High-resolution structures of the M2 channel from influenza A virus reveal dynamic pathways for proton stabilization...

Area of Science:

• Structural biology
• Virology
• Biophysics

Background:

• The matrix 2 (M2) protein is a crucial proton channel in the influenza A virus envelope.
• M2 protein's His37 residue acts as a critical selectivity filter for proton transport.
• Understanding M2 proton channel function is vital for developing antiviral therapies.

Purpose of the Study:

• To elucidate the high-resolution structural basis of M2 proton channel function.
• To investigate the role of water molecules and pH in M2 proton conduction.
• To reveal the dynamic mechanisms underlying proton flux through the M2 channel.

Main Methods:

• High-resolution cryogenic crystallography (1.10 Å) of the M2 transmembrane domain at varying pH.
• Room temperature crystallography to assess temperature and pH effects on water dynamics.
• Molecular dynamics simulations to analyze proton transport mechanisms and hydrogen bond dynamics.

Main Results:

• Detailed structures reveal water wires spanning the M2 pore, connecting the entrance to His37.
• Pore-lining carbonyl groups stabilize hydronium ions through second-shell water interactions.
• Water within the pore becomes more fluid at lower pH and higher temperatures, facilitating proton flux.
• Molecular dynamics simulations show collective hydrogen bond reorientation linked to His37 protonation dynamics.

Conclusions:

• The M2 protein utilizes intricate water networks and specific residue interactions to facilitate proton transport.
• Dynamic changes in water structure and His37 protonation state are key to directional proton flux.
• These findings provide a molecular basis for M2 channel activity and potential drug targeting.