苯磺酰胺从碳酸酐酶II中脱离过程的分子动力学模拟

引用本文: 孙维琦, 张继龙, 郑清川, 孙志伟, 张红星. 苯磺酰胺从碳酸酐酶II中脱离过程的分子动力学模拟[J]. 物理化学学报, doi: 10.3866/PKU.WHXB201301183 shu

Citation: SUN Wei-Qi, ZHANG Ji-Long, ZHENG Qing-Chuan, SUN Zhi-Wei, ZHANG Hong-Xing. Molecular Dynamics Simulations of the Unbinding of Phenylsulfonamide from Carbonic Anhydrase II[J]. Acta Physico-Chimica Sinica, doi: 10.3866/PKU.WHXB201301183 shu

苯磺酰胺从碳酸酐酶II中脱离过程的分子动力学模拟

基金项目:
国家自然科学基金(21273095, 20903045, 21203072) (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 (20070183046)与吉林大学基本科研业务费(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:

English

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

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 Date: 08 November 2012
Available Online: 25 March 2013
Fund Project:
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

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:

1. [1]
  
  (1) Krishnamurthy, V. M.; Kaufman, G. K.; Urbach, A. R.; Gitlin,I.; Gudiksen, K. L.;Weibel, D. B.; Whitesides, G. M. Chem.Rev. 2008, 108, 946. doi: 10.1021/cr050262p
  (1) Krishnamurthy, V. M.; Kaufman, G. K.; Urbach, A. R.; Gitlin,I.; Gudiksen, K. L.;Weibel, D. B.; Whitesides, G. M. Chem.Rev. 2008, 108, 946. doi: 10.1021/cr050262p
2. [2]
  (2) Sanyal, G.; Maren, T. H. J. Biol. Chem. 1981, 256, 608.(2) Sanyal, G.; Maren, T. H. J. Biol. Chem. 1981, 256, 608.
3. [3]
  (3) Stabenau, E. K.; Heming, T. Comp. Biochem. Physiol. Part A:Mol. Integr. Physiol. 2003, 136, 271. doi: 10.1016/S1095-6433(03)00177-6(3) Stabenau, E. K.; Heming, T. Comp. Biochem. Physiol. Part A:Mol. Integr. Physiol. 2003, 136, 271. doi: 10.1016/S1095-6433(03)00177-6
4. [4]
  (4) Shah, G. N.; Ulmasov, B.;Waheed, A.; Becker, T.; Makani, S.;Svichar, N.; Chesler, M.; Sly,W. S. Proc. Natl. Acad. Sci. U. S.A. 2005, 102, 16771. doi: 10.1073/pnas.0508449102(4) Shah, G. N.; Ulmasov, B.;Waheed, A.; Becker, T.; Makani, S.;Svichar, N.; Chesler, M.; Sly,W. S. Proc. Natl. Acad. Sci. U. S.A. 2005, 102, 16771. doi: 10.1073/pnas.0508449102
5. [5]
  (5) Gay, C. V.;Weber, J. A. Crit. Rev. Eukaryotic Gene Expression2000, 10, 213.(5) Gay, C. V.;Weber, J. A. Crit. Rev. Eukaryotic Gene Expression2000, 10, 213.
6. [6]
  (6) Henry, R. P. Ann. Rev. Physiol. 1996, 58, 523. doi: 10.1146/annurev.ph.58.030196.002515(6) Henry, R. P. Ann. Rev. Physiol. 1996, 58, 523. doi: 10.1146/annurev.ph.58.030196.002515
7. [7]
  (7) Svastova, E.; Hulikova, A.; Rafajova, M.; Zatovicova, M.;Gibadulinova, A.; Casini, A.; Cecchi, A.; Scozzafava, A.;Supuran, C. T.; Pastorek, J.; Pastorekova, S. FEBS Lett. 2004,577, 439. doi: 10.1016/j.febslet.2004.10.043(7) Svastova, E.; Hulikova, A.; Rafajova, M.; Zatovicova, M.;Gibadulinova, A.; Casini, A.; Cecchi, A.; Scozzafava, A.;Supuran, C. T.; Pastorek, J.; Pastorekova, S. FEBS Lett. 2004,577, 439. doi: 10.1016/j.febslet.2004.10.043
