Département de chimie moléculaire

Recent advances in glycobiol. revealed the essential role of lectins for deciphering the glycocode by specific recognition of carbohydrates. Integrated multiscale approaches are needed for characterizing lectin specificity: combining on one hand high-throughput anal. by glycan array expts. and systematic mol. docking of oligosaccharide libraries and on the other hand detailed anal. of the lectin/oligosaccharide interaction by x-ray crystallog., microcalorimetry and free energy calcns. The lectins LecB from Pseudomonas aeruginosa and BambL from Burkholderia ambifaria are part of the virulence factors used by the pathogenic bacteria to invade the targeted host. These two lectins are not related but both recognize fucosylated oligosaccharides such as the histo-blood group oligosaccharides of the ABH(O) and Lewis epitopes. The specificities were characterized using semi-quant. data from glycan array and analyzed by mol. docking with the Glide software. Reliable prediction of protein/oligosaccharide structures could be obtained as validated by existing crystal structures of complexes. Addnl., the crystal structure of BambL/Lewis x was detd. at 1.6 {\AA} resoln., which confirms that Lewis x has to adopt a high-energy conformation so as to bind to this lectin. Free energies of binding were calcd. using a procedure combining the Glide docking protocol followed by free energy rescoring with the Prime/Mol. Mechanics Generalized Born Surface Area (MM-GBSA) method. The calcd. data were in reasonable agreement with exptl. free energies of binding obtained by titrn. microcalorimetry. The established predictive protocol is proposed to rationalize large sets of data such as glycan arrays and to help in lead discovery projects based on such high throughput technol. [on SciFinder(R)]