Related Experiment Video
Updated: Jun 4, 2026
Co-immunoprecipitation of the Mouse Mx1 Protein with the Influenza A Virus Nucleoprotein
Published on: April 21, 2015
Multiple Proton Confinement in the M2 Channel from the Influenza A Virus
Vincenzo Carnevale1, Giacomo Fiorin, Benjamin G Levine
1Institute for Computational Molecular Science, Temple University, Philadelphia, PA 19122-6078.
Abstract:
The tetrameric M2 protein bundle of the influenza A virus is the proton channel responsible for the acidification of the viral interior, a key step in the infection cycle. Selective proton transport is achieved by successive protonation of the conserved histidine amino acids at position 37. A recent X-ray structure of the tetrameric transmembrane (TM) domain of the protein (residues 22-46) resolved several water clusters in the channel lumen, which suggest possible proton pathways to the His37 residues. To explore this hypothesis, we have carried out molecular dynamics (MD) simulations of a proton traveling towards the His37 side chains using MD with classical and quantum force fields. Diffusion through the first half of the channel to the "entry" water cluster near His37 may be hampered by significant kinetic barriers due to electrostatic repulsion. However, once in the entry cluster, a proton can move to one of the acceptor His37 in a nearly barrierless fashion, as evidenced both by MD simulations and a scan of the potential energy surface (PES). Water molecules of the entry cluster, although confined in the M2 pore and restricted in their motions, can conduct protons with a rate very similar to that of bulk water.
Insights
Influenza A virus M2 protein channels facilitate proton transport via histidine residues. Molecular dynamics simulations reveal water clusters aid proton movement, with nearly barrierless transfer to histidine once a proton enters the cluster.
Area of Science:
- Virology
- Biophysics
- Computational Chemistry
Background:
- The influenza A virus M2 protein forms a tetrameric channel crucial for viral interior acidification.
- Proton transport through the M2 channel is essential for the viral infection cycle.
- Conserved histidine residues (His37) are key to selective proton transfer.
Purpose of the Study:
- To investigate the role of water clusters within the M2 channel lumen in facilitating proton transport.
- To explore the mechanism of proton movement towards His37 residues using computational simulations.
Main Methods:
- Molecular dynamics (MD) simulations utilizing classical and quantum force fields.
- Analysis of potential energy surfaces (PES) to determine proton transfer barriers.
- Modeling proton diffusion within the M2 transmembrane (TM) domain.
Main Results:
- Proton diffusion to the His37-proximal water cluster faces electrostatic repulsion barriers.
- Proton transfer from the water cluster to His37 residues occurs with minimal energy barriers.
- Confined water molecules in the M2 pore exhibit proton conductivity comparable to bulk water.
Conclusions:
- Water clusters within the M2 channel lumen play a significant role in mediating proton transport.
- The M2 channel's structure facilitates efficient proton transfer to key histidine residues.
- Understanding these mechanisms could inform antiviral drug development targeting M2 function.
More Related Videos
Related Concept Videos
02:28Leaky Scanning
01:27Influenza
01:25Inhibitors Of Virion Release