Molecular mechanisms of inhibition of influenza by surfactant protein D revealed by large-scale molecular dynamics simulation

Boon Chong Goh, Michael J. Rynkiewicz, Tanya R. Cafarella, Mitchell R. White, Kevan L. Hartshorn, Kimberly Allen, Erika C. Crouch, Oliviana Calin, Peter H. Seeberger, Klaus Schulten, Barbara A. Seaton

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Surfactant protein D (SP-D), a mammalian C-type lectin, is the primary innate inhibitor of influenza A virus (IAV) in the lung. Interactions of SP-D with highly branched viral N-linked glycans on hemagglutinin (HA), an abundant IAV envelope protein and critical virulence factor, promote viral aggregation and neutralization through as yet unknown molecular mechanisms. Two truncated human SP-D forms, wild-type (WT) and double mutant D325A+R343V, representing neck and carbohydrate recognition domains are compared in this study. Whereas both WT and D325A+R343V bind to isolated glycosylated HA, WT does not inhibit IAV in neutralization assays; in contrast, D325A+R343V neutralization compares well with that of full-length native SP-D. To elucidate the mechanism for these biochemical observations, we have determined crystal structures of D325A+R343V in the presence and absence of a viral nonamannoside (Man9). On the basis of the D325A+R343V-Man9 structure and other crystallographic data, models of complexes between HA and WT or D325A+R343V were produced and subjected to molecular dynamics. Simulations reveal that whereas WT and D325A+R343V both block the sialic acid receptor site of HA, the D325A+R343V complex is more stable, with stronger binding caused by additional hydrogen bonds and hydrophobic interactions with HA residues. Furthermore, the blocking mechanism of HA differs for WT and D325A+R343V because of alternate glycan binding modes. The combined results suggest a mechanism through which the mode of SP-D-HA interaction could significantly influence viral aggregation and neutralization. These studies provide the first atomic-level molecular view of an innate host defense lectin inhibiting its viral glycoprotein target.

Original languageEnglish
Pages (from-to)8527-8538
Number of pages12
JournalBiochemistry
Volume52
Issue number47
DOIs
StatePublished - Nov 26 2013

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