Related Experiment Video

Updated: Aug 20, 2025

Multi-target Parallel Processing Approach for Gene-to-structure Determination of the Influenza Polymerase PB2 Subunit
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Multi-target Parallel Processing Approach for Gene-to-structure Determination of the Influenza Polymerase PB2 Subunit

Published on: June 28, 2013

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Molecular origins of asymmetric proton conduction in the influenza M2 channel

Themis Lazaridis1

  • 1Department of Chemistry, City College of New York/CUNY, New York, New York; Graduate Programs in Chemistry, Biochemistry, and Physics, The Graduate Center, City University of New York, New York, New York.

Biophysical Journal
|November 20, 2022
PubMed

Insights

The M2 proton channel of influenza A preferentially allows inward proton flow, preventing outward flow. Specific residues like Asp44 and Trp41 create an energy barrier, explaining this directional proton transport.

Area of Science:

  • Biophysics
  • Structural Biology
  • Virology

Background:

  • The M2 proton channel in influenza A viruses facilitates virion acidification.
  • The channel exhibits asymmetric proton conductance, allowing inward but not outward flow under physiological conditions.
  • The precise mechanism preventing outward proton conductance, particularly the roles of Trp41 and Asp44, remains unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism behind the asymmetric proton transport of the influenza A M2 channel.
  • To investigate the role of key residues (Trp41, Asp44, His37) in dictating proton flow directionality.
  • To understand how voltage influences proton conductance compared to pH gradients.

Main Methods:

  • Classical molecular dynamics simulations.
  • Incorporation of periodic proton hops to model proton transport.
  • Analysis of proton trajectories and energetic barriers.

Main Results:

  • Inward proton movement is significantly more favorable than outward movement, especially with charged His37 residues.
  • Asp44 electrostatically traps hydronium ions, while Asp44 and Trp41 orient them inward, hindering outward Grotthuss hopping.
  • Trp41 further impedes outward flow by hydrogen bonding. Charged His residues trap ions in the channel vestibule.
  • Simulations replicate the increased outward conductance observed in M2 mutants.

Conclusions:

  • The M2 channel's asymmetry is governed by electrostatic interactions and specific residue orientations that favor inward proton flux.
  • Asp44 and Trp41 are critical in establishing a lower energy barrier for inward proton movement.
  • Applied voltage can overcome the pH gradient's asymmetry by orienting water and ions for outward transport.

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