Cation–π interaction in a folded polypeptide

Abstract

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 pi-orbitals of the aromatic group, leading to the name cation-pi interaction. The lysine and tyrosine containing peptide, N-acetyl-Pro-Pro-Lys-Tyr-Asp-Lys-NH(2), 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 (1)H 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-pi 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-pi signature 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-pi spectroscopic signature. The ensemble average spectroscopic signature effects in t6p are small and in agreement with observation.

Structural analysis of residues involving cation-π interactions in different folding types of membrane proteins

“…Recently, cation-interactions are observed to be an important factor for understanding the thermal stability of thermophilic proteins [6,26]. Further, the importance of this interaction has been stressed by several investigators in determining the helicity of ␣-helical peptides [44], folding of polypeptides [5], etc. On the other hand, cation-interactions are suggested to play a role in the stability of protein-DNA complexes and the specificity of protein-DNA recognition [39,48].…”

Myosin dynamics on the millisecond time scale

“…We calculate peak absorption energy, dipole strength, and rotatory strength (ground state spectroscopy) for W510 or TNP in TNP-S1 as described previously [39][40][41]71]. W510 electron transfer rate (excited state spectroscopy) to the backbone or other side chains is derived after the method suggested by Adams et al and described in the Supplementary material [72].…”

“…Positions and values for the ground state and transition monopole charges for the peptide primary, secondary, and tertiary amide groups, and, tryptophan, tyrosine, phenylalanine, and histadine side chains were taken from the literature [74][75][76][77][78][79]. In addition, transition monopoles amplitudes for (0, 1 L b ) and (0, 1 L a ) in tryptophan, or (0, 1 L b ) in tyrosine, were normalized to reproduce the dipole strength we observed from N-acetyl-Ltryptophanamide (NATpA) or N-acetyl-L-tyrosineamide (NATrA) in aqueous buffer at pH 7 [71]. Positions and values for ground state and transition monopole charges for the TNP-Lys side chain were computed as described previously [41].…”

Role of the Cation-π Interaction in Therapeutic Proteins: A Comparative Study with Conventional Stabilizing Forces

“…The importance of this interaction has been stressed by several investigators for their role in enhancement of the stability of thermophilic proteins (Chakravarty and Varadarajan, 2000;Gromiha et al, 2002), folding of polypeptides (Shi et al, 2002;Burghardt et al, 2002) and the stability of membrane proteins (Mulhern et al, 2000;Gromiha, 2003). Influence of cation-π interactions in protein-DNA complexes is studied by Gromiha et al, (2004).…”