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Quantifying the limits of transition state theory in enzymatic catalysis.

ABSTRACT: While being one of the most popular reaction rate theories, the applicability of transition state theory to the study of enzymatic reactions has been often challenged. The complex dynamic nature of the protein environment raised the question about the validity of the nonrecrossing hypothesis, a cornerstone in this theory. We present a computational strategy to quantify the error associated to transition state theory from the number of recrossings observed at the equicommittor, which is the best possible dividing surface. Application of a direct multidimensional transition state optimization to the hydride transfer step in human dihydrofolate reductase shows that both the participation of the protein degrees of freedom in the reaction coordinate and the error associated to the nonrecrossing hypothesis are small. Thus, the use of transition state theory, even with simplified reaction coordinates, provides a good theoretical framework for the study of enzymatic catalysis.

SUBMITTER: Zinovjev K

PROVIDER: S-EPMC5703300 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Quantifying the limits of transition state theory in enzymatic catalysis.

Zinovjev Kirill K Tuñón Iñaki I

Proceedings of the National Academy of Sciences of the United States of America 20171103 47

While being one of the most popular reaction rate theories, the applicability of transition state theory to the study of enzymatic reactions has been often challenged. The complex dynamic nature of the protein environment raised the question about the validity of the nonrecrossing hypothesis, a cornerstone in this theory. We present a computational strategy to quantify the error associated to transition state theory from the number of recrossings observed at the equicommittor, which is the best ...[more]

PMID: 29101125

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Project description:Deprotonation of the alkoxysulfonium intermediate has been shown to be rate-determining in the Swern oxidation of benzyl alcohol. Directly following this rate-determining step is the intramolecular syn-?-elimination of the ylide. In the present study, intramolecular (2)H kinetic isotope effects (KIEs) are used to gain insight into this syn-?-elimination step. As a result of the stereogenic sulfur center in the ylide intermediate, two diastereomeric transition states (endo-TS1 and exo-TS1) must be assumed to contribute to the intramolecular KIE. The intramolecular (2)H KIE determined at -78 °C is 2.82 ± 0.06. Attempts to reproduce this measurement computationally using transition state theory and a Bell tunneling correction yielded a value (1.58) far below that determined experimentally. Computational analysis is complicated by the existence of two distinct transition structures owing to the stereogenic center. Two extremes of Curtin-Hammett kinetics are explored using energies, vibrational frequencies, and moments of inertia from computed transition structures. Neither Curtin-Hammett scenario can reproduce the observed KIE to any acceptable degree of fidelity. Evidence based upon previous kinetics measurements and calculations upon a model system suggests that the stereogenic sulfur center is not likely to undergo inversion to a significant degree at the temperatures at which the Swern oxidation is performed here. Proceeding under the assumption of no stereoinversion at the sulfur center, calculations predict a nearly linear Arrhenius plot for the KIE--even with the inclusion of a one-dimensional tunneling correction. By contrast, the experimentally determined temperature dependence shows a significant concave upward curvature indicative of the influence of tunneling. Notably, KIEs measured in CCl(4), CHCl(3), CH(2)Cl(2), dichloroethane, and chlorobenzene at -23 °C showed little variance. This finding discounted the possible influence from dynamical effects due to incomplete vibrational relaxation. An ad hoc amplification of the imaginary frequencies corresponding to the first-order saddle points corresponding to endo-TS1 and exo-TS1 allowed us to reproduce the experimental temperature dependence of the KIE using only two adjustable parameters applied to a kinetic scenario that involves four isotopomeric transition states. The cumulative data and computational modeling strongly suggest that, even though the intramolecular (2)H KIE observed in these experiments is small, this reaction requires a multidimensional description of the tunneling phenomenon to accurately reproduce experimental trends.

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Quantifying the limits of transition state theory in enzymatic catalysis.

Publications

Quantifying the limits of transition state theory in enzymatic catalysis.

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