TRANSITION STRUCTURES FOR HYDRIDE TRANSFER-REACTIONS IN-VACUO AND THEIR ROLE IN ENZYME CATALYSIS

A general discussion as to the role of in vacuo transition structure i n enzyme catalysis is presented. Quantum mechanical aspects are emphas ized. The transition structures defined as saddle points of index one (SPi-1) for the hydride transfer step on different model enzyme system s from flavoproteins to dehydrogenases have been characterized with an alytical gradients at different levels of theory: semi-empirical; ab i nitio with different basis sets within the Hartree-Fock scheme; densit y functional theory using different approaches. Quantum chemical chara cteristics of the SPi-1 are used to discuss hydride transfer step in e nzyme catalyzed reactions and mechanistic implications. With the excep tion of dihydrofolate reductase, the results for all other systems stu died suggest that the endo relative orientation imposed by the active site on the reactants is essential for polarizing the C-d-H-l bond and situating the system in the quadratic region of the endo SPi-1. The g eometry and transition vector components are both model independent an d 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 sit e. The geometrical arrangement of the SPi-1 results in optimal frontie r LUMO orbital interactions, and the transition vector amplitudes show primary and secondary isotope effects to be strongly coupled. A compa rison between simple and sophisticated molecular models shows that the re is a minimal molecular model associated with geometrical parameters describing the essentials of the chemical interconversion step. For h ydride transfer, the corresponding transition vector is an invariant f eature.