The selective molecular recognition properties of two different calix[4]pyrrole receptors toward the cis isomer of acetylated lysine (cis-Kac) are investigated. The formation of a 1 : 1 complex is favoured for the aryl-extended receptor compared to the superaryl-extended featuring a deeper cavity for which the energetically not favourable desolvation of the aminoacidic group hampers the guest inclusion in the hydrophobic cavity.

Abstract

Post-translational modifications of lysine in histones, as methylation and acetylation, have well established functions in epigenetics and are emerging as important actors in broader biological regulation. Currently, the detection of acetylated lysine (Kac) in water solution as free amino acid or protein residue remains challenging. Acetylated lysine is a neutral amino acid, and the lack of ion–dipole interactions causes the decrease in binding affinity displayed by synthetic molecular receptors with respect to the other lysine modifications. Here, we report molecular modeling calculations and ¹H NMR experiments to investigate the binding properties of two different calix[4]pyrrole receptors towards Kac. Computational analyses reveal that tetra-aryl-extended calix[4]pyrrole (1) preferentially binds the cis-Kac conformer over the trans one due to steric considerations and more favorable interactions. Experimental ¹H NMR titration experiments confirm the formation of a 1 : 1 complex between receptor 1 and cis-Kac, with a K_a exceeding 10³ M⁻¹. Conversely, the super-aryl-extended calix[4]pyrrole 2 is less efficient in binding Kac, due to unfavorable solvation/desolvation effects, as proven by ¹H NMR experiments. Moreover, receptor 1 showed a higher affinity for Kac over other lysine modifications, such as methylated lysines.