Quantum dynamics of hydride transfer in enzyme catalysis

One of the strongest experimental indications of hydrogen tunneling in biol ogy has been the elevated Swain-Schaad exponent for the secondary kinetic i sotope effect in the hydride-transfer step catalyzed by liver alcohol dehyd rogenase. This process has been simulated using canonical variational trans ition-state theory for overbarrier dynamics and optimized multidimensional paths for tunneling. Semiclassical quantum effects on the dynamics are incl uded on a 21-atom substrate-enzyme-coenzyme primary zone embedded in the po tential of a substrate-enzyme-coenzyme-solvent secondary zone. The potentia l energy surface is calculated by treating 54 atoms by quantum mechanical e lectronic structure methods and 5506 protein, coenzyme, and solvent atoms b y molecular mechanical force fields. We find an elevated Swain-Schaad expon ent for the secondary kinetic isotope effect and generally good agreement w ith other experimental observables. Quantum mechanical tunneling is calcula ted to account for similar to 60% of the reactive flux, confirming the domi nance of tunneling that was inferred from the Swain-Schaad exponent. The ca lculations provide a detailed picture of the origin of the kinetic isotope effect and the nature of the tunneling process.