Calculation of relative free energy via indirect pathways

Abstract

A general method is presented to reduce the simulation time required to compute the relative free energy between two states X and Y of a molecular system by computer simulation. Although the free energy difference ΔA_x→y is, in principle, independent of the pathway chosen to change X into Y, in practice its choice strongly affects the accuracy of the obtained ΔA value. The optimum path is the one for which the relaxation time of the system τ_system attains a minimum, allowing the system to remain as close as possible near equilibrium during a simulation. Downscaling the relevant parts of the potential energy function before the change from X to Y is made, and upscaling afterwards is a rather general way to shorten τ_system and thus save computing time. For a model system of butane like molecules the proposed procedure is more than 1 order of magnitude more efficient than the conventional technique of direct interconversion from state X to state Y.