Hemagglutinin (HA) is an influenza viral envelope membrane protein responsible for the attachment of the virus to the human cell surface proteins with glycan receptors. The cell surface glycans are polysaccharides often terminated with a sialic acid (SIA) residue, which is crucial for HA binding. The SIA is attached to a Galactose residue through either alpha-2,3 or alpha-2,6 linkage, and this linkage difference has been hypothesized in many studies to be the determinant for species specificity. Avian influenza viruses are observed to prefer alpha-2,3 linked glycans, whereas those adapted to humans may have decreased alpha-2,3 glycan affinity, and increased alpha-2,6 glycan affinity (Figure 1). However, there are experimental data that cannot be explained by the linkage difference alone, including glycan microarray studies, as well as in vitro and in vivo assays (1). The glycan topology or shape, especially those longer than three residues, was proposed to be a critical determinant in species specificity shift (2).
Xu and colleagues have published a comparative molecular dynamics study on the interaction of HA from avian and swine species with natural pentasaccharides found in breast milk, which are analogues of the avian or human glycan receptors, namely, LSTa (alpha-2,3) and LSTc (alpha-2,6) (3). The study is a first extensive computational simulation of long glycan receptors (5 residues long) with HA from different species. The crystal structural studies often do not contain the complete glycan receptors, and models of the glycans were built where necessary. The results showed that the glycan topology could vary significantly during the course of the simulation, especially when the glycans are bound to different HA’s. Consistent with experimental studies, the SIA is found to account for more than half of the binding energy between HA and glycans. However, sequence specific interactions between the HA receptor binding domain (RBD) and glycans are also observed.
Using the MM-GBSA technique (4), and considering the entropic contributions from the complex formation, the authors were able to determine the relative binding affinity between the HA’s and the avian or human receptor analogues. The development of these computational simulation systems would enable in silico studies on potential HA RBD mutations that could occur in cases of a pandemic virus, as well as the role of glycan composition, cell surface expression patterns and other modifications to the glycan itself. Moreover, the presence of these natural glycan receptors for the influenza virus in human breast milk suggests a possible role in the protection of infants from viral infections. These studies could help guide the design of glycan based inhibitors to the influenza virus.
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Figure 1. Representative conformations of pentasaccharides with alpha-2,3 (LSTa) or alpha-2,6 (LSTc) linkages in complex with hemagglutinin H5 from avian influenza virus.
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References:
1. Nicholls, J. M., Chan, R. W., Russell, R. J., Air, G. M. & Peiris, J. S. (2008). Evolving complexities of influenza virus and its receptors. Trends Microbiol 16, 149-57.
2. Chandrasekaran, A., Srinivasan, A., Raman, R., Viswanathan, K., Raguram, S., Tumpey, T. M., Sasisekharan, V. & Sasisekharan, R. (2008). Glycan topology determines human adaptation of avian H5N1 virus hemagglutinin. Nat Biotechnol 26, 107-13.
3. Xu, D., Newhouse, I., Pao, H., Amaro, R. E., McCammon, J. A., Li, W. W. & Arzberger, P. W. (2009). Distinct Glycan Topology for Avian and Human Sialo-Pentasaccharide Receptor Analogues upon Binding Different Hemagglutinins: A Molecular Dynamics Perspective. J Mol Biol, In Press.
4. Srinivasan, J., Cheatham, T. E., 3rd, Cieplak, P., Kollman, P. A. & Case, D. A. (1998). Continuum solvent studies of the stability of DNA, RNA, and phosphoramidate-DNA helices. J Am Chem Soc 120, 9401-9409.
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