Molecular Dynamics Study on Function of 2-ylacetic acid-Benzothiophene in Binding of HIV-1 Protease and Inhibitor

doi:10.6023/A13030327

Acta Chimica Sinica ›› 2013, Vol. 71 ›› Issue (08): 1167-1174.DOI: 10.6023/A13030327 Previous Articles Next Articles

Article

分子动力学研究2-乙酸苯并噻吩在HIV-1蛋白酶与抑制剂结合中的作用

孟现美, 王加磊, 张少龙, 张庆刚

山东师范大学物理与电子科学学院济南 250014

投稿日期:2013-03-25 发布日期:2013-05-24
通讯作者: 张庆刚, E-mail: zhangqg@sdnu.edu.cn E-mail:zhangqg@sdnu.edu.cn
基金资助:
项目受山东省自然科学基金(No. ZR2011HM048)和国家自然科学基金(No. 11274206)资助.

Molecular Dynamics Study on Function of 2-ylacetic acid-Benzothiophene in Binding of HIV-1 Protease and Inhibitor

Meng Xianmei, Wang Jialei, Zhang Shaolong, Zhang Qinggang

College of Physics and Electronics, Shandong Normal University, Jinan 250014

Received:2013-03-25 Published:2013-05-24
Supported by:
Project supported by the Natural Science Foundation of Shandong Province (No. ZR2011HM048) and the National Natural Science Foundation of China (No. 11274206).

In order to study the role of allosteric fragment 2-ylacetic acid-benzothiophene (2FX) in the binding of HIV-1 protease (PR) and inhibitor, the molecular dynamics simulations of 100 nanoseconds have been successfully performed on two systems of HIV-1 protease and inhibitor, respectively, one of which 2FX is attached to and another is not. Both types of new force fields, ff99SBildn and ff12SB, and GPU parallel computing technology have been used for each of the two systems in the simulations. By investigating the influence of 2FX on the protease, it is found that the binding of 2FX induces a conformational change of the protease. The dynamics behaviors of the two systems under the two force fields are compared with the VMD visualization software and it is found that, to a certain extent, there exist differences between those from the different forces. The root-mean-square deviations (RMSD), the B-factors of the two systems, and structure superposition between the calculated and X-ray crystal structures, which display that the system with 2FX has a more stable dynamics process and the vibration extent of the residues decreases, indicate that the 2FX bound in the protease can stabilize the system. The binding free energies have been calculated using the two force fields and using two methods, MM-PB/GBSA, respectively. The resulting free energy values, ff99SBildn: -70.52 and -68.42 kcal/mol (PB), -86.72 and -89.40 kcal/mol (GB); ff12SB: -75.40 and -77.68 kcal/mol (PB), -87.01 and -93.75 kcal/mol (GB), 2FX-system being generally of greater magnitudes, also suggest the allosteric fragment stabilizes the binding of inhibitor and PR. The present results, despite the discrepancies between those from the two different force fields, demonstrate that the allosteric fragment 2FX unambiguously gives rise to subtle changes of structure of the PR and make the inhibitor and PR combine more firmly. In particular, it is clear that the fragment acts to weaken the flexibility of the flap, strengthening the combination of the inhibitor and PR. In addition, it is also found that, with ff12SB force field, the dynamics processes are more stable, the calculated binding free energies are more favorable, and the results are better consistent with the experiments than with ff99SBildn. It is expected that this work could be helpful to design new allosteric inhibitors in the future.

Key words: HIV-1 protease, inhibitor, molecular dynamics simulation, MM-PB/GBSA method, allosteric inhibitor

Cite this article

Meng Xianmei, Wang Jialei, Zhang Shaolong, Zhang Qinggang. Molecular Dynamics Study on Function of 2-ylacetic acid-Benzothiophene in Binding of HIV-1 Protease and Inhibitor[J]. Acta Chimica Sinica, 2013, 71(08): 1167-1174.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

References

[1] Sa-Filho, D. J.; Costa, L. J.; de Oliveira, C. F.; Guimaraes, A. P.; Accetturi, C. A.; Tanuri, A.; Diaz, R. S. J. Clin. Virol. 2003, 28, 186.

[2] Hong, L.; Zhang, X. C.; Hartsuck, J. A.; Tang, J. Protein Sci. 2004, 9, 1898.

[3] Hu, G. D.; Zhu, T.; Zhang, S. L.; Wang, D. Y.; Zhang, Q. G. Eur. J. Med. Chem. 2010, 45, 227.

[4] Hou,T.; Zhang, W.; Wang, J.; Wang, W. Proteins 2009, 74, 837.

[5] Stoica, I.; Sadiq, S. K.; Coveney, P. V. J. Am. Chem. Soc. 2008, 130, 2639.

[6] Yao, X. X.; XU, S. M. Acta Chim. Sinica 2011, 69, 405 (in Chinese).

(姚雪霞，徐素明，化学学报, 2011, 69, 405.)

