Path Sampling Methods for Enzymatic Quantum Particle Transfer Reactions

M. W. Dzierlenga, M. J. Varga, S. D. Schwartz

Research output: Chapter in Book/Report/Conference proceedingChapter

6 Scopus citations


The mechanisms of enzymatic reactions are studied via a host of computational techniques. While previous methods have been used successfully, many fail to incorporate the full dynamical properties of enzymatic systems. This can lead to misleading results in cases where enzyme motion plays a significant role in the reaction coordinate, which is especially relevant in particle transfer reactions where nuclear tunneling may occur. In this chapter, we outline previous methods, as well as discuss newly developed dynamical methods to interrogate mechanisms of enzymatic particle transfer reactions. These new methods allow for the calculation of free energy barriers and kinetic isotope effects (KIEs) with the incorporation of quantum effects through centroid molecular dynamics (CMD) and the full complement of enzyme dynamics through transition path sampling (TPS). Recent work, summarized in this chapter, applied the method for calculation of free energy barriers to reaction in lactate dehydrogenase (LDH) and yeast alcohol dehydrogenase (YADH). We found that tunneling plays an insignificant role in YADH but plays a more significant role in LDH, though not dominant over classical transfer. Additionally, we summarize the application of a TPS algorithm for the calculation of reaction rates in tandem with CMD to calculate the primary H/D KIE of YADH from first principles. We found that the computationally obtained KIE is within the margin of error of experimentally determined KIEs and corresponds to the KIE of particle transfer in the enzyme. These methods provide new ways to investigate enzyme mechanism with the inclusion of protein and quantum dynamics.

Original languageEnglish (US)
Title of host publicationComputational Approaches for Studying Enzyme Mechanism Part B
PublisherAcademic Press Inc.
Number of pages23
StatePublished - 2016

Publication series

NameMethods in Enzymology
ISSN (Print)0076-6879
ISSN (Electronic)1557-7988


  • Centroid molecular dynamics
  • Enzymatic reactions
  • Free energy
  • Hydride transfer
  • Kinetic isotope effects
  • Molecular dynamics
  • Nuclear quantum effects
  • Transition path sampling

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology


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