Replica exchange with solute tempering: A method for sampling biological systems in explicit water

An innovative replica exchange (parallel tempering) method called replica exchange with solute tempering (REST) for the efficient sampling of aqueous protein solutions is presented here. The method bypasses the poor scaling with system size of standard replica exchange and thus reduces the number of replicas (parallel processes) that must be used. This reduction is accomplished by deforming the Hamiltonian function for each replica in such a way that the acceptance probability for the exchange of replica configurations does not depend on the number of explicit water molecules in the system. For proof of concept, REST is compared with standard replica exchange for an alanine dipeptide molecule in water. The comparisons confirm that REST greatly reduces the number of CPUs required by regular replica exchange and increases the sampling efficiency. This method reduces the CPU time required for calculating thermodynamic averages and for the ab initio folding of proteins in explicit water.