Exploring the Effectiveness of Binding Free Energy Calculations

Increasing the accuracy of the evaluation of ligand binding energies is one of the most important tasks of current computational biology. Here we explore the accuracy of free energy perturbation approaches by comparing the performance of a “regular” Free Energy Perturbation (FEP) method to one using replica exchange to enhance sampling on a well-defined benchmark. The examination was limited to the so-called alchemical perturbations which are restricted to a fragment of the drug, and therefore the calculation is a relative one rather than the absolute binding energy of the drug. Our calculations are compared to the systematic study of ref 1. Overall, our calculations reach the 1 kcal/mol accuracy limit and are comparable to that of ref 1. It is also shown that the accurate prediction of the position of water molecules around binding pocket is important for FEP energy calculations. Interestingly, the replica exchange method does not significantly improve the accuracy of binding energies, suggesting that we...