title: Distinct functional determinants of influenza hemagglutinin-mediated membrane fusion.
abstract: Membrane fusion is the critical step for infectious cell penetration by enveloped viruses. We have previously used single-virion measurements of fusion kinetics to study the molecular mechanism of influenza-virus envelope fusion. Published data on fusion inhibition by antibodies to the 'stem' of influenza virus hemagglutinin (HA) now allow us to incorporate into simulations the provision that some HAs are inactive. We find that more than half of the HAs are unproductive even for virions with no bound antibodies, but that the overall mechanism is extremely robust. Determining the fraction of competent HAs allows us to determine their rates of target-membrane engagement. Comparison of simulations with data from H3N2 and H1N1 viruses reveals three independent functional variables of HA-mediated membrane fusion closely linked to neutralization susceptibility. Evidence for compensatory changes in the evolved mechanism sets the stage for studies aiming to define the molecular constraints on HA evolvability.
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, United States.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.|Department of Biochemistry, Brandeis University, Waltham, United States.
authors.forename: Tijana
authors.initials: T
authors.lastname: Ivanovic
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.|Howard Hughes Medical Institute, Harvard Medical School, Boston, United States.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Harrison
mesh_terms: D003198:Computer Simulation; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics* / Q000378:metabolism*; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics* / Q000502:physiology*; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics* / Q000502:physiology*; D053586:Virus Internalization
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus
keywords: biophysics; cell entry; enveloped viruses; fusion-protein catalysts; infectious disease; influenza; membrane fusion; microbiology; single molecule; structural biology; viruses