TY - JOUR
T1 - Another look at the mechanisms of hydride transfer enzymes with quantum and classical transition path sampling
AU - Dzierlenga, Michael W.
AU - Antoniou, Dimitri
AU - Schwartz, Steven D.
N1 - Publisher Copyright:
© 2015 American Chemical Society.
Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.
PY - 2015/4/2
Y1 - 2015/4/2
N2 - 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.
AB - 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.
KW - centroid molecular dynamics (CMD)
KW - enzymatic hydrogen transfer
KW - fast protein dynamics
KW - transition path sampling (TPS)
KW - tunneling in enzymes
KW - yeast alcohol dehydrogenase (YADH)
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U2 - 10.1021/acs.jpclett.5b00346
DO - 10.1021/acs.jpclett.5b00346
M3 - Article
C2 - 26262969
AN - SCOPUS:84926647779
VL - 6
SP - 1177
EP - 1181
JO - Journal of Physical Chemistry Letters
JF - Journal of Physical Chemistry Letters
SN - 1948-7185
IS - 7
ER -