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Influenza virus M2 protein: a molecular modelling study of the ion channel
1Laboratory of Molecular Biophysics, University of Oxford, UK.
Abstract:
The influenza A M2 protein forms cation-selective ion channels which are blocked by the anti-influenza drug amantadine. A molecular model of the M2 channel is presented in which a bundle of four parallel M2 transbilayer helices surrounds a central ion-permeable pore. Analysis of helix amphipathicity was used to aid determination of the orientation of the helices about their long axes. The helices are tilted such that the N-terminal mouth of the pore is wider than the C-terminal mouth. The channel is lined by residues V27, S31 and I42. Residues D24 and D44 are located at opposite mouths of the pore, which is narrowest in the vicinity of I42. Energy profiles for interaction of the channel with Na+, amantadine-H+ and cyclopentylamine-H+ are evaluated. The interaction profile for Na+ exhibits three minima, one at each mouth of the pore, and one in the region of residue S31. The amantadine-H+ profile exhibits a minimum close to S31 and a barrier near residue I42. This provides a molecular model for amantadine-H+ block of M2 channels. The profile for cyclopentylamine-H+ does not exhibit such a barrier. It is predicted that cyclopentylamine-H+ will not act as an M2 channel blocker.
Insights
This study presents a molecular model of the influenza A M2 protein channel, explaining how amantadine blocks ion flow. The model predicts that cyclopentylamine will not block the M2 channel.
Area of Science:
- Structural biology
- Virology
- Pharmacology
Background:
- Influenza A M2 protein forms ion channels essential for viral replication.
- These channels are targeted by antiviral drugs like amantadine.
- Understanding M2 channel structure is key to developing new influenza treatments.
Purpose of the Study:
- To develop a molecular model of the influenza A M2 ion channel.
- To elucidate the mechanism of amantadine block at the molecular level.
- To predict the channel-blocking potential of related compounds like cyclopentylamine.
Main Methods:
- Construction of a molecular model of the M2 channel based on helix bundle structure.
- Analysis of helix amphipathicity to determine helix orientation.
- Computational evaluation of energy profiles for ion and drug interactions within the channel.
Main Results:
- A model of four parallel M2 helices forming a cation-selective pore, wider at the N-terminus.
- Identification of key residues (V27, S31, I42) lining the pore and D24, D44 at the mouths.
- Energy profiles reveal amantadine-H+ interaction sites and a blocking barrier near I42, absent for cyclopentylamine-H+.
Conclusions:
- The molecular model provides a structural basis for amantadine's M2 channel blocking mechanism.
- The predicted lack of a blocking barrier suggests cyclopentylamine will not inhibit M2 channel function.
- This research aids in the design of novel M2 channel inhibitors.
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