Conformational Analysis of Complex Oligosaccharides: The CICADA Approach to the Uromodulin O-Glycans
| Authors | |
|---|---|
| Year of publication | 2004 |
| Type | Article in Periodical |
| Magazine / Source | Carbohydrate Research |
| MU Faculty or unit | |
| Citation | |
| Field | Biophysics |
| Keywords | conformational analysis; oligosaccharide; CICADA |
| Description | Uromodulin is the pregancy associated Tamm-Horsfall glycoprotein, with ability to inhibit T-cell proliferation. Pregnancy-associated structural changes mainly occur in the O-glycosylation of this glycoprotein. These include up to 12 glycan structures, made up of an unusual core type 2 sequence terminated with one, two, or three sialyl Lewisx sequences; they could serve as E- and P-selectin ligands. The present work focuses on the most complex one; a tetradecamer made up of a type 2 core carrying three sialyl Lewisx branches. Five monosaccharides are assembled by fourteen glycosidic linkages. The conformational behaviour of the constituting disaccharide segments was evaluated using the flexible residue procedure of the MM3 molecular mechanics procedure. For each disaccharide, the adiabatic energy surface, along with the local energy minima have been established. All these results were used for the generation, prior to complete optimization of the tetradecamer. This was followed by a complete exploration of conformational hyperspace throughout the use of Single Coordinate Method as implemented in the CICADA program. Despite the potential flexibility of the tetradecasaccharide, only four conformational families occur, accounting for more than 95% of the total low energy conformations. For each family, the molecular properties (electrostatic, lipophilicity and hydrogen potential) have been studied. The shape of the tetradecasaccharide is best described as a flat ribbon, flanked by three branches having terminal sialyl residues. Two of the branches interact through non-bonded interactions, bringing further energy stabilization, and limiting the conformational flexibility of the sialyl residues. Only one branch maintains the original conformational features of sialyl Lewisx. The O-glycan can be seen as a fascinating example of dendrimeric structure, where the spatial arrangement of three S-Lex epitopes throughout their complementary presentations for interactions with E- and P-selectins. |
| Related projects: |