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| Cation-pi interaction. Surfaces colored by electrostatic potential. Image adapted from one kindly provided by [http://www.its.caltech.edu/~dadgrp/research/molrec/index.html Dennis Dougherty].
| Cation-pi interaction. Surfaces colored by electrostatic potential. Image adapted from one kindly provided by [http://www.its.caltech.edu/~dadgrp/research/molrec/index.html Dennis Dougherty].
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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).
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)<ref name="dad2013">PMID: 23214924</ref>.
    
    
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]). -->
The flat face of an aromatic ring has a partial negative charge owing to the delocalized [[#Chemistry|pi electrons]]. <!-- ([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.
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 <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].  
==Visualization==
*[http://firstglance.jmol.org FirstGlance in Jmol] finds and displays potential cation-pi interactions, as described [http://firstglance.jmol.org/notes.htm?#catpi here].
<!-- protein explorer is obsolete.
*[http://proteinexplorer.org Protein Explorer] (requires CHIME plugin) finds and displays potential cation-pi interactions, as described [http://proteinexplorer.org/cationpi.htm here]. -->


==Chemistry==
==Chemistry==
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[[Image:Benzene Orbitals.png|frame|Credit: [http://en.wikipedia.org/wiki/File:Benzene_Orbitals.svg Wikimedia Commons].]]
[[Image:Benzene Orbitals.png|frame|Credit: [http://en.wikipedia.org/wiki/File:Benzene_Orbitals.svg Wikimedia Commons].]]
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'''.
 
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 [[amino acids|20 standard amino acids]]: namely [[Amino_Acids#Phenylalanine|phenylalanine]], [[Amino_Acids#Tryptophan|tryptophan]], and [[Amino_Acids#Tyrosine|tyrosine]]. One [http://en.wikipedia.org/wiki/P-orbital p atomic orbital] on each aromatic carbon overlaps in a pi ("sideways") fashion with its two neighbors to form a [http://en.wikipedia.org/wiki/Conjugated_system conjugated] pi (&pi;) orbital system.
The pi electrons of aromatic rings comprise [http://en.wikipedia.org/wiki/Delocalized_electron 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''')<ref name="lillya">[[User:Eric Martz|Eric Martz]] thanks [http://www.cns.umass.edu/faculty/directory/c-peter-lillya Peter Lillya] for help writing this paragraph.</ref> .
{{Clear}}
{{Clear}}


==Occurrence and Significance==
==Occurrence and Significance==
<table width='300' align='right' cellpadding='5'><tr><td rowspan='2'>&nbsp;</td><td bgcolor='#eeeeee'><applet load='1bl8' size='290' frame='true' align='right' scene='Cation-pi_interactions/1bl8_pi2/3' /></td></tr><tr><td bgcolor='#eeeeee'><center>'''Cation-pi interactions''' (<scene name='Cation-pi_interactions/1bl8_pi2/3'>initial scene</scene>).</center></td></tr></table>
<!--
<table width='300' align='right' cellpadding='5'><tr><td rowspan='2'>&nbsp;</td><td bgcolor='#eeeeee'><applet load='1bl8' size='290' frame='true' align='right' scene='Cation-pi_interactions/1bl8_pi2/3' /></td></tr><tr><td bgcolor='#eeeeee'><center>'''Cation-pi interactions''' (<scene name='Cation-pi_interactions/1bl8_pi2/3'>initial scene</scene>).</center></td></tr></table> -->
Gallivan and Dougherty (1999)<ref name='GD' /> 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 (1999)<ref name='GD' /> 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.


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==Examples==
==Examples==
<table width='300' align='right' cellpadding='5'><tr><td rowspan='2'>&nbsp;</td><td bgcolor='#eeeeee'><applet load='1gai' size='290' frame='true' align='right' scene='Cation-pi_interactions/1gai_pi4/1' /></td></tr><tr><td bgcolor='#eeeeee'><center>'''Cation-pi interactions''' (<scene name='Cation-pi_interactions/1gai_pi4/1'>initial scene</scene>).</center></td></tr></table>
<StructureSection load='1gai' size='350' side='right' scene='Cation-pi_interactions/Nicotine_catpi/5' caption='Cation-pi interactions'>
 
===Nicotinic Acetylcholine Receptor and Nicotine Addiction===
====Receptor====
The nicotinic acetylcholine receptor is a ligand-gated ion channel that responds to the neurotransmitter acetylcholine. It occurs in the central and peripheral nervous systems, and in the neuromuscular junction that controls muscle contraction. It has multiple forms, notably a ''neuronal type'' found in the brain, and a ''muscle type'' found in neuromuscular junctions. The nicotinic acetylcholine receptor is the basis for nicotine addiction, which kills over 4,000,000 people annually<ref name="XD">PMID: 19252481</ref>. As stated by Xiu ''et al.''<ref name="XD" />:
<blockquote>
"... if nicotine activated ACh receptors found in muscle as potently as it does brain receptors, smoking would cause intolerable and perhaps fatal muscle contractions."<ref name="XD" />
</blockquote>
Therefore, the difference between the neuronal type and muscle type of receptors makes nicotine addiction possible, and the chemical basis for the difference is of considerable interest.
 
