Dynamics of protein conformational fluctuation in enzyme catalysis with special attention to proton transfers in serine proteinases.

We have provided a quantum mechanical model for proteinase-catalyzed peptide, amide and ester hydrolysis. The model rests on electron and atom transfer theory, but incorporates the dynamics of conformational nuclear modes as a new element. The model is applied to acylation, but can straightaway be extended to deacylation, and is substantiated by recent structural and kinetic data for proteinase enzyme catalysis. The role of the conformational modes is found to be two-fold. First, the crystallographic distances for the proton transfers involved are far too large for direct transfer. His-57 mobility, handled stochastically, to bring the donor and acceptor groups within suitable reach, is therefore a crucial element of the theory. Secondly, the charge alignment in the Asp-102/His-57/tetrahedral intermediate system implies that the curvature of the potential surface along the conformational coordinates in this state is much lower than in the initial enzyme-substrate and final acyl states. A consequence of this is that the activation energy liberated after the first proton transfer is not dissipated, but stored in the conformational system and used in the second proton transfer step.