Molecular dynamics simulations used the pmemd and pmemd.cuda modules of AMBER14, with the former having been modified to support the msesMD methodology. A hydrogen mass repartitioning scheme (HMR) was used for all unbiased MD simulations, scaling solute hydrogen masses to 3 amu; 41 all msesMD, aMD and umbrella sampling simulations used standard masses. Unless otherwise indicated, a time step of 4 fs was used for mass repartitioned systems and 2 fs for standard mass systems. In all simulations, hydrogen atom motions were constrained using the SHAKE and SETTLE algorithms for the solutes and waters respectively. Long range electrostatic interactions were calculated using the particle mesh Ewald method and a 9 Å cutoff for short range nonbonded interactions. Thermal control was achieved using the Langevin thermostat and a collision frequency of 3.0 ps -1 .