Principled Approach for Computing Free Energy on Perturbation Graphs with Cycles

A common approach for computing free energy differences among multiple states is to build a perturbation graph connecting the states and compute free energy differences on all edges of the graph. Such perturbation graphs are often designed to have cycles. Because free energy is a function of states, the free energy around any cycle is zero, which we refer to as the cycle consistency condition. Since the cycle consistency condition relates free energy differences on edges of a cycle, it could be used to improve the accuracy of free energy estimates. Here we propose a Bayesian method called coupled Bayesian multistate Bennett acceptance ratio (CBayesMBAR) that can properly couple the calculations of free energy differences on edges of cycles in a principled way. We apply CBayesMBAR to compute free energy differences among harmonic oscillators and relative protein-ligand binding free energies. In both cases, CBayesMBAR provides more accurate results compared to methods that do not consider the cycle consistency condition. Additionally, it outperforms the cycle closure correction method that also uses cycle consistency conditions.