Quantum Mechanical/Molecular Mechanical Studies of the Triosephosphate Isomerase-Catalyzed Reaction: Verification of Methodology and Analysis of Reaction Mechanisms

Abstract

Three possible mechanisms for the reactions catalyzed by triosephosphate isomerase (TIM) have been studied by the combined quantum mechanical/molecular mechanical (QM/MM) approach at a number of QM levels including AM1, AM1 with specific reaction parameters (SRP), and B3LYP/6-31+G(d,p). The comparison of the various QM levels is used to verify the adequacy of our recent B3LYP/MM analysis of the reaction mechanism (Cui et al. J. Am. Chem. Soc. 2001, 123, 2284), which showed that the intramolecular proton transfer pathway is ruled out, due largely to the unfavorable interaction between the transition state and His 95. The relative contributions from the two other proposed pathways, however, are difficult to determine at the present level of theory; both pathways are also consistent with available experiments. To obtain information about the role of the enzyme, density functional calculations were made for model systems in the gas phase and in solution; selected models were also studied with ab initio calcul...