Quantum Dynamics of Hydride Transfer in Enzyme Catalysis

Abstract

One of the strongest experimental indications of hydrogen tunneling in biology has been the elevated Swain-Schaad exponent for the secondary kinetic isotope effect in the hydride-transfer step catalyzed by liver alcohol dehydrogenase. This process has been simulated using canonical variational transition-state theory for overbarrier dynamics and optimized multidimensional paths for tunneling. Semiclassical quantum effects on the dynamics are included on a 21-atom substrate-enzyme-coenzyme primary zone embedded in the potential of a substrate-enzyme-coenzyme-solvent secondary zone. The potential energy surface is calculated by treating 54 atoms by quantum mechanical electronic structure methods and 5506 protein, coenzyme, and solvent atoms by molecular mechanical force fields. We find an elevated Swain-Schaad exponent for the secondary kinetic isotope effect and generally good agreement with other experimental observables. Quantum mechanical tunneling is calculated to account for ∼60% of the reactive flux, confirming the dominance of tunneling that was inferred from the Swain-Schaad exponent. The calculations provide a detailed picture of the origin of the kinetic isotope effect and the nature of the tunneling process.

Elusive transition state of alcohol dehydrogenase unveiled

“…The model also indicates an asynchronized hybridization for the donor and acceptor carbons, which was first identified for dihydrofolate reductase (DHFR) by QM/MM calculations (33). Finally, in accordance with the ensemble-averaged variational transition state theory (VTST) results from Truhlar, Gao, and co-workers (24,25), the model supports the recently articulated hypothesis that the inflated mSSEs reported for many ADHs since 1989 result from deflated 2°D/T KIEs because of the shorter donor-acceptor distance (DAD) required for D transfer (1,34). The present model mirrors some of the previous empirical calculations on ADH and other systems (16,17,22,23,35) but provides a more comprehensive molecular and electronic interpretation.…”

“…Some empirical models (22,23) as well as quantum mechanical/molecular mechanical simulation (QM/MM) studies (24)(25)(26)(27) have achieved moderate success in replicating the observed 2°m…”

An Integrated Path Integral and Free-Energy Perturbation−Umbrella Sampling Method for Computing Kinetic Isotope Effects of Chemical Reactions in Solution and in Enzymes

“…One method that has been successfully introduced to computational enzymology is the ensembleaveraged variational transition-state theory with QM/MM sampling (EA-VTST-QM/MM), which has been applied to a number of enzyme systems. 2,3,[9][10][11][12][13] Both primary and secondary KIEs can be computed using the EA-VTST-QM/ MM method, and the method includes contributions of multidimensional tunneling. In another work, a grid-based hybrid approach was used to model quantum effects in hydrogen transfer reactions by numerically solving the vibrational wavefunction of the transferring hydrogen nucleus.…”

Molecular dynamics simulation exploration of unfolding and refolding of a ten-amino acid miniprotein

“…Under some conditions, such as high temperature, extremes of pH or mechanical forces, protein will unfold into random coil that loses biochemical function (Selkoe 2003). Since folding and unfolding are essential to life, literatures on the study of these processes are very rich (Gao and Truhlar 2002;Gao et al 2006;Freddolino et al 2010;Yang et al 2010;Alhambra et al 2000;Duan et al 2010;Shank et al 2010). And it has been greatly advanced in recent years by the development of fast time-resolved techniques.…”