Role of the Key Mutation in the Selective Binding of Avian and Human Influenza Hemagglutinin to Sialosides Revealed by Quantum-Mechanical Calculations

• Published in: Journal of the American Chemical Society 2010-12, Vol.132 (47), p.16862-16872
• Main Authors: Sawada, Toshihiko, Fedorov, Dmitri G, Kitaura, Kazuo
• Format: Article
• Language: English
• Subjects: Animals; Gases - chemistry; Hemagglutinin Glycoproteins, Influenza Virus - chemistry; Hemagglutinin Glycoproteins, Influenza Virus - genetics; Hemagglutinin Glycoproteins, Influenza Virus - metabolism; Humans; Influenza A virus - drug effects; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H3N8 Subtype; 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
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja105051e

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 NH2CO 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.