title: Conformational Heterogeneity in the Michaelis Complex of Lactate Dehydrogenase: An Analysis of Vibrational Spectroscopy Using Markov and Hidden Markov Models.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona , 1306 East University Boulevard, Tucson, Arizona 85721, United States.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona , 1306 East University Boulevard, Tucson, Arizona 85721, United States.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Schwartz
mesh_terms: D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism*; D008390:Markov Chains; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D019289:Pyruvic Acid / Q000378:metabolism; D017550:Spectroscopy, Fourier Transform Infrared; D013379:Substrate Specificity
chemical_list: D019289:Pyruvic Acid; D007770:L-Lactate Dehydrogenase