Hybrid quantum and classical methods for computing kinetic isotope effects of chemical reactions in solutions and in enzymes

Jiali Gao, Dan T. Major, Yao Fan, Yen Lin Lin, Shuhua Ma, Kin Yiu Wong

Research output: Chapter in Book/Report/Conference proceedingChapter

6 Scopus citations


A method for incorporating quantum mechanics into enzyme kinetics modeling is presented. Three aspects are emphasized: 1) combined quantum mechanical and molecular mechanical methods are used to represent the potential energy surface for modeling bond forming and breaking processes, 2) instantaneous normal mode analyses are used to incorporate quantum vibrational free energies to the classical potential of mean force, and 3) multidimensional tunneling methods are used to estimate quantum effects on the reaction coordinate motion. Centroid path integral simulations are described to make quantum corrections to the classical potential of mean force. In this method, the nuclear quantum vibrational and tunneling contributions are not separable. An integrated centroid path integral-free energy perturbation and umbrella sampling (PI-FEP/UM) method along with a bisection sampling procedure was summarized, which provides an accurate, easily convergent method for computing kinetic isotope effects for chemical reactions in solution and in enzymes. In the ensemble-averaged variational transition state theory with multidimensional tunneling (EA-VTST/MT), these three aspects of quantum mechanical effects can be individually treated, providing useful insights into the mechanism of enzymatic reactions. These methods are illustrated by applications to a model process in the gas phase, the decarboxylation reaction of N-methyl picolinate in water, and the proton abstraction and reprotonation process catalyzed by alanine racemase. These examples show that the incorporation of quantum mechanical effects is essential for enzyme kinetics simulations.

Original languageEnglish (US)
Title of host publicationMolecular Modeling of Proteins
PublisherHumana Press
Number of pages26
ISBN (Print)9781588298645
StatePublished - Jun 10 2008

Publication series

NameMethods in molecular biology (Clifton, N.J.)
PublisherHumana Press
ISSN (Print)1064-3745


  • Combined QM/MM
  • Dual-level potential
  • Enzyme kinetics
  • Kinetic isotope effects
  • Path integral simulations
  • Solvent effects


Dive into the research topics of 'Hybrid quantum and classical methods for computing kinetic isotope effects of chemical reactions in solutions and in enzymes'. Together they form a unique fingerprint.

Cite this