Proton transport through the influenza A M2 channel: three-dimensional reference interaction site model study

Area of Science:

• Biophysics
• Computational Chemistry
• Molecular Biology

Background:

• The influenza A M2 channel is crucial for viral uncoating.
• Understanding its proton conduction mechanism is vital for antiviral drug development.
• Histidine protonation states are key to channel gating and ion transport.

Purpose of the Study:

• To elucidate the proton conduction mechanism of the influenza A M2 channel.
• To investigate the role of histidine protonation states (0H-4H) in channel function.
• To characterize the distribution of water and hydronium ions within the channel.

Main Methods:

• Three-dimensional reference interaction site model (3D-RISM) theory was employed.
• Calculated three-dimensional distribution functions (DF) and potentials of mean force (PMF).
• Analyzed water and hydronium ion distributions across five protonated states (0H-4H).

Main Results:

• Channel water structure transitions from closed (0H-2H) to open (3H-4H) states.
• Hydronium ions are excluded in closed states but distributed in open states.
• The 3H state exhibits lower PMF barriers (3-5 kJ/mol) than 4H (5-7 kJ/mol), indicating higher proton permeability.

Conclusions:

• Proton permeability increases with histidine protonation, with the 3H state being more permeable.
• A novel proton transfer mechanism is proposed involving histidine residues and water molecules.
• This mechanism facilitates efficient proton transfer through hydrogen bonding interactions in the gating region.