Cation-pi interactions: Difference between revisions

Cationic moieties, such as sidechain nitrogens (lysine or arginine) or metal cations, 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 due to the [[#Chemistry|pi orbitals]]. <!-- ([http://www.molphys.leidenuniv.nl/monos/smo/index.html?basics/photophysics.htm schematic], [http://www.webelements.com/shop/product.php/129/molyorbital_molecular_orbital_organic_structures_set physical model]). -->

Cationic sidechains (Lys, Arg) or sometimes ligands (including metal ions) 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 <ref name='GD'>PMID: 10449714</ref>. Cation-pi interactions make a significant contribution to the overall stability of most proteins. Gallivan and Dougherty (1999)<ref name='GD' /> 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.

*[http://firstglance.jmol.org First Glance in Jmol] finds and displays potential cation-pi interactions, as described [http://firstglance.jmol.org/notes.htm?#catpi here].

*[http://proteinexplorer.org Protein Explorer] (requires CHIME plugin) finds and displays potential cation-pi interactions, as described [http://proteinexplorer.org/cationpi.htm here].  

Six-carbon aromatic rings occur in the sidechains of 3 of the [[amino acids|20 standard amino acids]]: namely [[Amino_Acids#Phenylalanine|phenylalanine]], [[Amino_Acids#Tryptophan|tryptophan]], and [[Amino_Acids#Tyrosine|tyrosine]]. The [http://en.wikipedia.org/wiki/P-orbital atomic p orbitals] of the carbons overlap sideways, forming a [http://en.wikipedia.org/wiki/Conjugated_system conjugated] pi (&pi;) orbital system, or pi cloud of [http://en.wikipedia.org/wiki/Delocalized_electron delocalized electrons]<ref name="lillya">[[User:Eric Martz|Eric Martz]] thanks [http://www.cns.umass.edu/faculty/directory/c-peter-lillya Peter Lillya] for help with terminology.</ref> ('''see Figure at right'''). The pi clouds on each face of the ring have a partial negative charge, while the edge of the ring has a compensating partial positive charge ('''see Figure above'''). Proximity of a positive charge to one face of the ring induces further polarization, and in the proper conformation produces an electrostatic interaction called a '''cation-pi interaction'''.

In 1998, Zhong ''et al.'' (with Dougherty)<ref name="zhong">PMID: 9770444</ref> provided evidence that the [http://en.wikipedia.org/wiki/Nicotinic_acetylcholine_receptor cation in '''acetylcholine'''] engages in a cation-pi interaction with Trp149 in the '''neuronal-type''' receptor, making an important contribution to the binding affinity. In 2002, Beene ''et al.'' (with Dougherty)<ref name="beene">PMID: 12162741</ref> provided evidence that no such cation-pi interaction is involved when '''nicotine''' binds to the '''muscle-type''' receptor, thus accounting in part for the lower affinity. In 2009, Xiu ''et al.'' (with Dougherty)<ref name="XD" /> provided evidence that a strong cation-pi interaction occurs between the cation of '''nicotine''' and Trp149 in the '''neuronal-type''' receptor. The crystal structure of a molluscan acetylcholine-binding protein confirms the existence of a cation-pi interaction between the homologous Trp (Trp143) and the nicotine cation. The lower affinity of nicotine for the muscle-type, compared to the neuronal type receptors, is accounted for by differences in cation-pi interaction strength and the absence of a nicotine-receptor hydrogen bond in the former<ref name="XD" />.

*[[1gai]]: a 472-amino acid chain (glucoamylase) with a spectacular cluster of four aromatic rings (two Trp's, two Tyr's) around a single Lys108 (<scene name='Cation-pi_interactions/1gai_pi4/1'>restore initial scene</scene>).