Computational studies of enzyme mechanism: linking theory with experiment in the analysis of enzymic H-tunnelling.

Hydrogen transfer--an essential component of most biological reactions--is a quantum problem. A crucial question of great current interest is how enzymes modulate the quantum dynamics of hydrogen transfer to achieve their outstanding catalytic properties. That tunnelling occurs is now widely accepted, with the conceptual frameworks incorporating protein motion into the enzymic H-tunnelling process. Computational simulation can be used to help elucidate how enzymes work and facilitate H-tunnelling at the atomic level. We review the strength of a multidisciplinary approach--combining computational simulations with enzyme kinetics and structural biology--in revealing tunnelling mechanisms in enzymes. We focus on two paradigm systems--aromatic amine dehydrogenase, in which H-tunnelling is facilitated by fast (sub-picosecond) short range motions, and dihydrofolate reductase, in which a network of long-range coupled motions drives the tunnelling event.