title: The influenza fusion peptide promotes lipid polar head intrusion through hydrogen bonding with phosphates and N-terminal membrane insertion depth.
abstract: Influenza infection requires fusion between the virus envelope and a host cell endosomal membrane. The influenza hemagglutinin fusion peptide (FP) is essential to viral membrane fusion. It was recently proposed that FPs would fuse membranes by increasing lipid tail protrusion, a membrane fusion transition state. The details of how FPs induce lipid tail protrusion, however, remain to be elucidated. To decipher the molecular mechanism by which FPs promote lipid tail protrusion, we performed molecular dynamics simulations of the wild-type (WT) FP, fusogenic mutant F9A, and nonfusogenic mutant W14A in model bilayers. This article presents the peptide-lipid interaction responsible for lipid tail protrusion and a related lipid perturbation, polar head intrusion, where polar heads are sunk under the membrane surface. The backbone amides from the four N-terminal peptide residues, deeply inserted in the membrane, promoted both perturbations through H bonding with lipid phosphates. Polar head intrusion correlated with peptides N-terminal insertion depth and activity: the N-termini of WT and F9A were inserted deeper into the membrane than nonfusogenic W14A. Based on these results, we propose that FP-induced polar head intrusion would complement lipid tail protrusion in catalyzing membrane fusion by reducing repulsions between juxtaposed membranes headgroups. The presented model provides a framework for further research on membrane fusion and influenza antivirals.
authors.affiliation: Département de Biochimie, Microbiologie et Bio-informatique, Institut de Biologie Intégrative et des Systèmes (IBIS), Centre de Recherche sur la Fonction, la Structure et l'ingénierie des Protéines (PROTEO), Université Laval, Quebec City, Quebec, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Légaré
authors.forename: Patrick
authors.initials: P
authors.lastname: Lagüe
mesh_terms: D002462:Cell Membrane / Q000378:metabolism / Q000821:virology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D053122:Influenza A Virus, H3N2 Subtype / Q000378:metabolism; D007251:Influenza, Human; D008055:Lipids / Q000737:chemistry; D008561:Membrane Fusion / Q000502:physiology; D056004:Molecular Dynamics Simulation; D010710:Phosphates / Q000737:chemistry; D014760:Viral Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D017376:Viral Tail Proteins / Q000378:metabolism*; D053585:Virus Attachment; D053586:Virus Internalization
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D008055:Lipids; D010710:Phosphates; D014760:Viral Fusion Proteins; D017376:Viral Tail Proteins; C483468:hemagglutinin, human influenza A virus
keywords: lipid mixing; lipid polar head intrusion; lipid tail protrusion; membrane fusion; membrane peptide; peptide N-terminus-lipid phosphate H bond