title: Role of water molecules in structure and energetics of Pseudomonas aeruginosa lectin I interacting with disaccharides.
abstract: Calcium-dependent lectin I from Pseudomonas aeruginosa (PA-IL) binds specifically to oligosaccharides presenting an alpha-galactose residue at their nonreducing end, such as the disaccharides alphaGal1-2betaGalOMe, alphaGal1-3betaGalOMe, and alphaGal1-4betaGalOMe. This provides a unique model for studying the effect of the glycosidic linkage of the ligands on structure and thermodynamics of the complexes by means of experimental and theoretical tools. The structural features of PA-IL in complex with the three disaccharides were established by docking and molecular dynamics simulations and compared with those observed in available crystal structures, including PA-IL.alphaGal1-2betaGalOMe complex, which was solved at 2.4 A resolution and reported herein. The role of a structural bridge water molecule in the binding site of PA-IL was also elucidated through molecular dynamics simulations and free energy calculations. This water molecule establishes three very stable hydrogen bonds with O6 of nonreducing galactose, oxygen from Pro-51 main chain, and nitrogen from Gln-53 main chain of the lectin binding site. Binding free energies for PA-IL in complex with the three disaccharides were investigated, and the results were compared with the experimental data determined by titration microcalorimetry. When the bridge water molecule was included in the free energy calculations, the simulations predicted the correct binding affinity trends with the 1-2-linked disaccharide presenting three times stronger affinity ligand than the other two. These results highlight the role of the water molecule in the binding site of PA-IL and indicate that it should be taken into account when designing glycoderivatives active against P. aeruginosa adhesion.
authors.affiliation: Centre de Rechèrche sur les Macromolécules Végétales-CNRS (affiliated with Université Joseph Fourier and Institut de Chimie Moléculaire de Grenoble), BP 53, 38041 Grenoble Cedex 9, France.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Nurisso
authors.forename: Bertrand
authors.initials: B
authors.lastname: Blanchard
authors.forename: Aymeric
authors.initials: A
authors.lastname: Audfray
authors.forename: Lina
authors.initials: L
authors.lastname: Rydner
authors.forename: Stefan
authors.initials: S
authors.lastname: Oscarson
authors.forename: Annabelle
authors.initials: A
authors.lastname: Varrot
authors.forename: Anne
authors.initials: A
authors.lastname: Imberty
mesh_terms: D018829:Adhesins, Bacterial / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002151:Calorimetry / Q000379:methods; D018360:Crystallography, X-Ray; D004187:Disaccharides / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D037102:Lectins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013816:Thermodynamics; D017186:Titrimetry / Q000379:methods; D014867:Water / Q000737:chemistry*
chemical_list: D018829:Adhesins, Bacterial; D004187:Disaccharides; D037102:Lectins; C038692:adhesin, Pseudomonas; D014867:Water; D002118:Calcium
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