Drug Inhibition and Proton Conduction Mechanisms of the Influenza A M2 Proton Channel

摘要

The influenza A virus matrix protein 2 (M2 protein) is a pH-regulated proton channel embedded in the viral membrane. Inhibition of the M2 proton channel has been used to treat influenza infections for decades due to the crucial role of this protein in viral infection and replication. However, the widely-used M2 inhibitors, amantadine and rimantadine, have gradually lost their efficiencies because of naturally-occurring drug resistant mutations. Therefore, investigation of the structure and function of the M2 proton channel will not only increase our understanding of this important biological system, but also lead to the design of novel and effective anti-influenza drugs. Despite the simplicity of the M2 molecular structure, the M2 channel is highly flexible and there have been controversies and arguments regarding the channel inhibition mechanism and the proton conduction mechanism. In this book chapter, we will first carefully review the experimental and computational studies of the two possible drug binding sites on the M2 protein and explain the mechanisms regarding how inhibitors prevent proton conduction. Then, we will summarize our recent molecular dynamics simulations of the drug-resistant mutant channels and propose mechanisms for drug resistance. Finally, we will discuss two existing proton conduction mechanisms and talk about the remaining questions regarding the proton-relay process through the channel. The studies reviewed here demonstrate how molecular modeling and simulations have complemented experimental work and helped us understand the M2 channel structure and function.