Transition-State Structural Variation in a Model for Carbonyl Reduction by Lactate Dehydrogenase: Computational Validation of Empirical Predictions Based upon Albery-More O'Ferrall-Jencks Diagrams

The transition-state (TS) structure for reduction of formaldehyde by dihydropyridine (hydride donor) and imidazolium (proton donor) has been located and characterized by use of the AM1 semiempirical MO method. The hydride-transfer (HT) and proton-transfer (PT) components of this concerted reaction are kinetically coupled but dynamically uncoupled. Increasing the basicity of the imidazole moiety, by means of a suitably placed dipole of variable magnitude, leads to essentially no change in the degree of PT in the TS but to a substantial increase in the degree of HT. This computational result validates the prediction made on the basis of an Albery-More O'Ferrall-Jencks diagram. Correspondingly, the primary kinetic isotope effect (KIE) calculated for replacement of the transferring proton by a deuteron shows little change, but there is a significant increase in the magnitude of the calculated primary KIE for replacement of the transferring protide by a deuteride as the TS structure changes with increasing basicity of the imidazole moiety. This accords with the conventional view of the relationship between TS structure and the magnitude of primary KIEs.