Optimization of Protein-Ligand Electrostatic Interactions Using an Alchemical Free-Energy Method

We present an alchemical free-energy method for optimizing the partial charges of a ligand to maximize the binding affinity with a receptor. This methodology can be applied to known ligand-protein complexes to determine an optimized set of ligand partial atomic changes. Three protein-ligand complexes have been optimized in this work: FXa, P38 and androgen receptor. The optimization of the ligand charges yielded improvements to binding affinity for all three systems. The sets of optimized charges can be used to identify design principles for chemical changes to the ligand which improve the binding affinity. In this work, beneficial chemical mutations are generated from these principles and the resulting molecules tested using free-energy perturbation calculations. We show that three quarters of our chemical changes are predicted to improve the binding affinity, with an average improvement of approximately 1 kcal/mol. The results demonstrate that charge optimization in explicit solvent is a useful tool for predicting beneficial chemical changes such as pyridinations, fluorinations, and oxygen to sulphur mutations.