It was explored, by means of a theoretical and experimental approach, how the increase in the peptide length and in the number of possible positions influences the formation of the complex and of the dynamic and conformational features of the peptide with it. It was demonstrated the 1:1 stoichiometry of each formed complex by means of Job’s method and evaluated the magnitude of its binding constant via UV–vis. The authors also described the molecular details of each interaction in both silico, by means of molecular docking and MD, and experimentally via 2D NMR spectroscopy. The data show how the behavior, the stability, and the Kbs of the β-CD/peptide system change with the modification of the tyrosine position within the peptide sequence. Tyr3, the peptide bearing the aromatic residue in central position, also in this case forms the most stable complex with the highest affinity for the β-CD host. The complex is stabilized by the interaction of the flanking residues with the CD upper rim. Important differences with respect to the previous tripeptides study are shown when the tyrosine residue is at the N- or at the C-terminal (Tyr1 and Tyr5, respectively). In the tripeptides the tyrosine in the first position did not align with the central axis of the CD while the tyrosine in the last position did not penetrate the cavity at all. In the case of the pentapeptides here reported, the extended length of the host peptides allows the aromatic ring to align with the longitudinal axis of the host molecule and facilitates the deep penetration into the β-CD hydrophobic cavity. Another interesting difference is found when the tyrosine is in central position: Tyr3 is arranged in a sort of U-shaped form indicating that the β-CD preferentially stabilizes this conformation.
A) Simulated models of Tyr3 not included complex along the trajectory at 0 ns, 50 ns, 100 ns, and 250 ns with RMSD timing evolution. B) Simulated models of Tyr3 included complex along the trajectory at 0 ns and 250 ns with RMSD timing evolution.
Martina Dragone, Gianluca D’Abrosca, Antonia D’Aniello, Domenico Alberga, Getasew Shitaye, Rinaldo Grazioso, Stefano Tomassi, Luigi Russo, Roberto Fattorusso, Salvatore Di Maro, Giuseppe F. Mangiatordi, Michele Saviano,* Gaetano Malgieri, Carla Isernia,* and Rosa Iacovino (2025) β-Cyclodextrin Inclusion Complexes with Model Pentapeptides: Role of the Tyrosine Position within the Peptide Chain. ChemistryOpen e202500223. https://doi.org/10.1002/open.202500223