Mechanism of glycan receptor recognition and specificity switch for avian, swine, and human adapted influenza virus hemagglutinins: a molecular dynamics perspective.

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 (alpha-2,3 linkage) and LSTc (alpha-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 approximately 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

Вихретоковый анизотропный термоэлектрический первичный преобразователь лучистого потока

Представлена оригинальная конструкция первичного преобразователя лучистого потока, который может служить основой для создания приемника неселективного излучения с повышенной чувствительностью

Genesis of the 1918 H1N1 Spanish influenza into the 2009 swine origin influenza

The influenza A virus surface hemagglutinin (HA) plays the critical role in governing the viral adaptation of a human host by switching binding specificity from long [alpha]-2, 3 to long α-2, 6 sialylated glycans receptors. The relationship between HA receptor binding domain (RBD) mutation and HA-glycan binding specificity, however, is not well understood due to varying experimental results. The human 1918 pandemic virus, A/South Carolina/1/18 (SC18) and its D190E/D225G avian-type mutant (AV18*) serves as an excellent paradigm for mutagenesis investigation of the molecular mechanisms of the double mutation, which has been qualitative and limited to visual inspection of superimposed crystal structures. In this study, a computational approach that integrates explicit molecular dynamics (MD) simulations, statistical glycan conformational clustering analysis, molecular mechanics- Generalized Born surface area (MM-GBSA) residue based pairwise energy decomposition and molecular mechanics- Poisson-Boltzmann Surface Area (MM-PBSA) binding free energy calculation was developed. Using this approach, key HA-glycan residue interactions and relative overall binding free energies of SC18, AV18*, a 2009 swine-origin like S145K/A227E double mutant (CA18*), and CA04 bound to physiological [alpha]-2, 3 and [alpha]-2, 6 sialylated glycans receptors at atomic level have been identified. The structural and energetic data reveal the markedly distinct binding patterns of SC18 and AV18*, the deterministic role of residue 190 in anchoring sialic acid and the auxiliary role of residue 225 coupled with [alpha] -2, 3/[alpha]-2, 6 linkage. Furthermore, destabilization of D190 by A227E and increased importance of the 130-loop in the RBD causes an increase of overall [alpha]-2, 3/ [alpha]-2, 6 binding in CA18* and swine-origin A/ California/04/2009 (CA04

Mechanism of glycan receptor recognition and specificity switch for avian, swine, and human adapted influenza virus hemagglutinins: a molecular dynamics perspective.

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 (alpha-2,3 linkage) and LSTc (alpha-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 approximately 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