Prediction of Ligand Binding Affinity by the Combination of Replica-Exchange Method and Double-Decoupling Method

A prediction method for ligand binding affinities to proteins is proposed. We first predict the structures of protein–ligand complex by the replica-exchange umbrella sampling or its extension. We then calculate ligand binding affinities based on these predicted ligand–protein bound structures by the double-decoupling method. As a test of the effectiveness of the proposed method, we applied it to the system of the oncoprotein MDM2 and a ligand. The value of the predicted binding affinity turned out to be in good agreement with that from experiments.