Molecular dynamics simulations of carbohydrate-mimetic haptens in complex with a complementary anti-carbohydrate antibody

The monoclonal antibody SYA/J6 is specific for the O-polysaccharide of the Shigella flexneri Y bacterium. Two haptens, a pentasaccharide and a mimetic octapeptide, bind to SYA/J6 with moderate binding affinities. In a previous attempt to obtain improved binding affinity to SYA/J6, two glycopeptide chimeras (α-glycopeptide and β-glycopeptide) were designed based on the structures of the pentasaccharide and the octapeptide, as well as a molecular docking study. Despite the overall fit of the ligand, the α-glycopeptide showed no inhibition of the SYA/J6 antibody binding to the O-polysaccharide. In this work, we conducted conventional molecular dynamics simulations of the SYA/J6 Fab in complex with these four related haptens. Several conformational differences between crystal structures and bioactive structures for the pentasaccharide binding and the octapeptide binding were identified. More significantly, the MD simulations revealed that the Fab complexes of both α-glycopeptide and β-glycopeptide were not stable, with the ligand dissociating from the combining site. This behavior provides a reasonable explanation for the lack of binding of the α-glycopeptide, and implies further that the β-glycopeptide would not be a hapten that binds the SYA/J6 antibody.

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► All-atom, explicit-solvent MD simulations were conducted without constraints.
► Binding features not observed in crystal structures were identified for the pentasaccharide 1 and the peptide 2.
► The lack of binding of the α-glycopeptide 3 was explained.