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Insights into enzym...
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Oanca, GabrielNatl Inst Chem, Lab Biocomp & Bioinformat, Ljubljana, Slovenia.;Alexandru Ioan Cuza Univ, Fac Phys, Iasi, Romania.
(författare)
Insights into enzyme point mutation effect by molecular simulation : phenylethylamine oxidation catalyzed by monoamine oxidase A
- Artikel/kapitelEngelska2016
Förlag, utgivningsår, omfång ...
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2016
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Royal Society of Chemistry (RSC),2016
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LIBRIS-ID:oai:DiVA.org:uu-298085
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-298085URI
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https://doi.org/10.1039/c6cp00098cDOI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:art swepub-publicationtype
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The I335Y point mutation effect on the kinetics of phenylethylamine decomposition catalyzed by monoamine oxidase A was elucidated by means of molecular simulation. The established empirical valence bond methodology was used in conjunction with the free energy perturbation sampling technique and a classical force field representing the state of reactants and products. The methodology allows for the simulation of chemical reactions, in the present case the breaking of the alpha-C-H bond in a phenylethylamine substrate and the subsequent hydrogen transfer to the flavin cofactor, resulting in the formation of the N-H bond on flavin. The empirical parameters were calibrated against the experimental data for the simulated reaction in a wild type protein and then used for the calculation of the reaction free energy profile in the I335Y mutant. In very good agreement with the measured kinetic data, mutation increases the free energy barrier for the rate limiting step by slightly more than 1 kcal mol(-1) and consequently decreases the rate constant by about an order of magnitude. The magnitude of the computed effect slightly varies with simulation settings, but always remains in reasonable agreement with the experiment. Analysis of trajectories reveals a major change in the interaction between phenyl rings of the substrate and the neighboring Phe352 residue upon the I335Y mutation due to the increased local polarity, leading to an attenuated quadrupole interaction between the rings and destabilization of the transition state. Additionally, the increased local polarity in the mutant allows for a larger number of water molecules to be present near the active site, effectively shielding the catalytic effect of the enzyme and contributing to the increased barrier.
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Purg, MihaUppsala universitet,Struktur- och molekylärbiologi(Swepub:uu)mihpu392
(författare)
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Mavri, JanezNatl Inst Chem, Lab Biocomp & Bioinformat, Ljubljana, Slovenia.
(författare)
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Shih, Jean C.Univ So Calif, Sch Pharm, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA USA.;Univ So Calif, USC Taiwan Ctr Translat Res, Los Angeles, CA USA.;Univ So Calif, Keck Sch Med, Dept Cell & Neurobiol, Los Angeles, CA 90033 USA.
(författare)
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Stare, JernejNatl Inst Chem, Lab Biocomp & Bioinformat, Ljubljana, Slovenia.
(författare)
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Natl Inst Chem, Lab Biocomp & Bioinformat, Ljubljana, Slovenia.;Alexandru Ioan Cuza Univ, Fac Phys, Iasi, Romania.Struktur- och molekylärbiologi
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Physical Chemistry, Chemical Physics - PCCP: Royal Society of Chemistry (RSC)18:19, s. 13346-133561463-90761463-9084
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