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QM/MM Molecular Dynamics Study of the O-GlcNAc Transferase Reaction Mechanism

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KOZMON Stanislav KUMARI Manju TVAROŠKA Igor KOČA Jaroslav

Rok publikování 2014
Druh Konferenční abstrakty
Fakulta / Pracoviště MU

Středoevropský technologický institut

Citace
Popis Glycosylation is one of the important post-translational modifications that provide greater proteomic diversity This event is also critical for a wide range of biological processes, such as cell adhesion, defense mechanism, cell proliferation, cancer metastasis etc through variety of glycoconjugates. These glycoconjugates are formed by glycosyltransferases which add saccharides onto proteins, lipids sugars etc. Here we are exploring the reaction mechanisms of O-GlcNAc transferase (OGTs), where GlcNAc is transferred to –OH group of Ser/Thr of the proteins. Three groups have proposed mechanisms on different crystal structures of OGTs, suggesting different catalytic base to abstract proton from Ser, 1) His498[1], 2) alpha-phosphate[2], and 3) water molecule shunting[3] , but still the process is not clear. In presented study we were trying to confirm one of the proposed mechanisms employing hybrid QM/MM CPMD molecular dynamics. We have modelled all three proposed mechanisms. The enzyme was partitioned for catalytic site as quantum zone and rest of the protein was treated with MM in explicit solvent box. Whole model has approximately 92000 atoms. Observed results suggest that in all the three mechanisms nucleophilic attack is followed by bond dissociation, proton transfer and bond formation. Obtained energy profiles favour reaction mechanism where alpha-phosphate serves as catalytic base.
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