Regulating Peptide Self-Assemblies by Halogen Bonding and Other Halogen Effects

This work demonstrates the modulation of peptide self-assembly by halogen bonding (XB) and other halogen effects in synergy with the orthogonal hydrogen bonding of the peptide backbone. Three pentapeptides (featuring a common self-assembling FFK (phenylalanine-phenylalanine-lysine) motif were synthesized. Two peptides were functionalized with a common N-terminal tetrafluoroiodophenyl (TFIP) moiety as the XB donor, while the C-terminal carried either a phenylalanine or a histidine moiety, to examine the effect of XB. Histidine-functionalized peptide displayed a significant C-I···N XB between its TFIP donor and imidazole acceptor, whereas phenylalanine-terminated analogue showed negligible XB interaction. Despite the presence of XB, histidine-containing peptide exhibited diminished thermal stability and lower self-assembly propensity because of the weaker hydrophobic effect of its imidazole ring as compared to the phenylalanine residue. To probe the halogen effect, iodine atom was substituted with fluorine to generate another control peptide. Comprehensive studies revealed markedly higher stability and enhanced viscoelastic properties of the iodine-containing peptide over its fluorinated analogue, along with distinct self-assembly mechanisms (cooperative vs. isodesmic), which was attributed to the greater hydrophobicity and polarizability of iodine atom compared to fluorine. Overall, the observed stability order highlights a subtle balance among XB, HB, and hydrophobic interactions in fine-tuning peptide self.