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题名: How Does Influenza Virus A Escape from Amantadine?
作者: Qin, Guangrong1;  Yu, Kunqian1;  Shi, Ting1;  Luo, Cheng1;  Li, Guohui2;  Zhu, Weiliang1, 3;  Jiang, Hualiang1, 3
刊名: JOURNAL OF PHYSICAL CHEMISTRY B
发表日期: 2010-07-01
DOI: 10.1021/jp911588y
卷: 114, 期:25, 页:8487-8493
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Physical Sciences
类目[WOS]: Chemistry, Physical
研究领域[WOS]: Chemistry
英文摘要: Antiflu drugs such as amantadine (AMT) were reported to be insensitive to influenza A virus gradually after their marketing. Mutation experiments indicate that the trans-membrane domain of M2 protein plays an essential role in AMT resistance, especially the S31N mutation. To investigate the details of structure and mechanism, molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations have been carried out on both the wild-type protein and its S31N mutant. Our MD simulations reveal AMT can occupy different binding positions in the pore of M2 channel, and the binding modes have also been verified and analyzed by QM/MM calculations. More importantly, we find the formation of a water wire modulated by the binding position of AMT to be essential for the function of M2 protein, and, the block of water wire can inhibit channel function in the WT system. Failure of channel blocking would cause AMT drug resistance in the S31N mutant. These results support one of the conflicting views about M2 drug binding sites: AMT binds to the pore of M2 channel. Our findings help clarify the resistant mechanism of AMT to M2 protein and should facilitate the discovery of new drugs for treating influenza A virus.
关键词[WOS]: M2 PROTON CHANNEL ;  A VIRUS ;  DRUG-INHIBITION ;  ION-CHANNEL ;  MECHANISM ;  ONIOM ;  GEOMETRY ;  PROTEIN ;  MODEL ;  OPTIMIZATION
语种: 英语
WOS记录号: WOS:000278982200024
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/141972
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.Chinese Acad Sci, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Mol Modeling & Design, State Key Lab Mol React Dynam, Dalian 116023, Peoples R China
3.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China

Recommended Citation:
Qin, Guangrong,Yu, Kunqian,Shi, Ting,et al. How Does Influenza Virus A Escape from Amantadine?[J]. JOURNAL OF PHYSICAL CHEMISTRY B,2010,114(25):8487-8493.
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