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

Collective variable (CV)-based enhanced sampling tech- niques are widely used today for accelerating barrier- crossing events in molecular simulations. A class of these methods, which includes Temperature Accelerated Molecu- lar Dynamics (TAMD)/driven-Adiabatic Free Energy Dy- namics (d-AFED), Unified Free Energy Dynamics (UFED), and Temperature Accelerated Sliced Sampling (TASS), use a unique extended variable formalism to achieve quick explo- ration of conformational space. These techniques are pow- erful, as they permit the simultaneous sampling of a large number of CVs compared to other techniques. Extended variables are kept at a much higher temperature than the physical temperature by ensuring adiabatic separation be- tween the extended and physical subsystems and employ- ing rigorous thermostatting. In this work, we present a computational platform to perform extended CV-based en- hanced sampling simulations using the open-source molec- ular 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 con- formational 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.