Deciphering multivalent glycocluster–lectin interactions through AFM characterization of the self-assembled nanostructures
Résumé
Pseudomonas aeruginosa is a human opportunistic pathogen responsible for lung infections in cystic fibrosis patients. The emergence of resistant strains and its ability to form a biofilm seems to give a selective advantage to the bacterium and thus new therapeutic approaches are needed. To infect lung, the bacterium uses several virulence factors, like LecA lectins. These proteins are involved in bacterial adhesion thanks to their specific interaction with carbohydrates of the host epithelial cells. The tetrameric LecA lectin specifically binds galactose residues. A new therapeutic approach is based on the development of highly affine synthetic glycoclusters able to selectively link with LecA to interfere the natural carbohydrate-LecA interaction. In this study, we combined Atomic Force Microscopy imaging and Molecular Dynamics simulations to visualize and understand the arrangements formed by LecA and five different glycoclusters. Our glycoclusters are small scaffolds characterized by a core and four branches, which terminate by a galactose residue. Depending on the nature of the core and the branches, the glycocluster-lectin interaction can be modulated and the affinity increased. We show that glycocluster-LecA arrangements highly depend on the glycocluster architecture: the core influences the rigidity of the geometry and the directionality of the branches, whereas the nature of the branch determines the compactness of the structure and the ease of the binding.
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