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- W1977239232 abstract "Cation−π interactions between amino acid side chains are increasingly being recognized as important structural and functional features of proteins and other biomolecules. Although these interactions have been found in static protein structures, they have not yet been detected in dynamic biomolecular systems. We determined, by 1H NMR spectroscopic titrations, the energies of cation−π interactions of the amino acid derivative AcLysOMe (1) with AcPheOEt (2) and with AcTyrOEt (3) in aqueous and three organic solvents. The interaction energy is substantial; it ranges from −2.1 to −3.4 kcal/mol and depends only slightly on the dielectric constant of the solvent. To assess the effects of auxiliary interactions and structural preorganization on formation of cation−π interactions, we studied these interactions in the association of pentapeptides. Upon binding of the positively-charged peptide AcLysLysLysLysLysNH2 (5) to the negatively-charged partner AcAspAspXAspAspNH2 (6), in which X is Leu (6a), Tyr (6b), and Phe (6c), multiple interactions occur. Association of the two pentapeptides is dynamic. Free peptides and their complex are in fast exchange on the NMR time-scale, and 2D 1H ROESY spectra of the complex of the two pentapeptides do not show intermolecular ROESY peaks. Perturbations of the chemical shifts indicated that the aromatic groups in peptides 6b and 6c were affected by the association with 5. The association constants KA for 5 with 6a and with 6b are nearly equal, (4.0 ± 0.7) × 103 and (5.0 ± 1.0) × 103 M-1, respectively, while KA for 5 with 6c is larger, (8.3 ± 1.3) × 103 M-1. Molecular-dynamics (MD) simulations of the pentapeptide pairs confirmed that their association is dynamic and showed that cation−π contacts between the two peptides are stereochemically possible. A transient complex between 5 and 6 with a prominent cation−π interaction, obtained from MD simulations, was used as a template to design cyclic peptides CX featuring persistent cation−π interactions. The cyclic peptide CX had a sequence in which X is Tyr, Phe, and Leu. The first two peptides do, but the third does not, contain the aromatic residue capable of interacting with a cationic Lys residue. This covalent construct offered conformational stability over the noncovalent complexes and allowed thorough studies by 2D NMR spectroscopy. Multiple conformations of the cyclic peptides CTyr and CPhe are in slow exchange on the NMR time-scale. In one of these conformations, cation−π interaction between Lys3 and Tyr9/Phe9 is clearly evident. Multiple NOEs between the side chains of residues 3 and 9 are observed; chemical-shift changes are consistent with the placement of the side chain of Lys3 over the aromatic ring. In contrast, the cyclic peptide CLeu showed no evidence for close approach of the side chains of Lys3 and Leu9. The cation−π interaction persists in both DMSO and aqueous solvents. When the disulfide bond in the cyclic peptide CPhe was removed, the cation−π interaction in the acyclic peptide ACPhe remained. To test the reliability of the pKa criterion for the existence of cation−π interactions, we determined residue-specific pKa values of all four Lys side chains in all three cyclic peptides CX. While NOE cross-peaks and perturbations of the chemical shifts clearly show the existence of the cation−π interaction, pKa values of Lys3 in CTyr and in CPhe differ only marginally from those values of other lysines in these dynamic peptides. Our experimental results with dynamic peptide systems highlight the role of cation−π interactions in both intermolecular recognition at the protein−protein interface and intramolecular processes such as protein folding." @default.
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- W1977239232 date "2001-06-07" @default.
- W1977239232 modified "2023-10-16" @default.
- W1977239232 title "The Role of Cation−π Interactions in Biomolecular Association. Design of Peptides Favoring Interactions between Cationic and Aromatic Amino Acid Side Chains" @default.
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- W1977239232 doi "https://doi.org/10.1021/ja010401u" @default.
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