Cation-pi interactions

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Image:Cation-pi-dougherty.jpg
Cation-pi interaction. Surfaces colored by electrostatic potential. Image adapted from one kindly provided by Dennis Dougherty.

Cationic moieties that are within 6.0 Å of the face of an aromatic ring (phenylalanine, tyrosine, or tryptophan) may engage in polar interactions called cation-pi interactions (cation-π interactions).

The flat face of an aromatic ring has a partial negative charge owing to the delocalized pi electrons. Cations such as the sidechains of Lys or Arg, cationic ligands, or metal cations often align themselves centered over the faces of aromatic rings. Over one fourth of Trp's in the Protein Data Bank interact with cations, and 99% of significant cation-pi interactions occur within a distance of 6.0 Angstroms [1]. Cation-pi interactions make a significant contribution to the overall stability of most proteins. Gallivan and Dougherty (1999)[1] concluded that "cation-pi interactions should be considered alongside the more conventional hydrogen bonds, salt bridges, and hydrophobic effects in any analysis of protein structure". They can also contribute significantly to intermolecular contacts and interactions with ligands.

Contents

Visualization

Chemistry

Credit: Wikimedia Commons.
Credit: Wikimedia Commons.

The cation-pi interaction is a stabilizing electrostatic interaction of a cation with the polarizable pi electron cloud of an aromatic ring. Six-carbon aromatic rings occur in the sidechains of 3 of the 20 standard amino acids: namely phenylalanine, tryptophan, and tyrosine. One p atomic orbital on each aromatic carbon overlaps in a pi ("sideways") fashion with its two neighbors to form a conjugated pi (π) orbital system. The pi electrons of aromatic rings comprise delocalized annular clouds above and below the ring plane (see Figure at right). Proximity of a positive charge to one face of the ring attacts and polarizes the pi electron cloud. In the proper conformation, this proximity forms an energetically significant cation-pi interaction (see Figure above)[2] .

Occurrence and Significance

Gallivan and Dougherty (1999)[1] reported results from a quantitative survey of cation-pi interactions in high-resolution structures in the Protein Data Bank. Using an energy-based criterion for identifying significant sidechain interactions, they studied 593 sequence dissimilar proteins. They found an average of one such interaction per 77 residues, with no significant effect of chain length, or multiple-chain vs. single chain structures. Arg was more likely than Lys to participate in a cation-pi interaction, and the likelihood of aromatic sidechain participation was Trp > Tyr > Phe. Over one quarter of all Trp's were involved in cation-pi interactions, with the cation typically positioned over the 6-atom ring of Trp. Because of the frequencies of amino acids in the database, Arg participates in nearly twice as many cation-pi interactions as does Lys, and the numbers of cation-pi interactions involving Trp, Tyr and Phe are roughly similar. Their study did not include His because, depending on its protonation state, it could participate either as a cation or as a pi-system. Lys and Arg were assumed always to be protonated and hence cationic.

Gallivan and Dougherty conclude "When a cationic sidechain is near an aromatic sidechain, the geometry is biased toward one that would experience a favorable cation-pi interaction", and "cation-pi interactions should be considered alongside the more conventional hydrogen bonds, salt bridges, and hydrophobic effects in any analysis of protein structure". They provide a server that lists text results from their program CaPTURE.

Zacharias and Dougherty (2002)[3] reviewed cation-pi interactions in the binding of ligands to proteins. Cation-pi interactions are usually energetically important when the ligand has either positive charge or an aromatic ring, and are involved in control of ion channels, G-protein-coupled receptors, transporters, and enzymatic catalysis.

Examples

Cation-pi interactions

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Eric Martz, Wayne Decatur, Alexander Berchansky, Michal Harel

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