高等学校化学学报 ›› 2015, Vol. 36 ›› Issue (11): 2226.doi: 10.7503/cjcu20150628

• 物理化学 • 上一篇    下一篇

人类细胞色素P450 2E1酶在不同乙醇浓度下构象变化的分子动力学模拟

王衍2, 郑清川1,2()   

  1. 1. 吉林大学分子酶学工程教育部重点实验室, 长春 130021
    2. 理论化学研究所, 长春 130021
  • 收稿日期:2015-08-07 出版日期:2015-11-10 发布日期:2015-10-23
  • 作者简介:联系人简介: 郑清川, 男, 博士, 教授, 主要从事生物大分子的分子动力学模拟的研究. E-mail:zhengqc@jlu.edu.cn
  • 基金资助:
    国家自然科学基金(批准号: 21273095)资助

Molecular Dynamics Simulation on the Conformational Changes of CYP2E1 Enzyme Under Different Concentrations of Ethyl Alcohol

WANG Yan2, ZHENG Qingchuan1,2,*()   

  1. 1. Key Laborabory for Molecular Enzymology and Engineering, Ministry of Education, Jilin University, Changchun 130021, China
    2. Institute of Theoretical Chemistry, Jilin University, Changchun 130021, China
  • Received:2015-08-07 Online:2015-11-10 Published:2015-10-23
  • Contact: ZHENG Qingchuan E-mail:zhengqc@jlu.edu.cn

摘要:

细胞色素P450(CYP) 2E1家族酶是一种具有双重功能的单加氧酶, 能够参与市场上6%药物的代谢而具有重要的作用. 这类酶与酒精的消耗、 糖尿病、 肥胖症以及厌食症等密切相关, 引起了广泛的研究兴趣. 目前尚未见从原子水平上对这种酶在不同乙醇浓度下构象行为的研究. 基于此, 本文研究了花生四烯酸(AA)与CYP2E1复合物结构在不同乙醇浓度下构象与能量变化的特点. 对于在不同乙醇浓度下AA与CYP2E1的复合物结构, 采用分子动力学模拟结合自由能计算的方法进行研究. 分子动力学模拟结果表明, His109和Lys243氨基酸残基对AA与CYP2E1的结合起到了至关重要的作用. 当体系的乙醇浓度较高时, AA的结合能力有所下降, 这种结合能力的下降是由于AA与CYP2E1之间氢键相互作用力的减弱所致. 本研究对于AA与CYP2E1复合物结构在不同乙醇浓度下, AA分子与CYP2E1分子结合能力下降以及CYP2E1的构象变化给出了详细的解释. 本研究工作得到的结论对于实验和理论研究均有重要意义, 可为后续细胞色素P450酶类催化活性的研究提供理论支持.

关键词: 细胞色素P450 2E1酶, 分子动力学模拟, 结合自由能计算

Abstract:

Cytochrome P450(CYP) 2E1 is a dual function monoxygenase with a crucial role in the metabolism of 6% of drugs on the market at present. The enzyme is of tremendous interest for its association with alcohol consumption, diabetes, obesity and fasting. The enzyme’s conformational changes at different ethanol concentrations have not been rationalized at the atomic level. In this regard, we have investigated the effects of different ethanol concentrations on the structural and energetic characteristics upon the complex of arachidonic acid and CYP2E1(AA-CYP2E1). The molecular dynamics(MD) simulation combined with binding free energy calculations was carried out on AA-CYP2E1 complex at different ethanol concentrations. Based on the MD simulation results, two residues, His109 and Lys243, are responsible for the binding of AA molecule. The binding ability of AA molecue is decreased at high concentrations of ethanol. This is due to the loss of certain hydrogen bond interaction. The high concentration of ethanol can also affect the surface structure of AA-CYP2E1. Our work provides detailed atomistic insights into the structure-function relationships of CYP2E1 at different ethanol concentrations under dynamics conditions. This work also provides particular explanations on how different ethanol concentrations affect the surface structure of CYP2E1. Furthermore, the mutational effects on the activity of CYP2E1 obtained in the present study are beneficial to both experiment and computation of CYPs and may allow researchers to achieve desirable changes in enzymatic activities.

Key words: Cytochrome P450(CYP) 2E1 enzyme, Molecular dynamics(MD) simulation, Binding free energy calculation

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