Restricted N-glycan Conformational Space in the PDB and Its Implication in Glycan Structure Modeling

Abstract

Understanding glycan structure and dynamics is central to understanding protein-carbohydrate recognition and its role in protein-protein interactions. Given the difficulties in obtaining the glycan's crystal structure in glycoconjugates due to its flexibility and heterogeneity, computational modeling could play an important role in providing glycosylated protein structure models. To address if glycan structures available in the PDB can be used as templates or fragments for glycan modeling, we present a survey of the N-glycan structures of 35 different sequences in the PDB. Our statistical analysis shows that the N-glycan structures found on homologous glycoproteins are significantly conserved compared to the random background, suggesting that N-glycan chains can be confidently modeled with template glycan structures whose parent glycoproteins share sequence similarity. On the other hand, N-glycan structures found on non-homologous glycoproteins do not show significant global structural similarity. Nonetheless, the internal substructures of these N-glycans, particularly, the substructures that are closer to the protein, show significantly similar structures, suggesting that such substructures can be used as fragments in glycan modeling. Increased interactions with protein might be responsible for the restricted conformational space of N-glycan chains. Our results suggest that structure prediction/modeling of N-glycans of glycoconjugates using structure database could be effective and different modeling approaches would be needed depending on the availability of template structures.

Delineating the conformational flexibility of trisaccharides from NMR spectroscopy experiments and computer simulations

“…This result for ψ was also observed in many crystal structures for gluco - and manno -configured hexopyranoses as the non-reducing end unit. 86, 87 …”

Identification and Characterization of Complex Glycosylated Peptides Presented by the MHC Class II Processing Pathway in Melanoma

“…Glycans, on the other hand, have high conformational mobility, a property that limits their resolution in X-ray crystallography and complicates modeling of their structures. 32 Here, the simplified glycan fragments (GlcNAc) 2 (Mannose) 3 and (GlcNAc) 2 (Fucose)(Mannose) 3 were appended to the constructed peptides (Table 2), and ensembles of conformations were generated to approximate the steric effect imposed by each peptide’s glycan(s).…”

Terminal sialic acids on CD44 N-glycans can block hyaluronan binding by forming competing intramolecular contacts with arginine sidechains

“…Glycans are highly flexible, and a given glycan can assume multiple conformations at physiological temperatures . This is in contrast to many proteins that fold to a single well‐defined three dimensional (3D) conformation.…”

“…Glycans are highly flexible, and a given glycan can assume multiple conformations at physiological temperatures. 39,40 This is in contrast to many proteins that fold to a single well-defined three dimensional (3D) conformation. Therefore, compared to the many proteins whose unique atomic coordinates have been determined by X-ray crystallography or NMR studies, relatively few 3D structures of glycan components of glycoproteins exist, especially beyond the first or second residue from the point of attachment to the protein.…”