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J Phys Chem B. 2016 Aug 25;120(33):8590-9. doi: 10.1021/acs.jpcb.6b02655. Epub 2016 May 12.

Microsecond Molecular Dynamics Simulations of Influenza Neuraminidase Suggest a Mechanism for the Increased Virulence of Stalk-Deletion Mutants.

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  • 1Department of Chemistry & Biochemistry and the National Biomedical Computation Resource, University of California San Diego , La Jolla, California 92093, United States.
  • 2Department of Ecology & Evolutionary Biology, University of California Irvine , Irvine, California 92697, United States.

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.

PMID:
27141956
PMCID:
PMC5002936
DOI:
10.1021/acs.jpcb.6b02655
[PubMed - in process]
Free PMC Article
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