TY - JOUR
T1 - Conformational heterogeneity in the michaelis complex of lactate dehydrogenase
T2 - An analysis of vibrational spectroscopy using Markov and hidden Markov models
AU - Pan, Xiaoliang
AU - Schwartz, Steven D.
N1 - Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/7/14
Y1 - 2016/7/14
N2 - Lactate dehydrogenase (LDH) catalyzes the interconversion of pyruvate and lactate. Recent isotope-edited IR spectroscopy suggests that conformational heterogeneity exists within the Michaelis complex of LDH, and this heterogeneity affects the propensity toward the on-enzyme chemical step for each Michaelis substate. By combining molecular dynamics simulations with Markov and hidden Markov models, we obtained a detailed kinetic network of the substates of the Michaelis complex of LDH. The ensemble-average electric fields exerted onto the vibrational probe were calculated to provide a direct comparison with the vibrational spectroscopy. Structural features of the Michaelis substates were also analyzed on atomistic scales. Our work not only clearly demonstrates the conformational heterogeneity in the Michaelis complex of LDH and its coupling to the reactivities of the substates, but it also suggests a methodology to simultaneously resolve kinetics and structures on atomistic scales, which can be directly compared with the vibrational spectroscopy.
AB - Lactate dehydrogenase (LDH) catalyzes the interconversion of pyruvate and lactate. Recent isotope-edited IR spectroscopy suggests that conformational heterogeneity exists within the Michaelis complex of LDH, and this heterogeneity affects the propensity toward the on-enzyme chemical step for each Michaelis substate. By combining molecular dynamics simulations with Markov and hidden Markov models, we obtained a detailed kinetic network of the substates of the Michaelis complex of LDH. The ensemble-average electric fields exerted onto the vibrational probe were calculated to provide a direct comparison with the vibrational spectroscopy. Structural features of the Michaelis substates were also analyzed on atomistic scales. Our work not only clearly demonstrates the conformational heterogeneity in the Michaelis complex of LDH and its coupling to the reactivities of the substates, but it also suggests a methodology to simultaneously resolve kinetics and structures on atomistic scales, which can be directly compared with the vibrational spectroscopy.
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U2 - 10.1021/acs.jpcb.6b05119
DO - 10.1021/acs.jpcb.6b05119
M3 - Article
C2 - 27347759
AN - SCOPUS:84978732960
SN - 1520-6106
VL - 120
SP - 6612
EP - 6620
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
IS - 27
ER -