Energetic analysis of the two controversial drug binding sites of the M2 proton channel in influenza A virus.
Understanding the mechanism of the M2 proton channel of influenza A is crucially important to both basic research and drug discovery. Recently, the structure was determined independently by high-resolution NMR and X-ray crystallography. However, the two studies lead to completely different drug-binding mechanisms: the X-ray structure shows the drug blocking the pore from inside; whereas the NMR structure shows the drug inhibiting the channel from outside by an allosteric mechanism. Which one of the two is correct? To address this problem, we conducted an in-depth computational analysis. The conclusions drawn from various aspects, such as energetics, the channel-gating dynamic process, the pK(a) shift and its impact on the channel, and the consistency with the previous functional studies, among others, are all in favour to the allosteric mechanism revealed by the NMR structure. The findings reported here may stimulate and encourage new strategies for developing effective drugs against influenza A, particularly in dealing with the drug-resistant problems.
Du
Qi-Shi
QS
Guangxi Academy of Sciences, Nanning, Guangxi, China. qishi_du@yahoo.com.cn
Huang
Ri-Bo
RB
Wang
Cheng-Hua
CH
Li
Xiao-Ming
XM
Chou
Kuo-Chen
KC
D000547:Amantadine / Q000378:metabolism; D000998:Antiviral Agents / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral; D009980:Influenza A virus / Q000737:chemistry* / Q000378:metabolism; D015640:Ion Channel Gating; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D012299:Rimantadine / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000737:chemistry* / Q000378:metabolism; D000086082:Viroporin Proteins
D000547:Amantadine; D000998:Antiviral Agents; D012299:Rimantadine; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins