Cation-π interaction in a folded polypeptide

Cationic and aromatic side chains from protein residues interact to stabilize tertiary structure. The stabilization energy originates in part from electrostatic attraction between the cation, and regions of high electron density in π-orbitals of the aromatic group, leading to the name cation-π interaction. The lysine and tyrosine containing peptide, N-acetyl-Pro-Pro-Lys-Tyr-Asp-Lys-NH₂, has near uv CD characteristic of tyrosine in a structured environment. Nuclear Overhauser effect (NOE), coupling constant, and ring current chemical shift constraints obtained with ¹H NMR confirm that the peptide (t6p) folds. Simulated annealing consistent with all NMR constraints produces a 40-structure ensemble for t6p with potential energies within one standard deviation of the lowest value observed. Calculated binding energies indicate that cation-π and cation-phenolic OH interactions exists between the Lys3 and Tyr4 side chains in most of the structures. The t6p peptide in solution is a model for these interactions in a protein. A perturbing electric field from the cationic ground state charge intermingles the excited states of the aromatic group. This intermingling effect may provide a cation-π signatare effect in the tyrosine spectroscopy. The absorption and CD for the lowest energy electronic transitions of the tyrosine phenol were computed for the ensemble. Red-shifted peak energy and hypochromicity in the absorbance band, and decreasing rotational strength, correlates with increasing binding energy of the complex indicating the cation-π spectroscopic signature. The ensemble average spectroscopic signature effects in t6p are small and in agreement with observation.