Simple, Efficient, and Reliable Computation of Multiple Free Energy Differences from a Single Simulation: A Reference Hamiltonian Parameter Update Scheme for Enveloping Distribution Sampling (EDS).

Abstract

We present an automatic adaptive scheme which allows fast optimization of the reference Hamiltonian parameters in enveloping distribution sampling (EDS). Six different variants of the update scheme have been tested on a condensed phase test system which included the recurrent deletion and creation of complete water molecules in water. All six schemes gave accurate free energy estimates with absolute errors of up to 1 kJ/mol for the worst scheme and up to 0.1 kJ/mol for the best scheme. Configurational sampling is focused on the regions where the end state energy difference distributions intersect, explaining the high accuracy and precision of the free energy estimates. The new update scheme makes the application of EDS to other systems, e.g. in ligand binding studies, easy as no reference state Hamiltonian parameters have to be chosen by the user. The only necessary input are the Hamiltonians of the various end states involved.