title: Molecular tweezers with varying anions: a comparative study.
abstract: Selective binding of the phosphate-substituted molecular tweezer 1a to protein lysine residues was suggested to explain the inhibition of certain enzymes and the aberrant aggregation of amyloid petide Aβ42 or α-synuclein, which are assumed to be responsible for Alzheimer's and Parkinson's disease, respectively. In this work we systematically investigated the binding of four water-soluble tweezers 1a-d (substituted by phosphate, methanephosphonate, sulfate, or O-methylenecarboxylate groups) to amino acids and peptides containing lysine or arginine residues by using fluorescence spectroscopy, NMR spectroscopy, and isothermal titration calorimetry (ITC). The comparison of the experimental results with theoretical data obtained by a combination of QM/MM and ab initio(1)H NMR shift calculations provides clear evidence that the tweezers 1a-c bind the amino acid or peptide guest molecules by threading the lysine or arginine side chain through the tweezers' cavity, whereas in the case of 1d the guest molecule is preferentially positioned outside the tweezer's cavity. Attractive ionic, CH-π, and hydrophobic interactions are here the major binding forces. The combination of experiment and theory provides deep insight into the host-guest binding modes, a prerequisite to understanding the exciting influence of these tweezers on the aggregation of proteins and the activity of enzymes.
authors.affiliation: Department of Chemistry, University of Duisburg-Essen, Universitätsstr. 7, 45117 Essen, Germany.
authors.forename: Som
authors.initials: S
authors.lastname: Dutt
authors.forename: Constanze
authors.initials: C
authors.lastname: Wilch
authors.forename: Thomas
authors.initials: T
authors.lastname: Gersthagen
authors.forename: Peter
authors.initials: P
authors.lastname: Talbiersky
authors.forename: Kenny
authors.initials: K
authors.lastname: Bravo-Rodriguez
authors.forename: Matti
authors.initials: M
authors.lastname: Hanni
authors.forename: Elsa
authors.initials: E
authors.lastname: Sánchez-García
authors.forename: Christian
authors.initials: C
authors.lastname: Ochsenfeld
authors.forename: Frank-Gerrit
authors.initials: FG
authors.lastname: Klärner
authors.forename: Thomas
authors.initials: T
authors.lastname: Schrader
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000838:Anions / Q000737:chemistry; D002151:Calorimetry; D019281:Dimerization; D005470:Fluorometry; D006873:Hydroquinones / Q000737:chemistry*; D008279:Magnetic Resonance Imaging; D008958:Models, Molecular; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D010710:Phosphates / Q000737:chemistry; D011522:Protons; D011789:Quantum Theory; D012997:Solvents; D013431:Sulfates / Q000737:chemistry; D013816:Thermodynamics; D017186:Titrimetry
chemical_list: D000596:Amino Acids; D000838:Anions; D006873:Hydroquinones; D063065:Organophosphonates; D010455:Peptides; D010710:Phosphates; D011522:Protons; D012997:Solvents; D013431:Sulfates; C031927:hydroquinone