ORIGINAL PAPER Receptor recognition mechanism of human influenza A H1N1 (1918), avian influenza A H5N1 (2004), and pandemic H1N1 (2009) neuraminidase Nipa Jongkon & Chak Sangma Received: 25 January 2011 /Accepted: 24 March 2011 /Published online: 27 April 2011 # Springer-Verlag 2011 Abstract Influenza A neuraminidase (NA) is a target for anti-influenza drugs. The function of this enzyme is to cleave a glycosidic linkage of a host cell receptor that links sialic acid (Sia) to galactose (Gal), to allow the virus to leave an infected cell and propagate. The receptor is an oligosaccharide on the host cell surface. There are two types of oligosaccharide receptor; the first, which is found mainly on avian epithelial cell surfaces, links Sia with Gal by an α2,3 glycosidic linkage; in the second, found mainly on human epithelial cell surfaces, linkage is via an α2,6 linkage. Some researchers believe that NAs from different viruses show selectivity for each type of linkage, but there is limited information available to confirm this hypothesis. To see if the linkage type is more specific to any particular NA, a number of NA-receptor complexes of human influenza A H1N1 (1918), avian influenza A H5N1 (2004), and a pandemic strain of H1N1 (2009) were constructed using homology modeling and molecular dynamics simulation. The results show that the two types of receptor analogues bound to NAs use different mecha- nisms. Moreover, it was found that a residue unique to avian virus NA is responsible for the recognition of the Siaα2,3Gal receptor, and a residue unique to human virus NA is responsible for the recognition of Siaα2,6Gal. We believe that this finding could explain how NAs of different virus origins always possess some unique residues. Keywords Avian influenza . Hemagglutinin . Neuraminidase . Binding mechanism . Molecular dynamics . Molecular recognition . Glycosidic linkage . Cell receptor Introduction To infect a host cell, the influenza virus uses hemagglutinin (HA) to attach to oligosaccharide cell receptors and enter the cell [1]. When the virus is ready to leave to infect another cell, it uses neuraminidase (NA) to cleave the sialic acid– galactose (Sia–Gal) glycosidic linkage in order to be able to exit the cell. As depicted in Fig. 1, pentasaccharides on the cell surface are the main cell receptors for influenza HAs. There are two types of receptors, one with an α2,3 glycosidic linkage between Sia and Gal, i.e., Siaα2,3Galβ1,3Glc- NAcβ1,3Galβ1,4Glc (LSTa), and the other with an α2,6 linkage between Sia and Gal i.e., NeuAcα2,6Galβ1,4Glc- NAcβ1,3Galβ1,4Glc (LSTc). Most of the pentasaccharides found in human epithelial cells have the α2,6 linkage (referred to as human receptor) while most avian cells have the α2,3 linkage (referred to as avian receptor). Evidence shows that influenza HAs from different origins have some selectivity for the type of receptors found in their hosts [2–4]. For example, HA from human influenza virus seems to prefer the α2,6 cell receptor [5, 6]. In contrast, HA from avian influenza seems to prefer the α2,3 receptor [7–9], and HA from some swine influenza can bind equally to both receptors [10]. These observations are associated with the different types of amino acids near the glycosidic linkage binding site, i.e., residues 222 and 224 (H5 numbering) [11, 12]. This selectivity for host cell receptor according to HA is believed to be a barrier that prevents cross-species infection by the bird flu virus [13]. However, some experiments have N. Jongkon (*) : C. Sangma (*) Cheminformatics Research Unit, Department of Chemistry, Faculty of Science, Kasetsart University, Bangkok, Thailand 10900 e-mail: g5084005@ku.ac.th C. Sangma e-mail: fscicsm@ku.ac.th J Mol Model (2012) 18:285–293 DOI 10.1007/s00894-011-1071-y