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The M2 channel of influenza A virus: a molecular dynamics study
Q Zhong1, T Husslein, P B Moore
1Center for Molecular Modeling and Department of Chemistry, University of Pennsylvania, Philadelphia 19104-6323, USA.
Abstract:
Molecular dynamics simulations have been performed on a tetramer of the 25-residue (SSDPLVVAASIIGILHLILWILDRL) synthetic peptide [1] which contains the transmembrane domain of the influenza A virus M2 coat protein. The peptide bundle was initially assembled as a parallel alpha-helix bundle in the octane portion of a phase separated water/octane system, which provided a membrane-mimetic environment. A 4-ns dynamics trajectory identified a left-handed coiled coil state of the neutral bundle, with a water filled funnel-like structural motif at the N-terminus involving the long hydrophobic sequence. The neck of the funnel begins at V27 and terminates at H37, which blocks the channel. The C-terminus is held together by inter-helix hydrogen bonds and contains water below H37. Solvation of the S23 and D24 residues, located at the rim of the funnel, appears to be important for stability of the structure. The calculated average tilt of the helices in the neutral bundle is 27 +/- 5 degrees, which agrees well with recent NMR data.
Insights
Molecular dynamics simulations reveal the M2 protein
Area of Science:
- Biophysics
- Structural Biology
- Virology
Background:
- The M2 protein of influenza A virus forms an ion channel essential for viral replication.
- Its transmembrane domain is a tetrameric alpha-helix bundle.
- Understanding its structure is key to developing antiviral drugs.
Purpose of the Study:
- To investigate the structure and dynamics of the M2 protein transmembrane domain.
- To elucidate the mechanism of ion channel formation and blockage.
Main Methods:
- Molecular dynamics (MD) simulations of a synthetic M2 peptide tetramer.
- Simulations performed in a membrane-mimetic water/octane system.
- Analysis of a 4-ns dynamics trajectory.
Main Results:
- A left-handed coiled coil structure was identified for the neutral peptide bundle.
- A water-filled funnel-like motif at the N-terminus was observed.
- Histidine 37 (H37) was found to block the channel, with water present below this residue.
- Solvation of residues S23 and D24 is crucial for structural stability.
- The average helix tilt angle was calculated as 27 +/- 5 degrees, consistent with NMR data.
Conclusions:
- The M2 protein forms a stable, left-handed coiled coil in a membrane environment.
- A funnel structure and specific residues (H37) play critical roles in channel gating.
- The simulation results provide insights into M2 channel function and potential drug targets.