Theoretical Studies of Triosephosphate Isomerase: Catalytic Mechanisms and Proton Tuneling


Three mechanisms proposed for triosephosphate isomerase (TIM) catalyzed reactions were studied with the combined 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, in satisfactory agreement with experiment. By contrast, the mechanism that involve intramolecular proton transfer in the enediolate species was found to be energetically unfavorable due to the presence of His 95, which is a conserved residue in the TIM's from different organisms. Finally, the importance of proton tunneling in the TIM reactions were briefly studied using variational transition state theory with a semiclassical tunneling model. It was found that the effect of tunneling on the transfer rate constants is less than a factor of ten at room temperature. Nevertheless, proton tunneling has a substantial influence on the kinetic isotope effects.

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