物理化学学报 >> 2013, Vol. 29 >> Issue (04): 843-848.doi: 10.3866/PKU.WHXB201301183

生物物理化学 上一篇    下一篇

苯磺酰胺从碳酸酐酶II中脱离过程的分子动力学模拟

孙维琦1,3, 张继龙2, 郑清川2, 孙志伟1,4, 张红星2   

  1. 1 吉林大学公共卫生学院, 长春 130021;
    2 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 130023;
    3 北华大学公共卫生学院, 吉林 132013;
    4 首都医科大学公共卫生与家庭医学院, 北京 100069
  • 收稿日期:2012-11-08 修回日期:2013-01-15 发布日期:2013-03-25
  • 通讯作者: 郑清川, 孙志伟 E-mail:zhengqc@jlu.edu.cn; zwsun@ccmu.edu.cn
  • 基金资助:

    国家自然科学基金(21273095, 20903045, 21203072), 高等学校博士点学科专项基金(20070183046)与吉林大学基本科研业务费(201003044)资助项目

Molecular Dynamics Simulations of the Unbinding of Phenylsulfonamide from Carbonic Anhydrase II

SUN Wei-Qi1,3, ZHANG Ji-Long2, ZHENG Qing-Chuan2, SUN Zhi-Wei1,4, ZHANG Hong-Xing2   

  1. 1 School of Public Health, Jilin University, Changchun 130021, P. R. China;
    2 State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130023, P. R. China;
    3 School of Public Health, Beihua University, Jilin 132013, P. R. China;
    4 School of Public Health and Family Medicine, Capital Medical University, Beijing 100069, P. R. China
  • Received:2012-11-08 Revised:2013-01-15 Published:2013-03-25
  • Supported by:

    The project was supported by the National Natural Science Foundation of China (21273095, 20903045, 21203072), Specialized Research Fund for the Doctoral Program of Higher Education, China (20070183046), and Specialized Fund for the Basic Research of Jilin University, China (201003044).

摘要:

综合运用分子动力学模拟和自由能计算方法研究了苯磺酰胺分子从碳酸酐酶II (CA II)的活性位点脱离过程中底物与酶之间的动态相互作用. 脱离过程的平均力势(PMF)显示, 底物脱离时存在一个特殊的结合状态. 其中, 静电相互作用占据了主导地位. 轨迹分析显示, 除了金属离子的配位作用之外, 底物脱离路径上的关键残基Leu198、Thr199和Thr200通过与底物磺胺基的氢键作用阻碍了底物从酶中的脱离. 当前的研究对于深入认识磺胺类药物与CA II的详细结合过程和相关的药物改良与设计具有重要的指导意义.

关键词: 分子动力学模拟, 自由能, 苯磺酰胺, 碳酸酐酶II, 底物结合

Abstract:

Molecular dynamics (MD) simulations and free energy calculations were integrated to investigate substrate-enzyme dynamic interactions during the unbinding of phenylsulfonamide from carbonic anhydrase II (CA II). The potential of mean force (PMF) along the unbinding pathway shows that a special ligand-binding state exists, and the electrostatic interaction dominates the ligand?s binding with CA II. The analysis of trajectories reveals that, apart from the zinc ion, the key residues in the unbinding pathway, Leu198, Thr199, and Thr200, prevent the substrate?s unbinding from the enzyme by hydrogen bonding with the sulfanilamide group of the substrate. The present results are of direct significance for the in-depth understanding of the sulfonamide-CA II binding process and related drug design.

Key words: Molecular dynamics simulation, Free energy, Phenylsulfonamide, Carbonic anhydrase II, Substrate’s binding

MSC2000: 

  • O641