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Mechanism of DNA Cytosine Methylation Determined by Ab Initio Quantum Mechanical/Molecular Mechanical-Molecular Dynamics Approach.

机译：从头算量子力学/分子力学-分子动力学方法确定DNA胞嘧啶甲基化的机理。

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摘要

DNA cytosine methyltransferases regulate the expression of the genome through the precise epigenetic marking of certain cytosines with a methyl group, and aberrant methylation is a hallmark of human diseases, including cancer. Targeting these enzymes for drug design is currently a high priority. We have utilized ab initio quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations to extensively investigate the reaction mechanism of the representative DNA methyltransferase HhaI (M.HhaI) from prokaryotes, whose mechanism is shared with the mammalian enzymes. We obtain for the first time full free energy profiles for the complete reaction, together with reaction dynamics in atomistic detail. Our results show an energetically preferred mechanism in which nucleophilic attack of cytosine C5 on the S-adenosyl-L-methionine (AdoMet) methyl group is concerted with formation of the Michael adduct between a conserved Cys in the active site with cytosine C6. Spontaneous and reversible proton transfer between a conserved Glu in the active site and cytosine N3 at the transition state was observed in our simulations, revealing the chemical participation of this Glu residue in the catalytic mechanism. Subsequently, the beta-elimination of the C5 proton utilizes as base an OH -- derived from a conserved crystal water that is part of a proton wire water channel, and this syn-elimination reaction is the rate-limiting step. Design of novel cytosine methylation inhibitors would be advanced by our structural and thermodynamic characterization of the reaction mechanism.
机译：DNA胞嘧啶甲基转移酶通过某些带有甲基的胞嘧啶的精确表观遗传学标记来调控基因组的表达，异常的甲基化是包括癌症在内的人类疾病的标志。目前，将这些酶用于药物设计是当务之急。我们已利用从头开始的量子力学/分子机械（QM / MM）分子动力学（MD）模拟来广泛研究原核生物中代表性DNA甲基转移酶HhaI（M.HhaI）的反应机制，该机制与哺乳动物酶共有。我们首次获得完整反应的完全自由能分布以及原子动力学中的反应动力学。我们的结果显示了一种能量学上优选的机制，其中胞嘧啶C5对S-腺苷-L-甲硫氨酸（AdoMet）甲基的亲核攻击与在活性位点中保守的Cys与胞嘧啶C6之间的迈克尔加合物的形成相协调。在我们的模拟中观察到活性位点中保守的Glu与过渡态胞嘧啶N3之间的自发和可逆的质子转移，揭示了该Glu残留物在催化机理中的化学参与。随后，C5质子的β消除反应使用的是OH-作为基础，而OH-来源于作为质子丝水通道一部分的保守结晶水，该消除反应是限速步骤。通过我们对反应机理的结构和热力学表征，可以设计新型胞嘧啶甲基化抑制剂。

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  • 作者

    Yang, Jin.;

  • 作者单位

    New York University.;

  • 授予单位 New York University.;
  • 学科 Chemistry Organic.;Chemistry Analytical.;Biology Molecular.;Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 113 p.
  • 总页数 113
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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