Computational studies on the interaction of ABO-active saccharides with the norovirus VA387 capsid protein can explain experimental binding data

Abstract

Norovirus strains are known to cause recurring epidemics of winter vomiting disease. The crystal structure of the capsid protein of VA387, a representative of the clinically important GII.4 genocluster, was recently solved in complex with histo-blood group A- and B-trisaccharides. However, the VA387 strain is known to bind also to other natural carbohydrates for which detailed structural information of the complexes is not available. In this study we have computationally explored the fit of the VA387 with a set of naturally occurring carbohydrate ligands containing a terminal alpha1,2-linked fucose. MD simulations both with explicit and implicit solvent models indicate that type 1 and 3 extensions of the ABO-determinant including ALe(b) and BLe(b) pentasaccharides can be well accommodated in the site. Scoring with Glide XP indicates that the downstream extensions of the ABO-determinants give an increase in binding strength, although the alpha1,2-linked fucose is the single strongest interacting residue. An error was discovered in the geometry of the GalNAc-Gal moiety of the published crystal structure of the A-trisaccharide/VA387 complex. The present modeling of the complexes with histo-blood group A-active structures shows some contacts which provide insight into mutational data, explaining the involvement of I389 and Q331. Our results can be applicable in structure-based design of adhesion inhibitors of noroviruses.

Molecular Details of the Recognition of Blood Group Antigens by a Human Norovirus as Determined by STD NMR Spectroscopy

“…[21] Our MD simulation samples three conformational families in the bound state (Figure 3 and Figures S10 and S12 in the Supporting Information) substantiating the hypothesis that the 2,3-glycosidic linkage retains flexibility in the bound state. Two of these families correspond to the main minima "a" and "b" identified previously [18] (cf.…”

Norovirus drug candidates that inhibit viral capsid attachment to human histo-blood group antigens

“…In their study, Koppisetty et al (2010) showed that computational studies on the interaction of HBGA with the norovirus VA387 capsid protein are in agreement with experimental binding (systemic mutational) data as derived by Tan et al (2008). This has provided a strong framework with which to investigate and develop inhibitors of this interaction further using structure based analysis techniques.…”

“…Recent determination of the recognition requirements between norovirus attachment protein VP1 and host receptors and, in particular, solving of the crystal structure of the complex of norovirus P domain and HBGAs (Cao et al, 2007) have provided a new opportunity to develop drugs targeting the first attachment step in norovirus infection (Huang et al, 2005; Koppisetty et al, 2010; Lundborg et al, 2013). The idea of targeting viral binding is well established in antiviral drug development.…”

“…The molecular details of the interactions of norovirus GII.4 with fucosylated HBGAs were investigated using molecular dynamics (MD) simulations based on the crystal structure of HBGA trisaccharide B in complex with VA387 GII.4 norovirus P dimer, a region of the norovirus capsid protein that contains the HBGA binding site (Koppisetty et al, 2010). In their study, Koppisetty et al (2010) showed that computational studies on the interaction of HBGA with the norovirus VA387 capsid protein are in agreement with experimental binding (systemic mutational) data as derived by Tan et al (2008).…”

“…It was concluded that the HBGA A trisaccharide in PDB ID 2OBS was not correct (Koppisetty et al, 2010), and therefore, the focus was put on HBGA B trisaccharide (Lundborg et al, 2013). The binding free energies of the HBGA trisaccharides and the top 20 fragments from each of the two libraries (Maybridge Ro3 and ZINC) were calculated.…”