Buckets Instead of Umbrellas for Enhanced Sampling and Free Energy Calculations.

Umbrella sampling has been a workhorse for free energy calculations in molecular simulations for several decades. In conventional umbrella sampling, restraining bias potentials are strategically applied along one or several collective variables. Major drawbacks associated with this method are the requirement of a large number of bias windows and the poor sampling of the transverse coordinates.

Boosting the conformational sampling by combining replica exchange with solute tempering and well-sliced metadynamics.

Methods that combine collective variable (CV) based enhanced sampling and global tempering approaches are used in speeding-up the conformational sampling and free energy calculation of large and soft systems with a plethora of energy minima. In this paper, a new method of this kind is proposed in which the well-sliced metadynamics approach (WSMTD) is united with replica exchange with solute tempering (REST2) method. WSMTD employs a divide-and-conquer strategy wherein high-dimensional slices of a free energy surface are independently sampled and combined.