Conformational heterogeneity in the michaelis complex of lactate dehydrogenase: An analysis of vibrational spectroscopy using Markov and hidden Markov models

Xiaoliang Pan, Steven D Schwartz

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6612-6620
Number of pages9
JournalJournal of Physical Chemistry B
Volume120
Issue number27
DOIs
StatePublished - Jul 14 2016

ASJC Scopus subject areas

  • Surfaces, Coatings and Films
  • Physical and Theoretical Chemistry
  • Materials Chemistry

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