Role of the key mutation in the selective binding of avian and human influenza hemagglutinin to sialosides revealed by quantum-mechanical calculations.
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.
Nanosystem Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki 305-8568, Japan. sawada-t@aist.go.jp
Toshihiko
T
Sawada
Dmitri G
DG
Fedorov
Kazuo
K
Kitaura
D000818:Animals; D005740:Gases / Q000737:chemistry; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype; D053123:Influenza A Virus, H3N8 Subtype; D009980:Influenza A virus / Q000187:drug effects; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D011789:Quantum Theory; D012794:Sialic Acids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013379:Substrate Specificity; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
D005740:Gases; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D050505:Mutant Proteins; D012794:Sialic Acids; C109963:hemagglutinin, avian influenza A virus; C483468:hemagglutinin, human influenza A virus; D014867:Water