New Insight into Quantum Mechanical Hydrogen Tunneling in Enzymes

Quantum mechanical tunneling (QMT) is now recognized as a significant contributor to some enzyme catalyzed hydrogen transfer reactions. In this perspective, we examine recent theoretical and experimental advances that investigate when, and how, QMT contributes to enzyme catalysis. We highlight progress and challenges in computing the rate constants of reactions involving tunneling, including developments in semiclassical approaches and in nuclear-electronic orbital density functional theory. Case studies on flavoenzymes, ribonucleotide reductase, catechol O-methyl transferase and Morita-Baylis-Hillmanase illustrate how protein dynamics, vibrational gating and electrostatic effects apparently modulate barrier width and sustain tunneling-derived rate enhancements. We expect that continued integration of improved theoretical methods and dynamics-sensitive experiments will be essential to move QMT from a mechanistic phenomenon to a tunable design parameter in future enzyme engineering and rational catalyst development.