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While there has been no pandemic outbreak of influenza evolving from the H5N1 strain yet, the virus has already killed people. This suggests that without any significant mutations the influenza virus can live within the human body for days in which its life cycles can continue. The first step for infection is the host cell surface binding which is the function of the glycoprotein hemagglutinin (HA). In this investigation, quantum chemical calculations were performed on the systems comprising four structures coming from parts of the HA, with its cell receptor-analog substrate, determined from X-ray structures of the 1934 Spanish flu and avian influenza antigens. The calculations are aimed at partitioning the system into several parts, thus obtaining global and partial contributions of binding energy from each of them. As a result, it was possible to propose quantitatively the main contributions of key amino residues of the avian influenza virus glycoprotein around the binding pocket relevant to the binding process.

The main binding energy contributions of the Spanish flu HA were from Tyr95, Val135, Thr136, Ala137, Glu190, Asp225, and Gln226, while the main contributions of the avian flu HA were from Ser129, Val131, Ser132, and Ser133. It was also found that the effect from the HA with an avian characteristic, Gln226 and Gly228, was not relatively high according to the contributed binding energy, whereas the effect from nearby water molecules was significant. Thus, it was concluded that both human and avian virus HA could recognize human cell receptors better than the avian cell receptors according to the binding energy. Therefore, the preference to any particular cell receptor types might involve some other factors rather than being determined solely by the HA binding process.

The influenza A (H5N1) virus attracts a worldwide attention and calls for the urgent development of novel antiviral drugs. In this study, explicitly solvated flexible docking and molecular dynamics (MD) simulations were used to study the interactions between the H5N1 sub-type hemagglutinin (HA) and various catechin compounds, including EC ([–]-epicatechin), EGC ([–]-epigallocatechin), ECG ([–]-epicatechin gallate) and EGCG ([–]-epigallocatechin gallate). The four compounds have respective binding specificities and their interaction energies with HA decrease in the order of EGCG (-133.52) > ECG (-111.11) > EGC (-97.94) > EC (-83.39). Units in kcal mol^-1. Residues IleA267, LysA269, ArgB68 and GluB78 play important roles during all the binding processes. EGCG has the best bioactivity and shows potential as a lead compound. Besides, the importance was clarified for the functional groups it was revealed that the C5′ hydroxyl and trihydroxybenzoic acid groups are crucial for the catechin inhibitory activities, especially the latter. Combined with the structural and property analyses, this work also proposed the way to effectively modify the functional groups of EGCG. The experimental efforts are expected in order to actualize the catechin derivatives as novel anti-influenza agents in the near future.

Interactions between integral membrane proteins hemagglutinin (HA), neuraminidase (NA), M2 and membrane-associated matrix protein M1 of influenza A virus are thought to be crucial for assembly of functionally competent virions. We hypothesized that the amino acid residues located at the interface of two different proteins are under physical constraints and thus probably co-evolve. To predict co-evolving residue pairs, the EvFold (http://evfold.org) program searching the (nontransitive) Direct Information scores was applied for large samplings of amino acid sequences from Influenza Research Database (http://www.fludb.org/). Having focused on the HA, NA, and M2 cytoplasmic tails as well as C-terminal domain of M1 (being the less conserved among the protein domains) we captured six pairs of correlated positions. Among them, there were one, two, and three position pairs for HA–M2, HA–M1, and M2–M1 protein pairs, respectively. As expected, no co-varying positions were found for NA–HA, NA–M1, and NA–M2 pairs obviously due to high conservation of the NA cytoplasmic tail. The sum of frequencies calculated for two major amino acid patterns observed in pairs of correlated positions was up to 0.99 meaning their high to extreme evolutionary sustainability. Based on the predictions a hypothetical model of pair-wise protein interactions within the viral envelope was proposed.

Avian influenza viruses from migratory birds have managed to cross host species barriers and infected various hosts like human and swine. Epidemics and pandemics might occur when influenza viruses are adapted to humans, causing deaths and enormous economic loss. Receptor-binding specificity of the virus is one of the key factors for the transmission of influenza viruses across species. The determination of host tropism and understanding of molecular properties would help identify the mechanism why zoonotic influenza viruses can cross species barrier and infect humans. In this study, we have constructed computational models for host tropism prediction on human-adapted subtypes of influenza HA proteins using random forest. The feature vectors of the prediction models were generated based on seven physicochemical properties of amino acids from influenza sequences of three major hosts. Feature aggregation and associative rules were further applied to select top 20 features and extract host-associated physicochemical signatures on the combined model of nonspecific subtypes. The prediction model achieved high performance ($\mathrm{\text{Accuracy}}=0.948$, $\mathrm{\text{Precision}}=0.954$, $\mathrm{\text{MCC}}=0.922$). Support and confidence rates were calculated for the host class-association rules. The results indicated that secondary structure and normalized Van der Waals volume were identified as more important physicochemical signatures in determining the host tropism.

T-rays is sensitive to covalently cross-linked proteins and can be used to probe unique dynamic properties of water surrounding a protein. In this paper, we demonstrate the unique absorption properties of the dynamic hydration shells determined by hemagglutinin (HA) protein in terahertz frequency. We study the changes arising from different concentrations in detail and show that nonlinear absorption coefficient is induced by the dynamic hydration water. The binary and ternary component model were used to interpret the nonlinearity absorption behaviors and predict the thickness of the hydration shells around the HA protein in aqueous phase.