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

引用本文: 杨丽君, 刘茜, 袁文彬, 杨胜勇. 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[J]. 物理化学学报, 2013, 29(02): 423-430. doi: 10.3866/PKU.WHXB201211212 shu

Citation: YANG Li-Jun, LIU Qian, YUAN Wen-Bin, YANG Sheng-Yong. Molecular Dynamics Simulations of Interactional Mechanism and Binding Energy Calculations between Kinase ABL and Small Molecules Binding at Myristoyl Pocket[J]. Acta Physico-Chimica Sinica, 2013, 29(02): 423-430. doi: 10.3866/PKU.WHXB201211212 shu

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

基金项目:
四川省教育厅自然科学重点项目(11ZA294) (11ZA294)

西华师范大学科研启动项目(10B006)资助 (10B006)

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:

English

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

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 Date: 18 September 2012
Available Online: 14 January 2013
Fund Project:
四川省教育厅自然科学重点项目(11ZA294)

西华师范大学科研启动项目(10B006)资助

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:

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1.
沈阳化工大学材料科学与工程学院沈阳 110142

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

English

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

CCS Chemistry：嵌段共聚物自组装成 “三明治”二维有机材料，实现纳米级压力传感功能

CCS Chemistry：颜徐州、鲍哲南：你的皮肤可能是一片SPMs

CCS Chemistry：工作高效不疲劳，只须让催化剂动起来

CCS Chemistry：静电组装导向聚合- 聚电解质纳米凝胶量化制备新策略

CCS Chemistry：金黄色葡萄球菌醛基脱氢酶是如何识别特异性底物的？

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通讯作者: 陈斌, bchen63@163.com

中国化学会秘书处

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

English

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

CCS Chemistry：嵌段共聚物自组装成 “三明治”二维有机材料，实现纳米级压力传感功能

CCS Chemistry：颜徐州、鲍哲南： 你的皮肤可能是一片SPMs

CCS Chemistry：工作高效不疲劳，只须让催化剂动起来

CCS Chemistry：静电组装导向聚合- 聚电解质纳米凝胶量化制备新策略

CCS Chemistry：金黄色葡萄球菌醛基脱氢酶是如何识别特异性底物的？

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