energy surfaces. As a demonstration, we present simulation results on the high dimensional conformational landscapes of the alanine tripeptide in vacuo, tetra‐N‐methylglycine (tetra‐sarcosine) peptoid in implicit solvent, and the Trp‐cage mini protein in explicit water.