A study of norovirus-HBGA interactions; Computational studies on the interaction of norovirus surface protein with ABO- blood group active saccharides
Examensarbete för masterexamen
Noroviruses are one of the major causes of non-bacterial gastroenteritis epidemics in humans. Different histo-blood group antigens (HBGA) bind to different norovirus strains and are considered as essential attachment factors on the host cell. Among the human HBGAs, the ABO structures and Lewis are involved in norovirus receptor binding. The norovirus strain VA387 is of dominating clinical importance. The surface protein of this strain in complex with the A-trisaccharide and the B-trisaccharide, both sharing the Fucα1-2Galβ moiety, has been crystallized. The α-fucose of the ligands is buried in the binding pocket and is observed to have strong hydrogen bonding interactions with the binding site and hence plays a key role in the binding. The focus of this study is to understand the observed binding specificity for a series of oligosaccharides sharing the Fucα1-2Galβ moiety and then to predict their relative binding strength. The favoured conformations of the HBGAs were computed using the mm4-based force field method GLYGAL. The prediction of the favoured poses of the HBGAs in the binding site of VA387 was carried out using molecular dynamics simulations. The orientation of the fucose ring of the HBGAs in the binding site was assumed to be similar to the fucose in the case of the reported B-trisaccharide/VA387 complex. Calculations were carried out for type-1, type-2 and type-3 chains of HBGAs. The AMBER suite of programs was used for the molecular dynamics studies with implicit solvent. The results from the molecular dynamics simulations for each complex were used to calculate the interaction score of the predicted complexes using the Glide XP scoring function. The major finding in the current study is the critically important role of the Fucα1,2 and the terminal Gal/GalNAc in the binding of VA387 with ABO-active saccharides. The results obtained from the present study give deeper insights into the structural details of the VA387 binding with HBGAs and are in good agreement with mutagenesis studies in which key protein residues for the binding of VA387 with ABO-active saccharides have been identified.
Datalogi , Bioinformatik och systembiologi , Computer science , Bioinformatics and Systems Biology