Transition structures for hydride transfer reactions in vacuo and their role in enzyme catalysis

Abstract

A general discussion as to the role of in vacuo transition structure in enzyme catalysis is presented. Quantum mechanical aspects are emphasized. The transition structures defined as saddle points of index one (SPi-1) for the hydride transfer step on different model enzyme systems from flavoproteins to dehydrogenases have been characterized with analytical gradients at different levels of theory: semi-empirical; ab initio with different basis sets within the Hartree-Fock scheme; density functional theory using different approaches. Quantum chemical characteristics of the SPi-1 are used to discuss hydride transfer step in enzyme catalyzed reactions and mechanistic implications. With the exception of dihydrofolate reductase, the results for all other systems studied suggest that the endo relative orientation imposed by the active site on the reactants is essential for polarizing the C dH t bond and situating the system in the quadratic region of the endo SPi-1. The geometry and transition vector components are both model independent and weakly dependent on the level of theory used in their determination. Comparisons of the SPi-1 geometries with available X-ray coordinates show that the SPi-1 can be fitted without any stress at the active site. The geometrical arrangement of the SPi-1 results in optimal frontier LUMO orbital interactions, and the transition vector amplitudes show primary and secondary isotope effects to be strongly coupled. A comparison between simple and sophisticated molecular models shows that there is a minimal molecular model associated with geometrical parameters describing the essentials of the chemical interconversion step. For hydride transfer, the corresponding transition vector is an invariant feature.