AB-INITIO QUANTUM-MECHANICAL AND DENSITY-FUNCTIONAL THEORY CALCULATIONS ON NUCLEOPHILE-CATALYZED AND NUCLEOPHILE AND ACID-CATALYZED OPENINGOF AN EPOXIDE RING - A MODEL FOR THE COVALENT BINDING OF EPOXYALKYL INHIBITORS TO THE ACTIVE-SITE OF GLYCOSIDASES

A model system consisting of methyloxirane, formate, and formic acid w as used to study the nucleophile-catalyzed and nucleophile and acid-ca talyzed opening of an epoxide ring using ab initio quantum mechanical (up to the MP4(SDQ)/6-31+G*//MP2/6-31+G** level) and density function al theory calculations (Becke3LYP/6-31+G*). This system serves as a m odel for the covalent binding of the epoxide inhibitor to the active s ite of glycosidase. The effects of solvation on reaction energies were estimated using the isodensity surface polarized continuum model. The opening of the oxirane ring was calculated to preferably take place b etween the epoxide oxygen and the less-substituted carbon. In agreemen t with the earlier experimental inferences, the results indicate that both the nucleophile and the acid/base catalyst are needed for the rin g opening reaction to take place efficiently. The implications of the results for the enzyme-catalyzed opening of the epoxide ring were disc ussed.