How pH opens a H+ channel: The gating mechanism of influenza A M2

Itamar Kass, Isaiah T. Arkin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

63 Scopus citations


The tetrameric M2 protein from influenza A is one of the simplest pH-gated H+ channels known, offering the potential of structurally characterizing its gating mechanism. Since the only ionizable groups in the pore are four histidines, we investigated the stability and dynamics of all six possible protonation states of the protein by using molecular dynamics. We show that while all channel protonation states are surprisingly stable, only systems with two or more charged histidines are appreciably conductive. The structural switch, from a uniprotonated to a biprotonated channel, causes an electrostatic repulsion between the charged histidines that pushes the helices apart. This results in the formation of a continuous water file that conducts protons via a H+ wire. pKa calculations place this transition at a pH of 5.6, in remarkable agreement with the experimental value. Since the conversion from uniprotonation to biprotonation occurs during endosome acidification, this explains how M2 is activated in vivo.

Original languageAmerican English
Pages (from-to)1789-1798
Number of pages10
Issue number12
StatePublished - Dec 2005

Bibliographical note

Funding Information:
The authors wish to thank H. Leonov, E.R. Bennett, and E. Arbely for the helpful discussions, as well as D. Bashford for help with running the pKa calculations. This research was supported in part by grants from the Israel Science Foundation (784/01), Deutsche Forschungsgemeinschaft (SA 7772/6-1), and from Niedersachsen to I.T.A.


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