8. [8]
  (8) Sun, M. K.; Alkon, D. L. Trends Pharm. Sci. 2002, 23, 83. doi: 10.1016/S0165-6147(02)01899-0(8) Sun, M. K.; Alkon, D. L. Trends Pharm. Sci. 2002, 23, 83. doi: 10.1016/S0165-6147(02)01899-0
9. [9]
  (9) Scoozzafava, A.; Mastrolorenzo, A; Supuran, C. T. Expert Opin.Ther. Pat. 2006, 16, 1627. doi: 10.1517/etp.2006.16.issue-12(9) Scoozzafava, A.; Mastrolorenzo, A; Supuran, C. T. Expert Opin.Ther. Pat. 2006, 16, 1627. doi: 10.1517/etp.2006.16.issue-12
10. [10]
  (10) Pastorekova, S.; Parkkila, S.; Pastorek, J.; Supuran, C. T.J. Enzyme Inhib. Med. Chem. 2004, 19, 199. doi: 10.1080/14756360410001689540(10) Pastorekova, S.; Parkkila, S.; Pastorek, J.; Supuran, C. T.J. Enzyme Inhib. Med. Chem. 2004, 19, 199. doi: 10.1080/14756360410001689540
11. [11]
  (11) Khalifah, R. G. J. Biol. Chem. 1971, 246, 2561.(11) Khalifah, R. G. J. Biol. Chem. 1971, 246, 2561.
12. [12]
  (12) Wistrand, P. J.; Schenholm, M.; Lonnerholm, G. Invest.Ophthalmol. Vision Sci. 1986, 27, 419.(12) Wistrand, P. J.; Schenholm, M.; Lonnerholm, G. Invest.Ophthalmol. Vision Sci. 1986, 27, 419.
13. [13]
  (13) Alward,W. L. M. N. Engl. J. Med. 1998, 339, 1298. doi: 10.1056/NEJM199810293391808(13) Alward,W. L. M. N. Engl. J. Med. 1998, 339, 1298. doi: 10.1056/NEJM199810293391808
14. [14]
  (14) Borthwick, K. J.; Kandemir, N.; Topaloglu, R.; Kornak, U.;Bakkaloglu, A.; Yordam, N.; Ozen, S.; Mocan, H.; Shah, G. N.;Sly,W. S.; Karet, F. E. J. Med. Genet. 2003, 40, 115. doi: 10.1136/jmg.40.2.115(14) Borthwick, K. J.; Kandemir, N.; Topaloglu, R.; Kornak, U.;Bakkaloglu, A.; Yordam, N.; Ozen, S.; Mocan, H.; Shah, G. N.;Sly,W. S.; Karet, F. E. J. Med. Genet. 2003, 40, 115. doi: 10.1136/jmg.40.2.115
15. [15]
  (15) Güzel, Ö.; Innocenti, A.; Scozzafava, A.; Salman, A.; Supuran,C. T. Bioorg. Med. Chem. Lett. 2009, 19, 3170. doi: 10.1016/j.bmcl.2009.04.123(15) Güzel, Ö.; Innocenti, A.; Scozzafava, A.; Salman, A.; Supuran,C. T. Bioorg. Med. Chem. Lett. 2009, 19, 3170. doi: 10.1016/j.bmcl.2009.04.123
16. [16]
  (16) Zhang, J. L.; Zheng, Q. C.; Li, Z. Q.; Zhang, H. X. PLoS ONE2012, 7, e39546.(16) Zhang, J. L.; Zheng, Q. C.; Li, Z. Q.; Zhang, H. X. PLoS ONE2012, 7, e39546.
17. [17]
  (17) Dong, X. Y.; Du,W. J.; Liu, F. F. Acta Phys. -Chim Sin. 2012,28, 2735. [董晓燕, 都文婕, 刘夫锋. 物理化学学报, 2012,28, 2735.] doi: 10.3866/PKU.WHXB201207162(17) Dong, X. Y.; Du,W. J.; Liu, F. F. Acta Phys. -Chim Sin. 2012,28, 2735. [董晓燕, 都文婕, 刘夫锋. 物理化学学报, 2012,28, 2735.] doi: 10.3866/PKU.WHXB201207162
