Ab Initio prediction of protein–ligand binding structures by replica‐exchange umbrella sampling simulations

Abstract

We have developed a prediction method for the binding structures of ligands with proteins. Our method consists of three steps. First, replica-exchange umbrella sampling simulations are performed along the distance between a putative binding site of a protein and a ligand as the reaction coordinate. Second, we obtain the potential of mean force (PMF) of the unbiased system using the weighted histogram analysis method and determine the distance that corresponds to the global minimum of PMF. Third, structures that have this global-minimum distance and energy values around the average potential energy are collected and analyzed using the principal component analysis. We predict the binding structure as the global-minimum free energy state on the free energy landscapes along the two major principal component axes. As test cases, we applied our method to five protein-ligand complex systems. Starting from the configuration in which the protein and the ligand are far away from each other in each system, our method predicted the ligand binding structures in excellent agreement with the experimental data from Protein Data Bank.