title: Combined QM(DFT)/MM molecular dynamics simulations of the deamination of cytosine by yeast cytosine deaminase (yCD).
abstract: Extensive combined quantum mechanical (B3LYP/6-31G*) and molecular mechanical (QM/MM) molecular dynamics simulations have been performed to elucidate the hydrolytic deamination mechanism of cytosine to uracil catalyzed by the yeast cytosine deaminase (yCD). Though cytosine has no direct binding to the zinc center, it reacts with the water molecule coordinated to zinc, and the adjacent conserved Glu64 serves as a general acid/base to shuttle protons from water to cytosine. The overall reaction consists of several proton-transfer processes and nucleophilic attacks. A tetrahedral intermediate adduct of cytosine and water binding to zinc is identified and similar to the crystal structure of yCD with the inhibitor 2-pyrimidinone. The rate-determining step with the barrier of 18.0 kcal/mol in the whole catalytic cycle occurs in the process of uracil departure where the proton transfer from water to Glu64 and nucleophilic attack of the resulting hydroxide anion to C2 of the uracil ring occurs synchronously. © 2016 Wiley Periodicals, Inc.
authors.affiliation: State Key Laboratory of Chemical Resource Engineering, Institute of Materia Medica, College of Science, Beijing University of Chemical Technology, Beijing, 100029, China.|Department of Chemistry, Western Michigan University, Kalamazoo, Michigan 49008.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Physical Chemistry of Solid Surfaces and Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 360015, China.|The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng, 475004, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry, The Center for Biological Modeling, Michigan State University, East Lansing, Michigan, 48824.|Department of Chemistry, The Center for Biological Modeling, Michigan State University, East Lansing, Michigan, 48824.
authors.forename: Honggao
authors.initials: H
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Physical Chemistry of Solid Surfaces and Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 360015, China.
authors.forename: Zexing
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Department of Chemistry, Western Michigan University, Kalamazoo, Michigan 49008.
authors.forename: Yirong
authors.initials: Y
authors.lastname: Mo
mesh_terms: D003596:Cytosine / Q000737:chemistry*; D043525:Cytosine Deaminase / Q000378:metabolism*; D003641:Deamination / Q000502:physiology*; D056004:Molecular Dynamics Simulation; D015003:Yeasts / Q000201:enzymology*
chemical_list: D003596:Cytosine; D043525:Cytosine Deaminase
keywords: DFT; combined QM/MM; cytosine; enzymatic catalysis; molecular dynamics