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Two possible conducting states of the influenza A virus M2 ion channel
Q Zhong1, D M Newns, P Pattnaik
1Center for Molecular Modeling and Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA.
Abstract:
Molecular dynamics simulations have been performed on protonated four-helix bundles based on the 25-residue Duff-Ashley transmembrane sequence of the M2 channel of the influenza A virus. Well-equilibrated tetrameric channels, with one, two and four of the H37 residues protonated, were investigated. The protonated peptide bundles were immersed in the octane portion of a phase-separated water/octane system, which provided a membrane-mimetic environment. The simulations suggest that there could be two conducting states of the M2 channel corresponding to tetramers containing one or two protonated histidines. The more open structure of the doubly protonated state suggests it would have the higher conductance.
Insights
Molecular dynamics simulations reveal two proton conducting states in the M2 channel of the influenza A virus. Protonation of histidine residues influences channel structure and conductance, suggesting distinct functional states.
Area of Science:
- Biophysics
- Computational Biology
- Structural Biology
Background:
- The M2 channel of the influenza A virus is a critical target for antiviral drugs.
- Understanding its proton transport mechanism is essential for developing new therapies.
Purpose of the Study:
- To investigate the structural and functional consequences of histidine protonation in the M2 channel.
- To identify potential conducting states of the M2 channel.
Main Methods:
- Molecular dynamics simulations were employed.
- Protonated four-helix bundles based on the M2 channel sequence were simulated.
- A membrane-mimetic environment using a water/octane system was utilized.
Main Results:
- Two distinct conducting states were proposed for the M2 channel.
- These states correlate with one or two protonated histidine (H37) residues.
- A doubly protonated state exhibited a more open structure, suggesting higher conductance.
Conclusions:
- Protonation of histidine residues plays a crucial role in M2 channel function.
- The M2 channel may exist in at least two distinct proton-conducting states.
- Structural changes induced by protonation directly impact proton conductance.