[7] Perryman, A. L.; Zhang, Q.; Soutter, H. H.; Rosenfeld, R. ; McRee, D. E; Olson, A. J.; Elder, J. E.; Stout, C. D. Chem Biol Drug Des. 2010, 75, 257.

[8] Cai, W. S.; Chipot, C. Acta Chim. Sinica 2013, 71, 159 (in Chinese).

(蔡文生, Christophe Chipot. 化学学报, 2013, 71, 159.)

[9] Wu, E. L.; Wong, K. Y.; Zhang, X.; Han, K. L.; Gao, J. L. J. Phys. Chem. B 2009, 113, 2477.

[10] Zhang, S. L.; Zou, J. W.; Jiang, Y. J.; Mao, X.; Zhang, B.; Liu, H. C.; Yu, Q. S. J. Med. Chem. 2005, 48, 7208.

[11] Hu, G. D.; Chen, J. Z.; Shi, S. H.; Yi, C. G.; Zhang, S. L.; Zhang, Q. G. Acta Chim. Sinica2010, 68, 603 (in Chinese).

(扈国栋，陈建中，时术华，尹长虹，张少龙，张庆刚，化学学报，2010, 68, 603.)

[12] Klepeis, J. L.; Lindorff-Larsen, L.; Dror, R. O.; Shaw, D. E. Curr. Opin. Struct. Biol. 2009, 19, 120.

[13] Case, D. A.; Darden, T. A.; Cheatham, T. E., III; Simmerling, C. L.; Wang, J.; Duke, R. E.; Luo, R.; Walker, R. C.; Zhang, W.; Merz, K. M.; Roberts, B. P.; Hayik, S.; Roitberg, A. E.; Seabra, G.; Swails, J.M.; Kolossváry, I.; Wong, K. F.; Paesani, F.; Vanicek, J.; Wolf, R. M.; Liu,J.; Wu, X.; Brozell, S. R.; Steinbrecher, T.; Gohlke, H.; Cai, Q.; Ye, X.;Wang, J.; Hsieh, M.-J.; Cui, G.; Roe, D. R.; Mathews, D. H.; Seetin, M. G.; Salomon-Ferrer, R.; Sagui, C.; Babin, V.; Luchko, T.; Gusarov, S.; Kovalenko, A.; Kollman, P. A. AMBER 12; University of California: San Francisco, CA, 2012.

[14] Leach, A. R.. Molecular Modelling Principles and Applications 2nd ed., Ed.: World Publising Company, Beijing, 2003, Chapter 4

[15] Hornak, V.; Abel, R.; Okur, A.; Strockbine, B.; Roitberg, A.; Simmerling C. PROTEINS: Structure , Function, and Bioinformatics 2006,65, 712

[16] Lindorff, L. K.; Piana, S.; Palmo, K.; Maragakis, P.; Klepeis, J. L.; Dror, R. O.; Shaw, D. E. Protein Force Field 2010, 78, 1950.

[17] Chen, J. Z.; Yang, M. Y.; Hu, G. D,; Shi, S. H.; Yi, C. H.; Zhang, Q. G. J. Mol. Model, 2009, 15, 1245.

[18] Wang, J.; Wolf, R. M.; Case, D. A.; Kollman, P. A. J. Comput. Chem. 2004, 25, 1157.

[19] Pearlman, D. A.; Case, D. A.; Caldwell, J. W. Computer Physics Communications 1995, 91, 1.

[20] Adcock, S. A.; McCammon, J. A. Chem. Rev. 2006, 106, 1589.

[21] Wu, E. L.; Han, K. L.; Zhang, J. Z. H. Chem. Eur. J. 2008, 14, 8704.

[22] Hu, J. P.; Sun, T. G.; Chen, W. Z.; Wang, C. X. Acta Chim. Sinica 2006, 64, 2079 (in Chinese).

(胡建平, 孙庭广, 陈慰祖, 王存新, 化学学报, 2006, 64, 2079.)

[23] Zhuang, S. L.; Yu, Q. S.; Zou, J. W.; Jiang, Y. J.; Chen, Y. D.; Zhang, H. X.; Jin, H. X.; Liu, H. C.; Zhang, N. J . Mol. Struct. (Theochem) 2006, 763, 97.

[24] Miller, III, B. R.; McGee, Jr., T. D.; Swails, J. M.; Homeyer, N.; Gohlke, H.; Roitberg , A. E. J. Chem. Theory Comput. 2012, 8, 3314.

[25] Fogolari, F.; Brigo, A.; Molinari, H. J. Mol. Recognit. 2002, 15, 377.

[26] Gohlke, H.; Kiel, C.; Cade, D. A. J. Mol. Biol. 2003, 330, 891.

[27] De Clercq, E. Nat Rev. Drug Discov. 2007, 6, 1001.

[28] Sun, D. F.; Wang, J. L.; Zhang, S. L.; Zhang, Q. G.; Zhang, Y. C. Shandong science, 2012, 25, 20 ( in Chinese ).

