Hemagglutinin (HA) binds to sialylated glycans exposed on the host cell surface in the initial stage of avian influenza virus infection. It has been previously hypothesized that glycan topology plays a critical role in the human adaptation of avian flu viruses, such as the potentially pandemic H5N1. Comparative molecular dynamics (MD) studies are complementary to experimental techniques including glycan microarray to understand better the mechanism of species specificity switch. The examined systems comprise explicitly solvated trimeric forms of avian H3, H5, and swine H9 in complex with avian and human glycan receptor analogs, α-2,3 linked lactoseries tetrasaccharide a (LSTa) and α-2,6 linked LSTc, respectively. The glycans adopted distinct topological profiles with inducible torsional angles when bound to different HA's. The corresponding receptor binding domain amino acid contact profiles were also distinct. Avian H5 was able to accommodate LSTc in a tightly "folded-umbrella"-like topology through interactions with all five sugar residues. After considering conformational entropy, the relative binding free energy changes, calculated using the molecular mechanics-generalized Born surface area (MM-GBSA) technique, were in agreement with previous experimental findings, and also provided insights on electrostatic, van der Waals, desolvation and entropic contributions to HA-glycan interactions. The topology profile and the relative abundance of free glycan receptors may influence receptor binding kinetics. Glycan composition and topological changes upon binding different HA may be important determinants in species specificity switch.

A group of flavanones and their chalcones, isolated from Boesenbergia rotunda L., were previously reported to show varying degrees of noncompetitive inhibitory activities toward Dengue virus type 2 (Den2) protease. Results obtained from automated docking studies are in agreement with experimental data in which the ligands were shown to bind to sites other than the active site of the protease. The calculated K(i) values are very small, indicating that the ligands bind quite well to the allosteric binding site. Greater inhibition by pinostrobin, compared to the other compounds, can be explained by H-bonding interaction with the backbone carbonyl of Lys74, which is bonded to Asp75 (one of the catalytic triad residues). In addition, structure-activity relationship analysis yields structural information that may be useful for designing more effective therapeutic drugs against dengue virus infections.

No 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.