Proton-Induced Conformational and Hydration Dynamics in the Influenza A M2 Channel

Area of Science:

• Structural biology
• Biophysics
• Virology

Background:

• The influenza A M2 protein functions as an acid-activated proton channel.
• This channel is essential for viral replication, facilitating the acidification of the virion interior.
• The precise molecular mechanisms underlying the M2 channel's acid activation and proton transport remain incompletely understood.

Purpose of the Study:

• To elucidate the molecular-level interactions governing proton transport through the influenza A M2 channel.
• To investigate the dynamic structural and water network changes associated with proton flux at different histidine charge states.
• To gain insights into the acid-activation mechanism and rectification properties of the M2 proton channel.

Main Methods:

• Extensive Multiscale Reactive Molecular Dynamics (MRMD) simulations were employed.
• Explicit Grotthuss-shuttling hydrated excess protons were utilized to model proton transport.
• Simulations were conducted across varying histidine charge states (+0, +1, +2) to mimic different pH conditions.

Main Results:

• The hydrated excess proton significantly influences the protein and water hydrogen-bonding network within the channel.
• Protonation dynamically alters protein structure, deviating from equilibrium distributions based on location and pH.
• Asymmetric proton distribution in the channel's cross-section was observed, suggesting implications for conduction.

Conclusions:

• The study provides detailed molecular insights into the acid-activation mechanism of the influenza A M2 proton channel.
• Findings highlight the critical role of hydrated protons in modulating channel structure and function.
• The observed asymmetry in proton distribution may inform future drug design strategies targeting viral entry.