Simulated Tempering-Enhanced Umbrella Sampling Improves Convergence of Free Energy Calculations of Drug Membrane Permeation.

Molecular dynamics simulations have been widely used to study solute permeation across biological membranes. The potential of mean force (PMF) for solute permeation is typically computed using enhanced sampling techniques such as umbrella sampling (US). For bulky drug-like permeants, however, obtaining converged PMFs remains challenging and often requires long simulation times, resulting in an unacceptable computational cost. Here, we augmented US with simulated tempering (ST), an extended-ensemble technique that consists in varying the temperature of the system along a pre-defined temperature ladder. Simulated tempering-enhanced US (STeUS) was employed to improve the convergence of PMF calculations for the permeation of methanol and three common drug molecules. To obtain sufficient sampling of the umbrella histograms, which were computed only from the ground temperature, we modified the simulation time fraction spent at the ground temperature between 1/