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Hydride transfer catalyzed by xylose isomerase: Mechanism and quantum effects
Author(s) -
GarciaViloca Mireia,
Alhambra Cristóbal,
Truhlar Donald G.,
Gao Jiali
Publication year - 2002
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.10154
Subject(s) - chemistry , kinetic isotope effect , molecular dynamics , valence bond theory , computational chemistry , quantum tunnelling , quantum , isomerization , activation energy , thermodynamics , catalysis , molecular orbital , atomic physics , quantum mechanics , physics , deuterium , molecule , organic chemistry
Abstract We have applied molecular dynamics umbrella‐sampling simulation and ensemble‐averaged variational transition state theory with multidimensional tunneling (EA‐VTST/MT) to calculate the reaction rate of xylose‐to‐ xylulose isomerization catalyzed by xylose isomerase in the presence of two Mg 2+ ions. The calculations include determination of the free energy of activation profile and ensemble averaging in the transmission coefficient. The potential energy function is approximated by a combined QM/MM/SVB method involving PM3 for the quantum mechanical (QM) subsystem, CHARMM22 and TIP3P for the molecular mechanical (MM) environment, and a simple valence bond (SVB) local function of two bond distances for the hydride transfer reaction. The simulation confirms the essential features of a mechanism postulated on the basis of kinetics and X‐ray data by Whitlow et al. (Whitlow, M.; Howard, A. J.; Finzel, B. C.; Poulos, T. L.; Winborne, E.; Gilliland, G. L. Proteins 1991, 9, 153) and Ringe, Petsko, and coworkers (Labie, A.; Allen, K.‐N.; Petsko, G. A.; Ringe, D. Biochemistry 1994, 33, 5469). This mechanism involves a rate‐determining 1,2‐hydride shift with prior and post proton transfers. Inclusion of quantum mechanical vibrational energy is important for computing the free energy of activation, and quantum mechanical tunneling effects are essential for computing kinetic isotope effects (KIEs). It is found that 85% of the reaction proceeds by tunneling and 15% by overbarrier events. The computed KIE for the ratio of hydride to deuteride transfer is in good agreement with the experimental results. The molecular dynamics simulations reveal that proton and hydride transfer reactions are assisted by breathing motions of the mobile Mg 2+ ion in the active site, providing evidence for concerted motion of Mg 2+ during the hydride transfer step. © 2002 Wiley Periodicals, Inc. J Comput Chem 24: 177–190, 2003