Triosephosphate isomerase: A theoretical comparison of alternative pathways

Three mechanisms proposed for the triosephosphate isomerase (TIM) catalyzed reactions were studied with the QM/MM approach using B3LYP/6-31+G(d,p) as the QM method. The two pathways that involve an enediol species were found to give similar values for the barriers and the calculated rates are in sat isfactory agreement with experiment. By contrast, the mechanism that involv es intramolecular proton transfer in the enediolate was found to be energet ically unfavorable due to electrostatic interactions with His 95, a conserv ed residue in TIM from different organisms. A perturbation analysis was use d to determine the residues that make the major contribution to catalysis.