物理化学学报 >> 2013, Vol. 29 >> Issue (02): 423-430.doi: 10.3866/PKU.WHXB201211212

生物物理化学 上一篇    下一篇

激酶ABL与肉豆蔻酰位点小分子作用机理的分子动力学模拟及自由能计算

杨丽君1, 刘茜1, 袁文彬1, 杨胜勇2   

  1. 1 西华师范大学化学化工学院, 化学合成与污染控制四川省重点实验室, 四川 南充 637009;
    2 四川大学华西医院生物治疗国家重点实验室, 成都 610041
  • 收稿日期:2012-09-18 修回日期:2012-11-21 发布日期:2013-01-14
  • 通讯作者: 杨丽君 E-mail:ljyang@cwnu.edu.cn
  • 基金资助:

    四川省教育厅自然科学重点项目(11ZA294)和西华师范大学科研启动项目(10B006)资助

Molecular Dynamics Simulations of Interactional Mechanism and Binding Energy Calculations between Kinase ABL and Small Molecules Binding at Myristoyl Pocket

YANG Li-Jun1, LIU Qian1, YUAN Wen-Bin1, YANG Sheng-Yong2   

  1. 1 Chemistry Synthesis and Pollution Key Laboratory of Sichuan Province, College of Chemistry and Chemical Engineering, China West Normal University, Nanchong 637009, Sichuan Province, P. R. China;
    2 State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, P. R. China
  • Received:2012-09-18 Revised:2012-11-21 Published:2013-01-14
  • Supported by:

    The project was supported by the Scientific Research Fund of Sichuan Provincial Education Department, China (11ZA294) and Scientific Research Starting Foundation of ChinaWest Normal University, China (10B006).

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摘要：

采用分子动力学方法研究激酶ABL 与ATP 位点小分子imatinib、P16 及变构位点小分子STJ、MS7、MS9、3YY、MYR等的结合, 并用GBSA (generalized Born surface area)方法将结合自由能分解到各残基. 自由能计算结果表明, 小分子STJ、MS7、MS9 有利于imatinib 与ABL 结合; 小分子STJ、MS7、MS9 与激酶ABL的结合自由能接近, 绝对值均大于ABL 与3YY、MYR 的结合自由能. 能量分解表明, ABL 残基ILE502、VAL506、LEU510与STJ和MYR的相互作用是αI 螺旋处于弯曲状态的重要原因. 模拟过程中ABL肉豆蔻酰口袋残基均方根偏差(RMSD)变化值表明, STJ等小分子抑制剂与ABL结合后降低了肉豆蔻酰口袋残基的柔性.

关键词: 分子动力学, 激酶, 豆蔻酰位点, 自由能, 抑制剂

Abstract:

We performed molecular dynamics simulations on complexes of ABL to investigate the binding of imatinib, P16 (binding at the ATP pocket), and STJ, MS7, MS9, 3YY, and MYR (binding at the myristoyl pocket). The calculated binding energies were then decomposed to determine the ligand-residue pair interactions, using the generalized Born surface area (GBSA) method. The results showed that the binding energies are almost the same for STJ, MS7, and MS9, and their absolute values are larger than those of 3YY and MYR. The decomposition of the binding energy revealed that three residues (ILE502, VAL506, and LEU510) contribute significantly to hold the αI-helix in a bent conformation in the STJ-ABL and MYR-ABL complexes. The root mean square deviation (RMSD) values for the residues forming myristoyl pocket showed that the inhibitors in this pocket decrease the flexibility of the corresponding residues.

Key words: Molecular dynamics, Kinase, Myristoyl pocket, Free energy, Inhibitor