文摘
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 A尾42 or 伪-synuclein, which are assumed to be responsible for Alzheimer鈥檚 and Parkinson鈥檚 disease, respectively. In this work we systematically investigated the binding of four water-soluble tweezers 1a鈥?b>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<sup>1sup>H NMR shift calculations provides clear evidence that the tweezers 1a鈥?b>c bind the amino acid or peptide guest molecules by threading the lysine or arginine side chain through the tweezers鈥?cavity, whereas in the case of 1d the guest molecule is preferentially positioned outside the tweezer鈥檚 cavity. Attractive ionic, CH-蟺, and hydrophobic interactions are here the major binding forces. The combination of experiment and theory provides deep insight into the host鈥揼uest binding modes, a prerequisite to understanding the exciting influence of these tweezers on the aggregation of proteins and the activity of enzymes.