Mechanism of Glycan Receptor Recognition and Specificity Switch for Avian, Swine, and Human Adapted Influenza Virus Hemagglutinins: A Molecular Dynamics Perspective

Abstract

Hemagglutinins (HA’s) from duck, swine, and human influenza viruses have previously been shown to prefer avian and human glycan receptor analogues with distinct topological profiles, pentasaccharides LSTa (α-2,3 linkage) and LSTc (α-2,6 linkage), in comparative molecular dynamics studies. On the basis of detailed analyses of the dynamic motions of the receptor binding domains (RBDs) and interaction energy profiles with individual glycan residues, we have identified ∼30 residue positions in the RBD that present distinct profiles with the receptor analogues. Glycan binding constrained the conformational space sampling by the HA. Electrostatic steering appeared to play a key role in glycan binding specificity. The complex dynamic behaviors of the major SSE and trimeric interfaces with or without bound glycans suggested that networks of interactions might account for species specificity in these low affinity and high avidity (multivalent) interactions between different HA and glycans. Contact frequency, energetic decomposition, and H-bond analyses revealed species-specific differences in HA−glycan interaction profiles, not readily discernible from crystal structures alone. Interaction energy profiles indicated that mutation events at the set of residues such as 145, 156, 158, and 222 would favor human or avian receptor analogues, often through interactions with distal asialo-residues. These results correlate well with existing experimental evidence, and suggest new opportunities for simulation-based vaccine and drug development.

Influenza virus binds its host cell using multiple dynamic interactions

“…MD simulations provide detailed information on the molecular structures and unbinding pathways that govern the interaction forces. In free simulations we observed that each receptor takes a slightly different conformation, although hydrogen bonds between four HA residues (Tyr98, Gly135, Ser136, and Asn137) and the receptor were always present, which is consistent with previous simulations (21,22). These four amino acids belong to the base and loop 130 of the HA receptor-binding pocket and are highly important for binding to the receptor (1).…”

H5N1 receptor specificity as a factor in pandemic risk

“…The glycan microarray assay can provide more detailed information for mutations that require more detailed characterization. It should also be noted that bioinformatics approaches for in silico assessment of receptor specificity is emerging (Chandrasekaran et al, 2008; Newhouse et al, 2009; Xu et al, 2009), and may ultimately be of utility for large-scale analysis of sequence information once the in silico assessment of receptor specificity is documented to be a reliable predictor of receptor specificity assessed with laboratory assays.…”

Antiviral Activity of (+)-Rutamarin against Kaposi's Sarcoma-Associated Herpesvirus by Inhibition of the Catalytic Activity of Human Topoisomerase II

“…MD simulations were performed in AMBER 12 (28) with the AMBER ff99SB force field (29,30). The docked structure of the Topo II␣ ATPase domain with (ϩ)-rutamarin was used as the initial coordinates for MD simulations.…”