The Influenza A Virus M2 Channel: A Molecular Modeling and Simulation Study

Abstract

The M2 protein of influenza virus forms ion channels activated by low pH which are proton permeable and play a key role in the life cycle of the virus. M2 is a 97-residue integral membrane protein containing a single transmembrane (TM) helix. M2 is present as disulfide-linked homotetramers. The TM domain of M2 has been modeled as a bundle of four parallel M2 helices. The helix bundle forms a left-handed supercoil surrounding a central pore. Residue H37 has been implicated in the mechanism of low-pH activation of the channel. Models generated with H37 in a fully deprotonated state exhibit a pore occluded by a ring of H37 side chains oriented toward the lumen of the pore. Models with H37 in a fully protonated state no longer exhibit such occlusion of the pore, as the H37 side chains adopt a more interfacial location. Extended molecular dynamics simulations with water molecules within and at the mouths of the pores support this distinction between the H37-deprotonated and H37-protonated models. These simulations suggest that only in the H37-protonated model is there a continuous column of water extending the entire length of the central pore. A mechanism for activation of M2 by low pH is presented in which the H37-deprotonated model corresponds to the "closed" form of the channel, while the H37-protonated model corresponds to the "open" form. A switch from the closed to the open form of the channel occurs if H37 is protonated midway through a simulation. The open channel is suggested to contain a wire of H-bonded water molecules which enables proton permeability.

Tidal surge in the M2 proton channel, sensed by 2D IR spectroscopy

“…It is therefore a biologically relevant model for structural analyses and understanding the conduction mechanism of M2. Models of M2 have been based on mutagenesis (19), molecular dynamics (MD) simulations (20)(21)(22), spectroscopic studies (23)(24)(25), and most recently from X-ray diffraction (26,27) and solution NMR studies (28). Protonation of the His37 residues in the TM domain activates the protein to conduct protons (19).…”

Viral Protein U (Vpu)-Mediated Enhancement of Human Immunodeficiency Virus Type 1 Particle Release Depends on the Rate of Cellular Proliferation

“…These proteins regulate various points of the viral life cycle by altering membrane permeability. In particular, the coxsackievirus 2B, hepatitis virus 2BC, and influenza virus M2 proteins alter ion and membrane permeabilities and enhance virion assembly and the release of each of these viruses (22,31,38). Vpu, which has been shown to form channels and alter permeability in bacteria, oocytes, and human cells, may act in a manner similar to that of these other small, hydrophobic proteins (8,13,15,34).…”

Multiscale simulation reveals a multifaceted mechanism of proton permeation through the influenza A M2 proton channel

“…1A), which has been experimentally shown (15) to account for the proton permeation behavior of the full AM2 protein. The "shutter" mechanism (16,17) suggests that the His37 tetrad works as a gate. At low pH the gate opens due to the electrostatic repulsion between the biprotonated, positively charged histidine residues.…”