Acid activation mechanism of the influenza A M2 proton channel

Ruibin Liang, Jessica M. Swanson, Jesper J. Madsen, Mei Hong, William F. DeGrado, Gregory A. Voth

Research output: Contribution to journalArticlepeer-review

Abstract

<jats:p>The homotetrameric influenza A M2 channel (AM2) is an acid-activated proton channel responsible for the acidification of the influenza virus interior, an important step in the viral lifecycle. Four histidine residues (His37) in the center of the channel act as a pH sensor and proton selectivity filter. Despite intense study, the pH-dependent activation mechanism of the AM2 channel has to date not been completely understood at a molecular level. Herein we have used multiscale computer simulations to characterize (with explicit proton transport free energy profiles and their associated calculated conductances) the activation mechanism of AM2. All proton transfer steps involved in proton diffusion through the channel, including the protonation/deprotonation of His37, are explicitly considered using classical, quantum, and reactive molecular dynamics methods. The asymmetry of the proton transport free energy profile under high-pH conditions qualitatively explains the rectification
Original languageEnglish
Pages (from-to)E6955-E6964
JournalProceedings of the National Academy of Sciences of the United States of America
DOIs
StatePublished - Nov 8 2016

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