Insights on the Origin of Catalysis on Glycine N-Methyltransferase from Computational Modeling
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comunitat-uji-handle2:10234/7013
comunitat-uji-handle3:10234/8638
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Title
Insights on the Origin of Catalysis on Glycine N-Methyltransferase from Computational ModelingDate
2018-02Publisher
American Chemical SocietyBibliographic citation
ŚWIDEREK, Katarzyna, et al. Insights on the Origin of Catalysis on Glycine N-Methyltransferase from Computational Modeling. Journal of the American Chemical Society, 2018, 140.12: 4327-4334.Type
info:eu-repo/semantics/articlePublisher version
https://pubs.acs.org/doi/abs/10.1021/jacs.7b13655Version
info:eu-repo/semantics/submittedVersionSubject
Abstract
The origin of enzyme catalysis remains a question of debate despite much intense study. We
report a QM/MM theoretical study of the SN2 methyl transfer reaction catalyzed by a glycine
N-methyltransferase (GNMT) and ... [+]
The origin of enzyme catalysis remains a question of debate despite much intense study. We
report a QM/MM theoretical study of the SN2 methyl transfer reaction catalyzed by a glycine
N-methyltransferase (GNMT) and three mutants to test whether recent experimental
observations of rate-constant reductions and variations in inverse secondary α-3H kinetic
isotope effects (KIEs) should be attributed to changes in the methyl donor−acceptor distance
(DAD): is catalysis due to a compression effect? Semiempirical (AM1) and DFT (M06-2X)
methods were used to describe the QM subset of atoms, while OPLS-AA and TIP3P classical
force fields were used for the protein and water molecules, respectively. The computed
activation free energies and KIEs are in good agreement with experimental data, but the
mutations do not meaningfully affect the DAD: compression cannot explain the experimental
variations on KIEs. On the contrary, electrostatic properties in the active site correlate with
the catalytic activity of wild type and mutants. The plasticity of the enzyme moderates the
effects of the mutations, explaining the rather small degree of variation in KIEs and
reactivities. [-]
Investigation project
panish Ministerio de Economi ́ a y Competitividad and FEDER funds (project CTQ2015-66223-C2), Generalitat Valenciana (PROME- TEOII/2014/022), Universitat Jaume I (project UJI · B2017- 31), and the USA National Institute of Health (ref No. NIH R01 GM065368) ; Spanish Ministerio de Educación Cultura y Deporte for travel financial support (project PRX17/00166)Rights
Copyright © 2018 American Chemical Society
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