title: A key n→π* Interaction in N-acyl homoserine lactones.
abstract: Many Gram-negative bacteria employ N-acyl homoserine lactones (AHLs) as signal molecules for quorum sensing. The binding of AHLs to their target LuxR-type receptor proteins can effect changes in growth, virulence, and other phenotypes. LuxR-type receptors therefore present attractive pharmaceutical targets for control of bacterial pathogenesis. Here, we present X-ray crystallographic and computational evidence that the conformation of free AHLs is biased away from the conformation observed when bound to their cognate receptor due to the influence of an n→π* interaction. In this n→π* interaction, the p-type lone pair (n) of the N-acyl oxygen overlaps with the π* orbital of the lactone carbonyl group. This overlap results in the release of approximately 0.64 kcal/mol of energy. We also show that this interaction can be attenuated by installing electron-withdrawing groups on the N-acyl chain. Modulating this previously unappreciated interaction could present a new avenue toward effective inhibitors of bacterial quorum sensing.
authors.affiliation: Department of Chemistry and ‡Department of Biochemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Newberry
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Raines
mesh_terms: D054742:Acyl-Butyrolactones / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation
chemical_list: D054742:Acyl-Butyrolactones