The role of reaction energy and hydrogen bonding in the reaction path of enzymatic proton transfers

The reaction path of the Interacting‐State Model is used with the Transition‐State Theory and the semiclassical correction for tunneling (ISM/scTST) to calculate proton transfer rates in rate‐determining CH bond breaking by enzymes such as mandelate racemase, triose‐phosphate isomerase, methylamine dehydrogenase (MADH), and aromatic amine dehydrogenase (AADH), as well as of the analogous uncatalyzed proton transfers in aqueous solution. This method employs the reaction energy, the bond distances in reactants and products, and properties of the reactive bonds to calculate the proton transfer rates. The comparison between the molecular factors that control reactivity in solution and in the enzymes reveals the following salient features of enzyme catalysis: (1) the change from a bimolecular reaction in solution to an intramolecular reaction with negligible activation entropy in the enzyme; (2) energetic stabilization of the intermediates; and (3) extreme tunneling corrections when hydrogen bonding to a carbon atom is present in the reaction path.