Combined QM(DFT)/MM Molecular Dynamics Simulations of the Deamination of Cytosine by Yeast Cytosine Deaminase (yCD)
Combined QM(DFT)/MM Molecular Dynamics Simulations of the Deamination of Cytosine by Yeast Cytosine Deaminase (yCD)
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酵母胞嘧啶脱氨酶 (yCD) 脱氨的 QM(DFT)/MM 分子动力学组合模拟
DOI：
10.1002/jcc.24306
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发表时间：
2016
影响因子：
3
通讯作者：
Mo Yirong
中科院分区：
文献类型：
--
作者：
Zhang Xin;Zhao Yuan;Yan Honggao;Cao Zexing;Mo Yirong
采用量子力学（B3 LYP/6 - 31 G *）和分子力学（QM/MM）相结合的分子动力学模拟方法，研究了酵母胞嘧啶脱氨酶（yCD）催化胞嘧啶水解脱氨生成尿嘧啶的机理.虽然胞嘧啶与锌中心没有直接结合，但它与配位到锌的水分子反应，并且相邻的保守Glu 64作为一般的酸/碱将质子从水穿梭到胞嘧啶。整个反应由几个质子转移过程和亲核攻击组成。鉴定了胞嘧啶和水与锌结合的四面体中间加合物，其与具有抑制剂2-嘧啶酮的yCD的晶体结构相似。在整个催化循环中，具有18.0 kcal/mol势垒的速率决定步骤发生在尿嘧啶离开的过程中，其中质子从水转移到Glu 64和所得氢氧根阴离子对尿嘧啶环的C2的亲核攻击同时发生。© 2016 Wiley Periodicals，Inc.
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.