title: Line-tension controlled mechanism for influenza fusion.
abstract: Our molecular simulations reveal that wild-type influenza fusion peptides are able to stabilize a highly fusogenic pre-fusion structure, i.e. a peptide bundle formed by four or more trans-membrane arranged fusion peptides. We rationalize that the lipid rim around such bundle has a non-vanishing rim energy (line-tension), which is essential to (i) stabilize the initial contact point between the fusing bilayers, i.e. the stalk, and (ii) drive its subsequent evolution. Such line-tension controlled fusion event does not proceed along the hypothesized standard stalk-hemifusion pathway. In modeled influenza fusion, single point mutations in the influenza fusion peptide either completely inhibit fusion (mutants G1V and W14A) or, intriguingly, specifically arrest fusion at a hemifusion state (mutant G1S). Our simulations demonstrate that, within a line-tension controlled fusion mechanism, these known point mutations either completely inhibit fusion by impairing the peptide's ability to stabilize the required peptide bundle (G1V and W14A) or stabilize a persistent bundle that leads to a kinetically trapped hemifusion state (G1S). In addition, our results further suggest that the recently discovered leaky fusion mutant G13A, which is known to facilitate a pronounced leakage of the target membrane prior to lipid mixing, reduces the membrane integrity by forming a 'super' bundle. Our simulations offer a new interpretation for a number of experimentally observed features of the fusion reaction mediated by the prototypical fusion protein, influenza hemagglutinin, and might bring new insights into mechanisms of other viral fusion reactions.
authors: Theoretical Molecular Biophysics Group, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany. hrissel@gwdg.de
authors: Herre Jelger
authors: HJ
authors: Risselada
authors: Giovanni
authors: G
authors: Marelli
authors: Marc
authors: M
authors: Fuhrmans
authors: Yuliya G
authors: YG
authors: Smirnova
authors: Helmut
authors: H
authors: Grubmüller
authors: Siewert Jan
authors: SJ
authors: Marrink
authors: Marcus
authors: M
authors: Müller
mesh_terms: D002462:Cell Membrane / Q000378:metabolism*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009980:Influenza A virus / Q000502:physiology; D007251:Influenza, Human / Q000378:metabolism* / Q000821:virology; D008051:Lipid Bilayers / Q000378:metabolism*; D008561:Membrane Fusion / Q000502:physiology*; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation / Q000235:genetics; D011487:Protein Conformation
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D008051:Lipid Bilayers; D010446:Peptide Fragments