title: Self-assembly of a simple membrane protein: coarse-grained molecular dynamics simulations of the influenza M2 channel.
abstract: The transmembrane (TM) domain of the M2 channel protein from influenza A is a homotetrameric bundle of alpha-helices and provides a model system for computational approaches to self-assembly of membrane proteins. Coarse-grained molecular dynamics (CG-MD) simulations have been used to explore partitioning into a membrane of M2 TM helices during bilayer self-assembly from lipids. CG-MD is also used to explore tetramerization of preinserted M2 TM helices. The M2 helix monomer adopts a membrane spanning orientation in a lipid (DPPC) bilayer. Multiple extended CG-MD simulations (5 x 5 micros) were used to study the tetramerization of inserted M2 helices. The resultant tetramers were evaluated in terms of the most populated conformations and the dynamics of their interconversion. This analysis reveals that the M2 tetramer has 2x rotationally symmetrical packing of the helices. The helices form a left-handed bundle, with a helix tilt angle of approximately 16 degrees. The M2 helix bundle generated by CG-MD was converted to an atomistic model. Simulations of this model reveal that the bundle's stability depends on the assumed protonation state of the H37 side chains. These simulations alongside comparison with recent x-ray (3BKD) and NMR (2RLF) structures of the M2 bundle suggest that the model yielded by CG-MD may correspond to a closed state of the channel.
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Carpenter
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bond
authors.forename: Syma
authors.initials: S
authors.lastname: Khalid
authors.forename: Mark S P
authors.initials: MS
authors.lastname: Sansom
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000378:metabolism; D003198:Computer Simulation; D006639:Histidine / Q000378:metabolism; D009980:Influenza A virus / Q000737:chemistry*; D007473:Ion Channels / Q000737:chemistry*; D008051:Lipid Bilayers / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D014763:Viral Matrix Proteins / Q000737:chemistry* / Q000378:metabolism*; D000086082:Viroporin Proteins
chemical_list: D015060:1,2-Dipalmitoylphosphatidylcholine; D006639:Histidine; D007473:Ion Channels; D008051:Lipid Bilayers; D008565:Membrane Proteins; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins