Tunneling in enzymatic and nonenzymatic hydrogen transfer reactions

This paper is a response to an invitation to share my viewpoint by writing an opinion piece (not a review) on proton tunneling, especially from the point of view of whether it has a greater importance in enzymatic reactions than in other reactions. The paper begins with a discussion of the emergence of a conceptual framework for including tunneling in reaction rate calculations; the framework is general enough to include not only transfer of protons but also transfer of hydrogen atoms and hydride ions and their isotopes, and not only enzymatically catalyzed reactions but also nonenzymatic reactions. Then the paper discusses the special issues that arise when the reaction rate under consideration is for an enzyme-catalyzed reaction. The emphasis is on physical considerations in reaction rate calculations, not on system-specific comparison of results for different modes of reaction. It is argued that enzymatic and nonenzymatic reactions may be treated within the same basic framework except that ensemble averaging, which is not usually required for gas-phase reactions, is essential for treating enzyme reactions. Enzymes explicitly discussed include methylamine dehydrogenase, aromatic amine dehydrogenase, E. coli dihydrofolate reductase, hyperthermophilic dihydrofolate reductase, liver alcohol dehydrogenase, methylmalonyl-CoA mutase, soybean lipoxygenase, copper amine oxidase, pentaerythritol tetranitrate reductase, morphinone reductase, enolase, xylose isomerase, and 4-oxalocrotonate tautomerase.