Interaction Between Heparan Sulfate Oligosaccharide and the Receptor Binding Domain of Wuhan and Omicron Variants of the SARS-CoV-2 Spike Protein

Heparan sulfate proteoglycans are known to serve as initial attachment site for several viruses and bacteria. Recent studies suggest that SARS-CoV-2 coronavirus similarly exploits these glycosaminoglycans, facilitating conformational changes in the spike protein, that promotes the interaction between the receptor binding domain (S1-RBD) and the cellular angiotensin-converting enzyme 2 receptor (ACE2), thereby triggering the virus internalization process. Until now, the molecular details that drive this process, particularly, the co-receptor role of the heparan sulfate (HS), remain not completely understood. Our research seeks to characterize the interaction between an HS hexasaccharide (hexa) and the N343 glycosylated S1-RBD of the Omicron and wild-type (WT) variants of SARS-CoV-2. The conformational properties of hexa in unbound and bound state with these S1-RBDs are investigated using multiple independent MD simulations; the proton binding epitope of hexa, as well as the details of the interaction between this glycan and S1-RBD of the Omicron variant, are characterized by comparing experimental and theoretical saturation transfer difference NMR signals. This investigation reinforces previous evidence about the low specificity and multi-modal nature of the interaction between HS oligosaccharides and these S1-RBDs, and underlines the role of the glycosyl moiety at N343 in potentially affecting this interaction in both selected variants.