title: Microsecond Molecular Dynamics Simulations of Influenza Neuraminidase Suggest a Mechanism for the Increased Virulence of Stalk-Deletion Mutants.
abstract: Deletions in the stalk of the influenza neuraminidase (NA) surface protein are associated with increased virulence, but the mechanisms responsible for this enhanced virulence are unclear. Here we use microsecond molecular dynamics simulations to explore the effect of stalk deletion on enzymatic activity, contrasting NA proteins from the A/swine/Shandong/N1/2009 strain both with and without a stalk deletion. By modeling and simulating neuraminidase apo glycoproteins embedded in complex-mixture lipid bilayers, we show that the geometry and dynamics of the neuraminidase enzymatic pocket may differ depending on stalk length, with possible repercussions on the binding of the endogenous sialylated-oligosaccharide receptors. We also use these simulations to predict previously unrecognized druggable "hotspots" on the neuraminidase surface that may prove useful for future efforts aimed at structure-based drug design.
authors.affiliation: Department of Chemistry & Biochemistry and the National Biomedical Computation Resource, University of California San Diego , La Jolla, California 92093, United States.
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Durrant
authors.affiliation: Department of Ecology & Evolutionary Biology, University of California Irvine , Irvine, California 92697, United States.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Bush
authors.affiliation: Department of Chemistry & Biochemistry and the National Biomedical Computation Resource, University of California San Diego , La Jolla, California 92093, United States.
authors.forename: Rommie E
authors.initials: RE
authors.lastname: Amaro
mesh_terms: D001665:Binding Sites; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D008051:Lipid Bilayers / Q000737:chemistry; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D009439:Neuraminidase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D025341:Principal Component Analysis; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D017384:Sequence Deletion; D013997:Time Factors; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014774:Virulence / Q000235:genetics / Q000502:physiology
chemical_list: D008051:Lipid Bilayers; D014764:Viral Proteins; C487630:NA protein, influenza A virus; D009439:Neuraminidase; D019158:N-Acetylneuraminic Acid