Mechanism of Proton Transport of the M2 Proton Channel Studied by Constant pH Molecular Dynamics

The M2 protein of the influenza virus is a proton-selective homotetrameric channel. During virus entry, M2 is activated by the low pH of the endosome and transports protons into the virion, initiating viral uncoating. A histidine tetrad in the pore of the M2 transmembrane domain is responsible for pH activation and proton selectivity. A number of different mechanisms have been proposed for proton transport of M2 based on experimental and computational studies. To test these hypotheses, we applied the explicit-solvent continuous constant pH molecular dynamics method to study the pH-dependent conformational dynamics of M2 in explicit membrane. The calculated pKa values of the histidine tetrad are comparable to experimental values. The C-terminal openning of M2 became wider when pH was lowered. This work provides novel insight into the coupled protonation and conformational dynamics of the M2 proton channel.