18. [18]
  (18) Zhao, Y. S.; Zheng, Q. C.; Zhang, H. X.; Chu, H. Y.; Sun, C. C.Acta Phys. -Chim. Sin. 2009, 25, 417. [赵勇山, 郑清川, 张红星, 楚慧郢, 孙家钟. 物理化学学报, 2009, 25, 417.] doi: 10.3866/PKU.WHXB20090304(18) Zhao, Y. S.; Zheng, Q. C.; Zhang, H. X.; Chu, H. Y.; Sun, C. C.Acta Phys. -Chim. Sin. 2009, 25, 417. [赵勇山, 郑清川, 张红星, 楚慧郢, 孙家钟. 物理化学学报, 2009, 25, 417.] doi: 10.3866/PKU.WHXB20090304
19. [19]
  (19) Zhang, J. L.; Zheng, Q. C.; Zhang, H. X. Comput. Biol. Chem.2011, 35, 50. doi: 10.1016/j.compbiolchem.2011.01.001(19) Zhang, J. L.; Zheng, Q. C.; Zhang, H. X. Comput. Biol. Chem.2011, 35, 50. doi: 10.1016/j.compbiolchem.2011.01.001
20. [20]
  (20) Humphrey,W.; Dalke, A.; Schulten, K. J. Mol. Graph. 1996, 14,33. doi: 10.1016/0263-7855(96)00018-5(20) Humphrey,W.; Dalke, A.; Schulten, K. J. Mol. Graph. 1996, 14,33. doi: 10.1016/0263-7855(96)00018-5
21. [21]
  (21) Darden, T.; York, D.; Pedersen, L. J. Chem. Phys. 1993, 98,10089. doi: 10.1063/1.464397(21) Darden, T.; York, D.; Pedersen, L. J. Chem. Phys. 1993, 98,10089. doi: 10.1063/1.464397
22. [22]
  (22) Hoover,W. G. Phys. Rev. A 1985, 31, 1695. doi: 10.1103/PhysRevA.31.1695(22) Hoover,W. G. Phys. Rev. A 1985, 31, 1695. doi: 10.1103/PhysRevA.31.1695
23. [23]
  (23) Hénin, J.; Chipot, C. J. Chem. Phys. 2004, 121, 2904. doi: 10.1063/1.1773132(23) Hénin, J.; Chipot, C. J. Chem. Phys. 2004, 121, 2904. doi: 10.1063/1.1773132
24. [24]
  (24) Zhang, J. L.; Zheng, Q. C.; Zhang, H. X. J. Phys. Chem. B 2010,114, 7383. doi: 10.1021/jp9113078(24) Zhang, J. L.; Zheng, Q. C.; Zhang, H. X. J. Phys. Chem. B 2010,114, 7383. doi: 10.1021/jp9113078
25. [25]
  (25) Zhang, J. L.; Zheng, Q. C.; Li, Z. Q.; Zhang, H. X. PLoS ONE2013, 8, e53811.(25) Zhang, J. L.; Zheng, Q. C.; Li, Z. Q.; Zhang, H. X. PLoS ONE2013, 8, e53811.
26. [26]
  (26) Zhang, J. L.; Zheng, Q. C.; Zhang, H. X. Chem. Phys. Lett.2010, 484, 338. doi: 10.1016/j.cplett.2009.12.022
  (26) Zhang, J. L.; Zheng, Q. C.; Zhang, H. X. Chem. Phys. Lett.2010, 484, 338. doi: 10.1016/j.cplett.2009.12.022

扫一扫看文章

计量

PDF下载量: 928
文章访问数: 1195
HTML全文浏览量: 12

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142

苯磺酰胺从碳酸酐酶II中脱离过程的分子动力学模拟

English

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

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？

计量

通讯作者: 陈斌, bchen63@163.com

中国化学会秘书处

苯磺酰胺从碳酸酐酶II中脱离过程的分子动力学模拟

English

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

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？

计量

文章相关

通讯作者: 陈斌, bchen63@163.com

中国化学会秘书处

CCS Chemistry：颜徐州、鲍哲南：你的皮肤可能是一片SPMs