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化学学报
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化学学报 ›› 2010, Vol. 68 ›› Issue (15): 1499-1506. 上一篇    下一篇

研究论文

HIV-1整合酶G140A/G149A及T66I/S153Y突变后的构象变化

胡建平*,1，唐典勇1，范晶1，常珊2   

  1. (1乐山师范学院化学与生命科学学院 乐山 614004)
    (2华南农业大学信息学院 广州 510642)
  • 投稿日期:2009-10-08 修回日期:2010-03-10 发布日期:2010-03-20
  • 通讯作者: 胡建平 E-mail:hujianping@emails.bjut.edu.cn
  • 基金资助:

    四川省自然科学基金（No.2008JY0119），四川省教育厅（No. 08ZB054）和乐山师范学院博士启动基金（Z0859）资助项目

Conformational Change of HIV-1 Integrase after the G140A/G149A and T66I/S153Y Mutation

Hu Jianping*,1 Tang Dianyong1 Fan Jing1 Chang Shan2   

  1. (1 College of Chemistry and Life Science, Leshan Teacher s College, Leshan 614004)
    (2 College of Informatics, South China Agricultural University, Guangzhou 510642)
  • Received:2009-10-08 Revised:2010-03-10 Published:2010-03-20
  • Contact: Jian-Ping HU E-mail:hujianping@emails.bjut.edu.cn

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对HIV-1整合酶(IN)野生体(WT), G140A/G149A和T66I/S153Y突变体分别进行了5 ns的分子动力学(MD)模拟, 并用成簇和动力学交叉相关图(DCCM)分析了突变前后的构象变化. 整体结构分析表明, 突变后IN的活性口袋尺寸变化不大, T66I/S153Y突变体分子的整体运动性提高, 而G140A/G149A突变体的功能loop区柔性明显上升. IN WT的方均根涨落(RMSF)模拟值与B因子实验值的较高相关性证明了柔性分析的合理性. 通过成簇分析发现, IN在突变后功能loop区构象有开合运动, 构象开放的概率是: 体系G140A/G149A＞T66I/S153Y＞WT. 最后DCCM分析结果表明, 功能性分区的弱化以及DDE基序残基运动相关性的降低均有可能是突变体G140A/G149A和T66I/S153Y产生抗药性的原因. 模拟结果对理解IN突变体的抗药机理以及为基于HIV-1 IN的药物分子设计提供了理论帮助.

关键词: 整合酶, 突变体, 成簇分析, 动力学交叉相关, 构象变化

Three 5 ns independent Molecular dynamics (MD) simulations were performed for HIV-1 Integrase (IN) wild-type (WT), G140A/G149A and T66I/S153Y mutants, respectively. Conformational change was explored after the mutations via cluster and domain cross correlation map (DCCM) analysis. The whole structure analysis shows that the dimension of the active pocket of IN maintains constant in despite of the mutation, while the T66I/S153Y and G140A/G149A mutants exhibit higher mobility in the whole system and functional loop region, respectively. The better correlation between the simulated data of the root mean square fluctuation (RMSF) of IN WT and the experimental B factor values confirms the validity of flexibility analysis. The cluster analysis shows that the functional loop region of IN possesses open-close motion after the mutation, and the systems ranked according to the open-close possibility from big to small are G140A/G149A, T66I/S153Y and WT. Finally, the DCCM analysis results show that both the attenuation of the functional region division and the decrease of the motive correlation of the DDE motif residues may cause the drug resistance for the G140A/G149A and T66I/S153Y mutants. The results generated from the above simulation should be theoretically useful for understanding the drug resistance mechanism of the IN mutant, also for the further drug design based on the structure of HIV-1 IN.

Key words: integrase, mutant, cluster analysis, domain cross correlation map, conformational change