We have developed a two-dimensional replica-exchange simulation method for predicting protein-ligand binding structures. The first dimension is the replica exchange umbrella sampling (REUS) along the reaction coordinate, which is the distance between a putative binding site of a protein and a ligand, and the second dimension is the replica exchange with solute tempering (REST). Our method consists of three steps. First, two-dimensional replica-exchange simulation is performed. Second, we obtain the potential of mean force (PMF) of the unbiased system by using the multistate bennett acceptance ratio 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 by 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 two protein-ligand complex systems. Starting from a configuration in which the protein and the ligand are far away from each other in each system, our new method predicted the ligand binding structures in excellent agreement with the experimental data from PDB with the improved sampling efficiency compared to our original REUS method.

2D replica-exchange method for the prediction of protein-ligand binding structures

246th National Meeting (2013)

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