FEP/REST Enhanced Sampling Method

Converging explicit solvent simulations to the desired precision is far from trivial. FEP+ uses the FEP/REST enhanced sampling method to enhance the sampling of protein or ligand local structural rearrangement [3,4,5]. REST2 is a Hamiltonian replica exchange method where only a small region of interest of the system is effectively “heated up” while the rest of the system stays “cold”.

FEP/REST uses the REST2 enhanced sampling method to achieve efficient sampling of the different conformations of ligands or protein residues close to the binding pocket. In FEP/REST, the effective temperature of the hot region is gradually increased from T₀ for the initial lambda window to T_h for the middle lambda window, and then gradually decreased to T₀ for the final lambda window. The effective temperature of the hot region is achieved by scaling the Hamiltonian, and exchange of configurations between neighboring lambda windows is attempted and accepted according to the detailed balance condition.

The hot region is the region that is relevant for protein-ligand binding, which usually includes atoms in the ligand and the protein residues surrounding the binding pocket.