title: Prediction of avian influenza A binding preference to human receptor using conformational analysis of receptor bound to hemagglutinin.
abstract: BACKGROUND
  It is known that the highly pathogenic avian influenza A virus H5N1 binds strongly and with high specificity to the avian-type receptor by its hemagglutinin surface protein. This specificity is normally a barrier to viral transmission from birds to humans. However, strains may emerge with mutated hemagglutinin, potentially changing the receptor binding preference from avian to human-type. This hypothesis has been proven correct, since viral isolates from Vietnam and Thailand have been found which have increased selectivity toward the human cell receptor. The change in binding preference is due to mutation, which can be computationally modelled. The aim of this study is to further explore whether computational simulation could be used as a prediction tool for host type selectivity in emerging variants.
  
  
  RESULTS
  Molecular dynamics simulation was employed to study the interactions between receptor models and hemagglutinin proteins from H5N1 strains A/Duck/Singapore/3/97, mutated A/Duck/Singapore/3/97 (Q222L, G224S, Q222L/G224S), A/Thailand/1(KAN-1)/2004, and mutated A/Thailand/1(KAN-1)/2004 (L129V/A134V). The avian receptor was represented by Sia alpha(2,3)Gal substructure and human receptor by Sia alpha(2,6)Gal. The glycoside binding conformation was monitored throughout the simulations since high selectivity toward a particular host occurs when the sialoside bound with the near-optimized conformation.
  
  
  CONCLUSIONS
  The simulation results showed all hemagglutinin proteins used the same set of amino acid residues to bind with the glycoside; however, some mutations alter linkage preferences. Preference toward human-type receptors is associated with a positive torsion angle, while avian-type receptor preference is associated with a negative torsion angle. According to the conformation analysis of the bound receptors, we could predict the relative selectivity in accordance with in vitro experimental data when disaccharides receptor analogs were used.
authors: Cheminformatics Research Unit, Department of Chemistry, Faculty of Science, Kasetsart University, Thailand. g5084005@ku.ac.th
authors: Nipa
authors: N
authors: Jongkon
authors: Wanwimon
authors: W
authors: Mokmak
authors: Daungmanee
authors: D
authors: Chuakheaw
authors: Philip J
authors: PJ
authors: Shaw
authors: Sissades
authors: S
authors: Tongsima
authors: Chak
authors: C
authors: Sangma
mesh_terms: D003198:Computer Simulation; D018360:Crystallography, X-Ray; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011991:Receptors, Virus / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011991:Receptors, Virus