Role of the key mutation in the selective binding of avian and human influenza hemagglutinin to sialosides revealed by quantum-mechanical calculations

J Am Chem Soc. 2010 Dec 1;132(47):16862-72. doi: 10.1021/ja105051e. Epub 2010 Nov 4.


The selective binding between avian and human influenza A viral hemagglutinins (HA) subtype H3 and Neu5Acα2-3 and α2-6Gal (avian α2-3, human α2-6) is qualitatively rationalized by the fragment molecular orbital (FMO) method. We suggest a general model of analyzing protein-ligand interactions based on the electrostatic, polarization, dispersion, and desolvation components obtained from quantum-mechanical calculations at the MP2/6-31G(d) level with the polarizable continuum model of solvation. The favorable avian H3 (A/duck/Ukraine/1963)-avian α2-3 binding arises from the hydrophilic interaction between Gal-4 OH and side-chain NH(2)CO on Gln226, which is supported by the intermolecular hydrogen-bond network to the 1-COO group on Neu5Ac moiety. A substitution of Gln226Leu in the avian H3 HA1 domain increases the binding affinity to human α2-6 due to the Leu226···human α2-6 dispersion with a small entropic penalty during the complex formation. The remarkable human H3 (A/Aichi/2/1968)-human α2-6 binding is not governed by the Ser228-OH···OH-9 Neu5Ac hydrogen bond. These fragment-based chemical aspects can help design monovalent inhibitors of the influenza viral HA-sialoside binding and the simulation studies on the viral HAs-human α2-6 binding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gases / chemistry
  • Hemagglutinin Glycoproteins, Influenza Virus / chemistry
  • Hemagglutinin Glycoproteins, Influenza Virus / genetics
  • Hemagglutinin Glycoproteins, Influenza Virus / metabolism*
  • Humans
  • Influenza A Virus, H3N2 Subtype
  • Influenza A Virus, H3N8 Subtype
  • Influenza A virus* / drug effects
  • Models, Molecular
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism*
  • Mutation*
  • Protein Binding / drug effects
  • Protein Stability
  • Protein Structure, Tertiary
  • Quantum Theory*
  • Sialic Acids / chemistry
  • Sialic Acids / metabolism*
  • Sialic Acids / pharmacology
  • Substrate Specificity
  • Thermodynamics
  • Water / chemistry


  • Gases
  • Hemagglutinin Glycoproteins, Influenza Virus
  • Mutant Proteins
  • Sialic Acids
  • hemagglutinin, avian influenza A virus
  • hemagglutinin, human influenza A virus
  • Water