Anderson Matthew A, Ogbay Benhur, Arimoto Rieko, Sha Wei, Kisselev Oleg G, Cistola David P, Marshall Garland R
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Am Chem Soc. 2006 Jun 14;128(23):7531-41. doi: 10.1021/ja058513z.
Interactions between cationic and aromatic side chains of amino acid residues, the so-called cation-pi interaction, are thought to contribute to the overall stability of the folded structure of peptides and proteins. The transferred NOE NMR structure of the G(t)alpha(340-350) peptide bound to photoactivated rhodopsin (R*) geometrically suggests a cation-pi interaction stabilizing the structure between the epsilon-amine of Lys341 and the aromatic ring of the C-terminal residue, Phe350. This interaction has been explored by varying substituents on the phenyl ring to alter the electron density of the aromatic ring of Phe350 and observing the impact on binding of the peptide to R*. The results suggest that while a cation-pi interaction geometrically exists in the G(t)alpha(340-350) peptide when bound to R*, its energetic contribution to the stability of the receptor-bound structure is relatively insignificant, as it was not observed experimentally. The presence of an adjacent and competing salt-bridge interaction between the epsilon-amine of Lys341 and the C-terminal carboxylate of Phe350 effectively shields the charge of the ammonium group. Experimental data supporting a significant cation-pi interaction can be regained through a series of Phe350 analogues where the C-terminal carboxyl has been converted to the neutral carboxamide, thus eliminating the shielding salt-bridge. TrNOE NMR experiments confirmed the existence of the cation-pi interaction in the carboxamide analogues. Various literature estimates of the strength of cation-pi interactions, including some that estimate strengths in excess of salt-bridges, are compromised by omission of the relevant anion in the calculations.
氨基酸残基的阳离子侧链与芳香族侧链之间的相互作用，即所谓的阳离子-π相互作用，被认为有助于肽和蛋白质折叠结构的整体稳定性。与光活化视紫红质（R*）结合的G(t)α(340 - 350)肽的转移核Overhauser效应（NOE）NMR结构从几何角度表明，阳离子-π相互作用稳定了赖氨酸341的ε-氨基与C端残基苯丙氨酸350的芳香环之间的结构。通过改变苯环上的取代基来改变苯丙氨酸350芳香环的电子密度，并观察其对肽与R结合的影响，对这种相互作用进行了研究。结果表明，虽然G(t)α(340 - 350)肽与R结合时在几何结构上存在阳离子-π相互作用，但其实验未观察到它对受体结合结构稳定性的能量贡献相对较小。赖氨酸341的ε-氨基与苯丙氨酸350的C端羧酸盐之间存在相邻且相互竞争的盐桥相互作用，有效地屏蔽了铵基团的电荷。通过一系列苯丙氨酸350类似物，其中C端羧基已转化为中性羧酰胺，从而消除了屏蔽盐桥，可以重新获得支持显著阳离子-π相互作用的实验数据。转移NOE NMR实验证实了羧酰胺类似物中存在阳离子-π相互作用。各种文献对阳离子-π相互作用强度的估计，包括一些估计强度超过盐桥的估计，在计算中由于遗漏了相关阴离子而受到影响。
