title: Validation of Reactivity Descriptors to Assess the Aromatic Stacking within the Tyrosine Gate of FimH.
abstract: Antagonists of the FimH adhesin, a protein almost universally present at the extremity of type-1 fimbriae expressed by Escherichia coli, have been abundantly in the spotlight as alternative treatments of urinary tract infections. The antagonists function as bacterial antiadhesives through highly specific α-d-mannose binding in a charged and polar pocket at the tip of the FimH lectin domain and by the stacking of alkyl or aromatic moieties substituted on the mannose with two tyrosine residues (Tyr48 and Tyr137) at the entrance of the mannose-binding pocket. Using high-resolution crystal data, interaction energies are calculated for the different observed aromatic stacking modes between the tyrosines and the antagonist. The dispersion component of the interaction energy correlates with the observed electron density. The quantum chemical reactivity descriptors local hardness and polarizability were successfully validated as prediction tools for ligand affinity in the tyrosine gate of FimH and therefore have potential for rapid drug screening.
authors.affiliation: General Chemistry, Vrije Universiteit Brussel, Structural Biology Brussels, VIB and Vrije Universiteit Brussel, and Brussels Center for Redox Biology, Pleinlaan 2, 1050 Brussels, Belgium ; General Chemistry, Vrije Universiteit Brussel, Structural Biology Brussels, VIB and Vrije Universiteit Brussel, and Brussels Center for Redox Biology, Pleinlaan 2, 1050 Brussels, Belgium ; General Chemistry, Vrije Universiteit Brussel, Structural Biology Brussels, VIB and Vrije Universiteit Brussel, and Brussels Center for Redox Biology, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Goedele
authors.initials: G
authors.lastname: Roos
authors.affiliation: General Chemistry, Vrije Universiteit Brussel, Structural Biology Brussels, VIB and Vrije Universiteit Brussel, and Brussels Center for Redox Biology, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Adinda
authors.initials: A
authors.lastname: Wellens
authors.affiliation: Department of Chemistry, Université du Québec à Montréal , Montréal, QC H3C 3P8, Canada ; Department of Chemistry and Biochemistry, Université de Moncton , Moncton, NB E1A 3E9, Canada.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Touaibia
authors.affiliation: Unité de Glycobiologie Structurale et Fonctionnelle, UMR8576 du CNRS, Université Lille 1 , 59655 Villeneuve d'Ascq, France.
authors.forename: Nao
authors.initials: N
authors.lastname: Yamakawa
authors.affiliation: General Chemistry, Vrije Universiteit Brussel, Structural Biology Brussels, VIB and Vrije Universiteit Brussel, and Brussels Center for Redox Biology, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Geerlings
authors.affiliation: Department of Chemistry, Université du Québec à Montréal , Montréal, QC H3C 3P8, Canada.
authors.forename: René
authors.initials: R
authors.lastname: Roy
authors.affiliation: General Chemistry, Vrije Universiteit Brussel, Structural Biology Brussels, VIB and Vrije Universiteit Brussel, and Brussels Center for Redox Biology, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Lode
authors.initials: L
authors.lastname: Wyns
authors.affiliation: General Chemistry, Vrije Universiteit Brussel, Structural Biology Brussels, VIB and Vrije Universiteit Brussel, and Brussels Center for Redox Biology, Pleinlaan 2, 1050 Brussels, Belgium ; Unité de Glycobiologie Structurale et Fonctionnelle, UMR8576 du CNRS, Université Lille 1 , 59655 Villeneuve d'Ascq, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Bouckaert
keywords: FimH; dispersion energy; electron distribution; local hardness; polarizability; stacking