Ab initio fragment molecular orbital studies of influenza virus hemagglutinin–sialosaccharide complexes toward chemical clarification about the virus host range determination

Abstract

If we predict the host range of new or mutant influenza virus in advance, we are able to measure against pandemic human influenza immediately after the new virus emerges somewhere. Influenza viral hemagglutinin(HA)-sialoside receptor interaction is a target event for in silico chemical prediction studies about the virus host range determination. We theoretically studied avian and human influenza A virus HA H3 subtype complexed with avian or human type receptor Neu5Acα(2-3 or 2-6)Gal analogues by ab initio fragment molecular orbital (FMO) method at the second order Møller-Plesset (MP2)/6-31G level, which can evaluate correctly not only electrostatic interactions but also lipophilic interactions based on van der Waals dispersion force. Avian H3 bound to avian α2-3 11.4 kcal/mol stronger than to human α2-6 in the model complexes with taking account of intermolecular lipophilic interaction. A substitution at the position 226 between Gln (avian) and Leu(human) on influenza H3 HA1 has altered Glycoconj J (2008) its virus host range between avian and human. In the ab initio FMO studies, binding energy of avian Gln226Leu H3-human α2-6 was quite similar to that in the human H3-human α2-6 complex with amino acid sequence differences at nine positions in the models. This similarity indicates that avian Gln226Leu H3 virus can infect human with the same level as human H3 virus. Opposite mutation Leu226Gln in the human H3 gave the moderate binding energies to avian α2-3 with similarity to avian H3-α2-3 complex that supported our previous virus-sialoside binding assay. Ab initio FMO studies have revealed the relationship between influenza H3 virus host range and H3-α(2-3 or 2-6) receptors binding. Our theoretical approach may predict the infectious level of new viruses and point out some unknown dangerous mutation positions on HA in advance.

Chemical Insight Into the Influenza A Virus Hemagglutinin Binding to the Sialoside Revealed by the Fragment Molecular Orbital Method

“…In 2006, the first trial study was performed at the FMOHartree-Fock (HF)/STO-3G level in the gas phase small model of HA-sialoside complexes (70 amino acid residues, about 1100 atoms) to find the key amino acid residue on the selective binding of HA subtype H3 to the sialosides [51]. In 2008, the small model complexes in gas phase were restudied correctly by the FMO method at the second-order Møller-Plesset perturbation theory (MP2) [52,53] with the 6-31G basis sets [54]. The full HA1 domain of human viral H3 in complex with the human-type sialoside Neu5Ac2-6Gal (328 amino acid residues, 5068 atoms) was studied in gas phase at the FMO-HF/STO-3G level in 2007 [55], at the FMO-MP2/6-31G level in 2009 [56], that demanded the consideration of the backyard bulkiness beyond the sialoside binding site.…”

Computational Studies of Influenza A Virus at Three Important Targets: Hemagglutinin, Neuraminidase and M2 Protein

“…Binding energy and interactions between a single mutation Q226L of avian H3 and SA--2,3-Gal or SA--2,6-Gal were studied by Sawada and coworkers [24][25][26]. By comparing the binding energy based ab initio FMO method, the avian Q226 H3 bound to avian-type receptor stronger than that observed in human-type analogue (by 8.2 kcal•mol -1 at FMO-HF/STO-3G or ~15-16 kcal•mol -1 at FMO-MP2/6-31G).…”

Fully analytic energy gradient in the fragment molecular orbital method

“…The FMO method has been applied to a number of large systems. [53][54][55][56][57][58][59][60][61][62][63][64][65][66] FMO-MD has been used [67][68][69][70][71][72][73][74][75][76][77][78] to study the dynamics of various processes such as chemical reactions. However, the FMO-MD method suffers from an accumulation of errors 67 with the time evolution due to an incomplete analytic FMO energy gradient.…”