Overlap perturbation methods for computing alchemical free energy changes: variants, generalizations and evaluations

Abstract

The efficient and reliable computation of relative free energy changes for alchemical mutation is very important in biomolecular simulations. In this study we examine the utility of computing alchemical free energy changes using overlap perturbation techniques. These techniques include both the overlap histogram method and the overlap sampling method (a fully optimized version of the overlap sampling technique is equivalent to Bennett's method), and commonly combine sets of perturbations from both alchemical states of interest to improve a free energy calculation. In addition, we propose new variants, present generalized formulas for overlap perturbation techniques and demonstrate differences from the prevailing direct averaging approach used in alchemical free energy calculations. These overlap perturbation methods can be applied to either equilibrium or non-equilibrium free energy simulations. The alchemical transformation of an adenosine molecule in aqueous solution is used as an example for evaluating these techniques. The calculations show that the methods are capable of producing excellent free energy estimates for an extended range of perturbation magnitudes. We suggest that these overlap perturbation methods should be more widely used for the computation of alchemical free energy changes in biomolecular simulations. † woolf@groucho.med.jhmi.edu