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The Chemical and Dynamical Influence of the Anti-Viral Drug Amantadine on the M₂ Proton Channel Transmembrane Domain

Jun Hu ^* , Riqiang Fu  and Timothy A. Cross ^*  

^* Department of Chemistry and Biochemistry, Institute of Molecular Biophysics, Florida State University; and National High Magnetic Field Laboratory, Tallahassee, Florida

Correspondence: Address reprint requests to T. A. Cross, Tel.: 850-644-0917; E-mail: cross{at}magnet.fsu.edu.

The M₂ proton channel plays a vital role in the life cycle of the influenza A virus. His³⁷, the key residue in the M₂ transmembrane domain (M₂-TMD), plays a central role in the proton conductance mechanism. The anti-influenza drug, amantadine, inhibits the channel activity through binding to the pore of the M₂ channel. The nuclear spin relaxation data and polarization inversion spin exchange at the magic angle spectra show that both the polypeptide backbone and His³⁷ side chain are more constrained in the presence of amantadine. Using ¹⁵N cross polarization magic-angle spinning NMR spectroscopy, the protonation of His³⁷ of M₂-TMD in lipid bilayers was monitored in the absence and presence of amantadine as a function of pH. Binding amantadine lowers the His³⁷ pK_a values by approximately three orders of magnitude compared with the first pK_a of histidine in amantadine-free M₂-TMD. Amantadine's influence on the His³⁷ chemical properties suggests a novel mechanism by which amantadine may inhibit proton conductance.

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