Reaction coordinate of an enzymatic reaction revealed by transition path sampling

Abstract

The transition path sampling method previously applied in our group to the reaction catalyzed by lactate dehydrogenase was used to generate a transition path ensemble for this reaction. Based on analysis of the reactive trajectories generated, important residues behind the active site were implicated in a compressional motion that brought the donor-acceptor atoms of the hydride closer together. In addition, residues behind the active site were implicated in a relaxational motion, locking the substrate in product formation. Although this suggested that the compression-relaxation motions of these residues were important to catalysis, it remained unproven. In this work, we used committor distribution analysis to show that these motions are integral components of the reaction coordinate.