title: Molecular recognition of Candida albicans (1->2)-β-mannan oligosaccharides by a protective monoclonal antibody reveals the immunodominance of internal saccharide residues.
abstract: A self-consistent model of β-mannan oligosaccharides bound to a monoclonal antibody, C3.1, that protects mice against Candida albicans has been developed through chemical mapping, NMR spectroscopic, and computational studies. This antibody optimally binds di- and trisaccharide epitopes, whereas larger oligomers bind with affinities that markedly decrease with increasing chain length. The (1→2)-β-linked di-, tri-, and tetramannosides bind in helical conformations similar to the solution global minimum. Antibody recognition of the di- and trisaccharide is primarily dependent on the mannose unit at the reducing end, with the hydrophobic face of this sugar being tightly bound. Recognition of a tetrasaccharide involves a frameshift in the ligand interaction, shown by strong binding of the sugar adjacent to the reducing end. We show that frameshifting may also be deliberately induced by chemical modifications. Molecular recognition patterns similar to that of mAb C3.1, determined by saturation transfer difference-NMR, were also observed in polyclonal sera from rabbits immunized with a trisaccharide glycoconjugate. The latter observation points to the importance of internal residues as immunodominant epitopes in (1→2)-β-mannans and to the viability of a glycoconjugate vaccine composed of a minimal length oligosaccharide hapten.
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada. maggie.johnson@ualberta.ca
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Johnson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cartmell
authors.forename: Nina E
authors.initials: NE
authors.lastname: Weisser
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Woods
authors.forename: David R
authors.initials: DR
authors.lastname: Bundle
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D002176:Candida albicans / Q000378:metabolism*; D002240:Carbohydrate Sequence; D003198:Computer Simulation; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology; D008351:Mannans / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular
chemical_list: D000911:Antibodies, Monoclonal; D016056:Immunodominant Epitopes; D008351:Mannans