Proton conduction through the M2 protein of the influenza A virus; a quantitative, mechanistic analysis of...

Area of Science:

• Biophysics
• Virology
• Computational Biology

Background:

• Influenza A virus M2 protein forms proton-selective ion channels crucial for viral uncoating.
• Amantadine targets the M2 channel, but resistance is common, necessitating a deeper understanding of its function.
• The pH and voltage dependence of M2 proton conduction are key functional characteristics.

Purpose of the Study:

• To quantitatively analyze existing experimental data on M2 proton channel function.
• To elucidate the mechanisms underlying the pH- and voltage-dependences of M2 proton conduction.
• To develop a mechanistic model explaining M2 channel behavior.

Main Methods:

• Quantitative examination of existing experimental electrophysiological data.
• Development and testing of a computational model incorporating protonation equilibria and diffusion rates.
• Analysis of M2 proton conduction in Rostock and Weybridge strains.

Main Results:

• A model involving protonation equilibria of Histidine 37 (His37) quantitatively explains M2 channel function.
• The model incorporates pH-dependent changes in diffusion rates across the channel pore.
• The model successfully accounts for reported pH- and voltage-dependent electrophysiological data.

Conclusions:

• Protonation state of His37 and diffusion dynamics are critical for M2 channel gating.
• The developed model provides a quantitative mechanistic basis for M2 proton conduction.
• This understanding could inform the development of new antiviral strategies targeting the M2 channel.