Theoretical analysis of binding specificity of influenza viral hemagglutinin to avian and human receptors based on the fragment molecular orbital method

Graduate School of Human Development and Environment, Kobe University, 3-11 Tsurukabuto, Nada, Kobe, Japan.
Computational Biology and Chemistry (Impact Factor: 1.12). 07/2008; 32(3):198-211. DOI: 10.1016/j.compbiolchem.2008.03.006
Source: PubMed


The hemagglutinin (HA) protein of the influenza virus binds to the host cell receptor in the early stage of viral infection. A change in binding specificity from avian 2-3 to human 2-6 receptor is essential for optimal human-to-human transmission and pandemics. Therefore, it is important to reveal the key factors governing the binding affinity of HA-receptor complex at the molecular level for the understanding and prediction of influenza pandemics. In this work, on the basis of ab initio fragment molecular orbital (FMO) method, we have carried out the interaction energy analysis of HA-receptor complexes to quantitatively elucidate the binding specificity of HAs to avian and human receptors. To discuss the binding property of influenza HA comprehensively, a number of HAs from human H1, swine H1, avian H3 and avian H5 viruses were analyzed. We performed detailed investigations about the interaction patterns of complexes of various HAs and receptor analogues, and revealed that intra-molecular interactions between conserved residues in HA play an important role for HA-receptor binding. These results may provide a hint to understand the role of conserved acidic residues at the receptor binding site which are destabilized by the electrostatic repulsion with sialic acid. The calculated binding energies and interaction patterns between receptor and HAs are consistent with the binding specificities of each HA and thus explain the receptor binding mechanism. The calculated results in the present analysis have provided a number of viewpoints regarding the models for the HA-receptor binding specificity associated with mutated residues. Examples include the role of Glu190 and Gln226 for the binding specificity of H5 HA. Since H5 HA has not yet been adapted to human receptor and the mechanism of the specificity change is unknown, this result is helpful for the prediction of the change in receptor specificity associated with forthcoming possible pandemics.

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Available from: Hirofumi Watanabe, Feb 26, 2014
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    • "Studies of H5N1 virus demonstrate that receptor recognition occurs in the RBD. The RBD consists of three secondary structure elements and four conserved residues: Helix190, Loop130 and Loop220 combined with 98Tyr, 153Trp, 183His, and 195Tyr [13]. The Q226L and G228S mutations in HA of H3N2 and H2N2 virus, correlated with the host switching from SA-α-2,3-Gal to SA-α-2,6-Gal receptor specificity [14]. "
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    ABSTRACT: Increasing numbers of H5N1 influenza viruses (IVs) are responsible for human deaths, especially in North Africa and Southeast Asian. The binding of hemagglutinin (HA) on the viral surface to host sialic acid (SA) receptors is a requisite step in the infection process. Phylogenetic analysis reveals that H5N1 viruses can be divided into 10 clades based on their HA sequences, with most human IVs centered from clade 1 and clade 2.1 to clade 2.3. Protein sequence alignment in various clades indicates the high conservation in the receptor-binding domains (RBDs) is essential for binding with the SA receptor. Two glycosylation sites, 158N and 169N, also participate in receptor recognition. In the present work, we attempted to construct a serial H5N1 HA models including diverse glycosylated HAs to simulate the binding process with various SA receptors in silico. As the SA-α-2,3-Gal and SA-α-2,6-Gal receptor adopted two distinctive topologies, straight and fishhook-like, respectively, the presence of N-glycans at 158N would decrease the affinity of HA for all of the receptors, particularly SA-α-2,6-Gal analogs. The steric clashes of the huge glycans shown at another glycosylation site, 169N, located on an adjacent HA monomer, would be more effective in preventing the binding of SA-α-2,3-Gal analogs.
    Full-text · Article · Jun 2012 · PLoS ONE
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    • "The full HA1 domain of human viral H3 in complex with the human-type sialoside Neu5Ac2-6Gal (328 amino acid residues, 5068 atoms) was studied in gas phase at the FMO-HF/STO-3G level in 2007 [55], at the FMO-MP2/6-31G level in 2009 [56], that demanded the consideration of the backyard bulkiness beyond the sialoside binding site. In 2008, Iwata et al. applied first the FMO-MP2 method to the truncated model of several HA-sialoside complexes in gas phase to discuss some important interaction patterns qualitatively [57]. In 2011, Fukuzawa et al. applied the gas phase FMO-MP2/6-31G(d) calculations to the HAs subtype H1 in complex with the sialooligosaccharides to discuss the electrostatic residue interactions without solvation effect [58]. "
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    ABSTRACT: The present mini-review aims first at an introduction to two thermodynamic essentials of the binding between the influenza A virus hemagglutinin (HA) and the cell surface receptor sialoside, (1) the equilibrium 1:1 binding of the HA with the sialoside, (2) the polyvalent effect of the HA binding to the polyvalent sialoside. Second, the review intro-duces the fragment molecular orbital (FMO) studies of the HA-sialoside (1:1) complexes. The recent FMO method with the polarizable continuum model as one of the residue-based energy analysis method has revealed the role of key amino acid residue on the selective HA subtype H3 binding to the sialosides.
    Preview · Article · May 2012 · Open Glycoscience
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    • "The FMO method has realized the QM calculation of biomacromolecule consisting of over 1000 atoms within realistic computation time with keeping high accuracy as well as conventional ab initio QM calculations. This method has been improved successively [24] and applied to many biomacromolecules [25] [26] [27] [28] [29] [30]. "
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    ABSTRACT: We report the molecular mechanism of protein–RNA complex stabilization based on the electronic state calculation. Fragment molecular orbital (FMO) method based quantum mechanical calculations were performed for neuro-oncological ventral antigen (NOVA)–RNA complex system. The inter-molecular interactions and their effects on the electronic state of NOVA were examined in the framework of ab initio quantum calculation. The strength of inter-molecular interactions was evaluated using inter-fragment interaction energies (IFIEs) associated with residue–RNA base and residue–RNA backbone interactions. Under the influence of inter-molecular interactions, the change of electronic state of NOVA upon the complex formation was examined based on IFIE values associated with intra-NOVA residue–residue interactions and the change of atomic charges by each residue. The results indicated that non-specifically recognized bases contributed to the stability of the complex as well as specifically recognized bases and that the secondary structure of NOVA was remarkably associated with the change of electronic state upon the complex formation.
    Full-text · Article · Dec 2010 · Journal of Molecular Structure THEOCHEM
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