(孙德福，王加磊，张少龙，张庆刚，张怿慈，山东科学，2012，25，20. )

分子动力学研究2-乙酸苯并噻吩在HIV-1蛋白酶与抑制剂结合中的作用

Molecular Dynamics Study on Function of 2-ylacetic acid-Benzothiophene in Binding of HIV-1 Protease and Inhibitor

PDF

Knowledge

Cited

Abstract

Cite this article

share this article

References

Related Articles 15

Recommended Articles

Metrics

Comments

[1]	Pei Qin, Hai Ma, Fa-Guang Zhang, Jun-An Ma. Synthesis of 6-CF₃-1,2,4-triazine-based Tyrosine Kinase Inhibitors and The Evaluation of Biological Activities^★ [J]. Acta Chimica Sinica, 2023, 81(7): 697-702.
[2]	Yingzhe Du, Heng Zhang, Shiling Yuan. Molecular Dynamics Simulation of Thermal Conductivity of Al₂O₃/PDMS Composites [J]. Acta Chimica Sinica, 2021, 79(6): 787-793.
[3]	Zhou Jiashen, Zhang Lin, Zhang Liang. Advances on Mechanism and Drug Discovery of Type-II Fatty Acid Biosynthesis Pathway [J]. Acta Chimica Sinica, 2020, 78(12): 1383-1398.
[4]	Wang Qin, Nie Zhou, Hu Yufang, Yao Shouzhuo. Electrochemical Assay for Acetylcholinesterase Activity Detection Based on Unique Electro-catalytic Activity of Cu(II)-thiol Coordination Polymer [J]. Acta Chim. Sinica, 2017, 75(11): 1109-1114.
[5]	Zhang Chuan, Zhang Lujia, Zhang Yang, Huang He, Hu Yi. Study on the Stability and Enzymatic Property Improvement of Porcine Pancreas Lipase Modified by Ionic Liquids Using Molecular Simulation [J]. Acta Chim. Sinica, 2016, 74(1): 74-80.
[6]	Du Xin, Xuan Bixia, Shen Zhengwu. Chemical Constituents with Neuraminidase Inhibitory Actives from Campylotropis Hirtella [J]. Acta Chim. Sinica, 2015, 73(7): 741-748.
[7]	Wang Chu, Chen Nan. Activity-based Protein Profiling [J]. Acta Chim. Sinica, 2015, 73(7): 657-668.
[8]	Sun Ting, Liu Qiang, Xiao Jijun, Zhao Feng, Xiao Heming. Molecular Dynamics Simulation of Interface Interactions and Mechanical Properties of CL-20/HMX Cocrystal and Its Based PBXs [J]. Acta Chimica Sinica, 2014, 72(9): 1036-1042.
[9]	Wang Shenfeng, Lin Jianping, He Peilan, Zuo Jianping, Long Yaqiu. 2-Aryl-3-carbonylquinolones：Design, Synthesis and Biological Evaluation of Novel HCV NS5B Polymerase Inhibitors [J]. Acta Chimica Sinica, 2014, 72(8): 906-913.
[10]	Wang Zhibin, Zhang Xuejing, Wang Yucong, Gao Jinpeng, Li Zhengping. Ultrasensitive Detection of Protein Kinase Activity by Using the Fluorescence Polarization Technique [J]. Acta Chimica Sinica, 2013, 71(12): 1620-1624.
[11]	Wang Yue. O-GlcNAc Transferase and Its Inhibitors [J]. Acta Chimica Sinica, 2013, 71(11): 1477-1487.
[12]	Hou Xueyan, Wu Feng, Zhou Meng, Luo Hao, Zhang Wenjuan, Han Xuan, Yan Guoyi, Shi Jianyou, Li Rui. Study of Fragmentation Mechanisms of Pyrrolo[3,4-c]pyrazole Derived Aurora Kinase Inhibitors by ESI-QTOF-MS/MS [J]. Acta Chimica Sinica, 2013, 71(08): 1161-1166.
[13]	Cai Wensheng, Christophe Chipot. Frontiers in High-Performance, Large-Scale Molecular Dynamics. 35 Years of Molecular-Dynamics Simulations of Biological Systems [J]. Acta Chimica Sinica, 2013, 71(02): 159-168.
[14]	Chen Xiaoguang, Zhao Xiaojie, Wang Song, Wang Liping, Li Wei, Sun Chiachong. Investigation of Interactive Mechanism between the Sirt1, Sirt2 and an Active Molecule of INA [J]. Acta Chimica Sinica, 2013, 71(02): 199-204.
[15]	Wang Yuan, Jiang Yongjun, Zhang Meiqing, Shen Yin. Synthesis, Biological Activity and Molecular Docking Research of α-Carbolines as GSK-3β Inhibitors [J]. Acta Chimica Sinica, 2012, 70(18): 1974-1978.