Conformation of Glycomimetics in the Free and Protein-Bound State: Structural and Binding Features of theC-glycosyl Analogue of the Core Trisaccharide α-d-Man-(1 → 3)-[α-d-Man-(1 → 6)]-d-Man

Abstract

The conformational properties of the C-glycosyl analogue of the core trisaccharide α-d-Man-(1 → 3)-[α-d-Man-(1 → 6)]-d-Man in solution have been carefully analyzed by a combination of NMR spectroscopy and time-averaged restrained molecular dynamics. It has been found that both the α-1,3- and the α-1,6-glycosidic linkages show a major conformational averaging. Unusual Φ ca. 60° orientations for both Φ torsion angles are found. Moreover, a major conformational distinction between the natural compound and the glycomimetic affects to the behavior of the ω₁₆ torsion angle around the α-1 → 6-linkage. Despite this increased flexibility, the C-glycosyl analogue is recognized by three mannose binding lectins, as shown by NMR (line broadening, TR−NOE, and STD) and surface plasmon resonance (SPR) methods. Moreover, a process of conformational selection takes place, so that these lectins probably bind the glycomimetic similarly to the way they recognize the natural analogue. Depending upon the architecture and extension of the binding site of the lectin, loss or gain of binding affinity with respect to the natural analogue is found.