Evidence for the Cation−π Interaction between Cu²⁺and Tryptophan

Abstract

The cation-pi interaction, a noncovalent interaction of electrostatic nature between a cation and an electron-rich pi system, is increasingly recognized as an important force that influences the structures and functions of molecules including proteins. Unlike other metal cations, the transition metal cation Cu2+ is not regarded to take part in a cation-pi interaction because Cu2+ tends to oxidize the pi electron system, in particular that of Trp, and to introduce covalency in the metal-pi electron interaction. This paper reports the first spectral evidence for the cation-pi interaction between Cu2+ and Trp. The Cu2+ ion bound to the amino N-terminal Cu2+/Ni2+ binding motif composed of three amino acid residues interacts with the indole ring of the fourth Trp residue in a noncovalent manner. The Cu2+-Trp interaction produces a distinct negative band at 223 nm in circular dichroism (CD), which disappears upon mutation or depletion of the Trp residue or upon replacement of the Cu2+ ion by Ni2+. In UV absorption, a pair of negative/positive intensity changes is generated at 222/231 nm by the Cu2+-Trp interaction, being consistent with the previous observations on the indole ring interacting with K+ or a cationic His imidazole ring. The negative CD band around 223 nm is characteristic of the Cu2+-Trp pair and may be useful as a marker of the Cu2+-Trp cation-pi interaction. Coordination of negatively charged ligands to Cu2+ is suggested to be important for the cation to be involved in a cation-pi interaction.

UV resonance Raman study of cation–π interactions in an indole crown ether

“…Tryptophan forms cation–π interactions more often than any other aromatic amino acid, with an estimated 26% of all tryptophan residues participating in this favorable interaction [1] The reason this amino acid is especially prevalent in cation–π interactions is because the indole ring of tryptophan exhibits the largest and most favorable electrostatic potential for binding of cations [5] Tryptophan has been shown to form these stabilizing interactions with alkali-metal ions, [6,7] positively charged amino acids, [8,9] and even a transition metal ion [10,11] Furthermore, tryptophan is an amphiphilic residue capable of forming hydrogen bonds in both hydrophobic and hydrophilic environments. Collectively, these properties enable tryptophan to simultaneously participate in several stabilizing interactions, including hydrophobic interactions, hydrogen-bond formation, and cation–π interactions.…”

Effect of dioxygen on copper(II) binding to α-synuclein

“…The higher energy minimum (Θ 230, 233 nm ) is reminiscent of the spectroscopic signature (Θ 223 nm ) assigned to a Cu-Trp cation-π interaction in a recent report by Takeuchi and coworkers on copper(II) binding to neuromedin C (NMC), a decapeptide involved in smooth muscle contraction [21]. The native NMC copper(II) binding site (GNHW) is thought to be composed of the free N-terminal nitrogen (NH 2 ), two deprotonated amide backbone nitrogens (N – ), a histidine (N im ), and a Cu II -Trp cation-π interaction.…”

UV Raman Markers for Structural Analysis of Aromatic Side Chains in Proteins

“…27 The Trp indole ring has also been found to undergo a cation-π interaction with the Cu ion. 57,58 For Phe and Tyr, no Raman markers of cation-π interaction have been reported.…”