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化学学报
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化学学报 ›› 2013, Vol. 71 ›› Issue (02): 199-204.DOI: 10.6023/A12110899 上一篇    下一篇

研究论文

Sirt1及Sirt2与活性分子INA的作用机制研究

陈晓光a, 赵晓杰b, 王嵩b, 王丽萍a, 李惟a, 孙家钟b   

  1. a 吉林大学生命科学学院 长春 130012;
    b 吉林大学理论化学研究所理论化学计算国家重点实验室 长春 130061
  • 投稿日期:2012-11-11 发布日期:2013-01-04
  • 通讯作者: 王嵩 E-mail:ws@jlu.edu.cn
  • 基金资助:

    项目受吉林省自然科学基金(No. 20101552);教育部博士点专项基金(No. 20090061120101)和吉林大学基本科研业务费专项资金(No. 450060488101)资助.

Investigation of Interactive Mechanism between the Sirt1, Sirt2 and an Active Molecule of INA

Chen Xiaoguanga, Zhao Xiaojieb, Wang Songb, Wang Lipinga, Li Weia, Sun Chiachongb   

  1. a College of Life Science, Jilin University, Changchun 130012;
    b State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130061
  • Received:2012-11-11 Published:2013-01-04
  • Supported by:

    Project supported by the Natural Science Foundation of Jilin Province in China (No. 20101552), Specialized Research Fund for the Doctoral Program of Higher Education (No. 20090061120101), and the Basic Research Fund of Jilin University (No. 450060488101).

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应用分子模拟理论与方法研究了人类沉默信息调节因子2相关酶类Sirtuin家族成员Sirt1及Sirt2与一种活性分子(命名为INA)的作用机制. 同源模建了Sirt1的三维结构, 通过分子对接手段得到Sirt1(NAD+)-INA及Sirt2(NAD+)- INA的两种复合物体系, 进行了分子动力学模拟. 并且分别计算了两种体系中关键氨基酸残基与INA的结合自由能值, 由此推测出Sirt1(NAD+)-INA、Sirt2(NAD+)-INA体系结合位点分别为Val72, Ser73和Arg272及Phe235, Leu264和Gly305, 确证了两种体系的结合模式. 模拟结果表明, 在Sirt1(NAD+)-INA体系中, INA与催化底物NAD+距离较近, 可以相互作用, 具有较高活性; 在Sirt2(NAD+)-INA体系中, INA与催化底物NAD+距离较远, 与在Sirt1体系中比较, INA对Sirt2体系的活性较弱, 结果与实验一致. 本文的研究, 对今后以去乙酰化酶Sirt1, Sirt2为靶点的新药开发具有一定指导意义.

关键词: 分子模拟, Sirt1, Sirt2, 活性分子INA, 作用机制

The molecular dynamics (MD) simulation is employed to investigate a certain enzymatic family of Sirtuin, which is related to the human silent information regulator 2. The interactive mechanism between Sirt1, Sirt2 (two members of the family of Sirtuin) and an active molecule (named INA in the present article) is studied in detail. The initial geometry of INA comes from the reference and is optimized at the B3LYP/6-311G** level. The homology modeling method is used to construct the conformation of Sirt1. Orderly, the NAD+ and INA are combined with the Sirt1 and Sirt2 (the initial Sirt2 conformation comes from the X-ray crystal diffraction) by using the molecular docking. In either system, the docking complex which has the lowest energy is set as the initial conformation in the next step. The MD simulations of 50 ns are carried out to optimize the two complexes of Sirt1(NAD+)-INA and Sirt2(NAD+)-INA, respectively. The MM-GBSA calculation is carried out to obtain the binding free energies between some key residues and INA. The decomposition values of binding free energies can indicate the binding sites of INA with the Sirt1(NAD+) and Sirt2(NAD+) complexes, respectively. It is located at Val72, Ser73 and Arg272 in the former and Phe235, Leu264 and Gly305 in the latter. The result of MD simulation can also indicate that the distance between INA and enzymatic substrate of NAD+ is longer in the Sirt2(NAD+)-INA than that in the Sirt1(NAD+)-INA complex, which leads to a weaker interaction between INA and NAD+in the former. Thus, the reactive activity of INA is weaker in Sirt2 than in Sirt1. The result is corresponding with that in experiment. And it is very significance to search some novel medicines which are mainly aimed at the histone acetylase of Sirt1 and Sirt2.

Key words: molecular dynamics simulation, Sirt1, Sirt2, active molecule of INA, interactive mechanism