Another Look at the Mechanisms of Hydride Transfer Enzymes with Quantum and Classical Transition Path Sampling.
The mechanisms involved in enzymatic hydride transfer have been studied for years, but questions remain due, in part, to the difficulty of probing the effects of protein motion and hydrogen tunneling. In this study, we use transition path sampling (TPS) with normal mode centroid molecular dynamics (CMD) to calculate the barrier to hydride transfer in yeast alcohol dehydrogenase (YADH) and human heart lactate dehydrogenase (LDH). Calculation of the work applied to the hydride allowed for observation of the change in barrier height upon inclusion of quantum dynamics. Similar calculations were performed using deuterium as the transferring particle in order to approximate kinetic isotope effects (KIEs). The change in barrier height in YADH is indicative of a zero-point energy (ZPE) contribution and is evidence that catalysis occurs via a protein compression that mediates a near-barrierless hydride transfer. Calculation of the KIE using the difference in barrier height between the hydride and deuteride agreed well with experimental results.
Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona 85721, United States.
Michael W
MW
Dzierlenga
Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona 85721, United States.
Dimitri
D
Antoniou
Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona 85721, United States.
Steven D
SD
Schwartz
D000426:Alcohol Dehydrogenase / Q000737:chemistry*; D003903:Deuterium / Q000737:chemistry; D006801:Humans; D006859:Hydrogen / Q000737:chemistry; D007770:L-Lactate Dehydrogenase / Q000737:chemistry*; D011789:Quantum Theory; D017670:Sodium Compounds / Q000737:chemistry*; D013816:Thermodynamics; D015003:Yeasts
D017670:Sodium Compounds; C524957:sodium hydride; D006859:Hydrogen; D003903:Deuterium; D000426:Alcohol Dehydrogenase; D007770:L-Lactate Dehydrogenase
centroid molecular dynamics (CMD); enzymatic hydrogen transfer; fast protein dynamics; transition path sampling (TPS); tunneling in enzymes; yeast alcohol dehydrogenase (YADH)