====Nicotine Cation====
Like acetylcholine, nicotine has a cationic nitrogen when the pH is neutral or acidic. This occurs in nicotine's 5-membered methylpyrrolidine ring (see [http://en.wikipedia.org/wiki/Nicotine nicotine structure]), which has a pK<sub>a</sub> of 8.0<ref>In contrast, the 6-membered pyridine ring has a pK<sub>a</sub> of 3.1, so is uncharged at neutral pH. The uncharged or ''free base'' form of nicotine is more volatile than the charged form. Cigarette manufacturers have long added ammonia to tobacco to increase absorption of nicotine by smokers. See Summerfield, 1999 cited elsewhere for details.</ref><ref>Summerfield, J. H. An acid-base chemistry example: conversion of nicotine. J. Chem. Ed. 76:1397-8 (1999).</ref>.
 
====Cation-Pi Interactions====
 
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 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" />.
 
The crystal structure of a molluscan acetylcholine-binding protein ([[1uw6]]) confirms the existence of a cation-pi interaction between the homologous Trp (Trp143) and the nicotine cation (<scene name='Cation-pi_interactions/Nicotine_catpi/5'>restore initial scene</scene>). Also seen is the <scene name='Cation-pi_interactions/Nicotine_catpi/6'>hydrogen bond</scene> proposed between nicotine and the main-chain oxygen of the proximal Trp for the rat receptor<ref name="XD" />. The molluscan crystal structure also reveals a remarkable <scene name='Cation-pi_interactions/Nicotine_catpi/7'>''aromatic box'' of 3 Tyr and 2 Trp surrounding nicotine</scene>.
 
====Summary====
 
:{| class="wikitable" style="text-align:center;"
|-
! Ligand-Receptor
! &nbsp;Cation-pi&nbsp;
! &nbsp;Hydrogen bond&nbsp;
|-
| &nbsp;Acetylcholine-Neuronal type<ref name="zhong" />&nbsp;
| Yes
| (not applicable)
|-
| Nicotine-Muscle type<ref name="beene" />
| No
| No
|-
| Nicotine-Neuronal type<ref name="XD" />
| Yes
| Yes
|}
 
===Examples from Gallivan and Dougherty<ref name='GD' />===
===Examples from Gallivan and Dougherty<ref name='GD' />===


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*[[:Category:Cation_pi|Entries in Proteopedia's Cation pi Category]] (no hyphen)
*[[:Category:Cation_pi|Entries in Proteopedia's Cation pi Category]] (no hyphen)
*[[:Category:Cation-pi_interaction|Entries in Proteopedia's Cation-pi interaction Category]]
*[[:Category:Cation-pi_interaction|Entries in Proteopedia's Cation-pi interaction Category]]
 
</StructureSection>
==Literature References==  
==Literature References & Notes==  
<references/>
<references/>


==Additional Literature and Resources==
==Additional Literature==
<ref group="xtra">PMID: 8539615</ref><ref group="xtra">PMID: 12162741</ref><ref group="xtra">PMID: 15225993</ref><ref group="xtra">PMID: 15726638</ref><ref group="xtra">PMID: 15769516</ref><ref group="xtra">PMID: 17154537</ref><ref group="xtra">PMID: 15726638</ref><ref group="xtra">PMID: 17513416</ref><ref group="xtra">PMID: 18759391</ref><ref group="xtra">PMID: 1678899</ref><ref group="xtra">PMID: 15098021</ref>
<ref group="xtra">PMID: 8539615</ref><ref group="xtra">PMID: 12162741</ref><ref group="xtra">PMID: 15225993</ref><ref group="xtra">PMID: 15726638</ref><ref group="xtra">PMID: 15769516</ref><ref group="xtra">PMID: 17154537</ref><ref group="xtra">PMID: 15726638</ref><ref group="xtra">PMID: 17513416</ref><ref group="xtra">PMID: 18759391</ref><ref group="xtra">PMID: 1678899</ref><ref group="xtra">PMID: 15098021</ref>
<references group="xtra"/>
<references group="xtra"/>
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*Tan XJ, Zhu WL, Cui M, Luo XM, Gu JD, Silman I, Sussman JL, Jiang HL, Ji RY, Chen KX. Noncovalent interaction or chemical bonding between alkaline earth cations and benzene? A quantum chemistry study with MP2 and density-functional theory methods. Chem. Phys. Lett. 2001 349:113-122.  [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TFN-44B4HC9-3&_user=1516330&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000053443&_version=1&_urlVersion=0&_userid=1516330&md5=aafae3391c122c6fdbfdf1d5c93e76a0 Abstract]
*Tan XJ, Zhu WL, Cui M, Luo XM, Gu JD, Silman I, Sussman JL, Jiang HL, Ji RY, Chen KX. Noncovalent interaction or chemical bonding between alkaline earth cations and benzene? A quantum chemistry study with MP2 and density-functional theory methods. Chem. Phys. Lett. 2001 349:113-122.  [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TFN-44B4HC9-3&_user=1516330&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000053443&_version=1&_urlVersion=0&_userid=1516330&md5=aafae3391c122c6fdbfdf1d5c93e76a0 Abstract]
*Sussman JL, Silman  I. Acetylcholinesterase: structure and use as a model for specific cation-protein interactions. Curr. Opin. Struct. Biol. 1992 2:721-729.  [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VS6-488FR7B-18&_user=10&_handle=V-WA-A-W-WV-MsSAYZW-UUW-U-AACCVECUCE-AACBUDCYCE-WADDYDE-WV-U&_fmt=summary&_coverDate=10%2F31%2F1992&_rdoc=12&_orig=browse&_srch=%23toc%236254%231992%23999979994%23411862!&_cdi=6254&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=311482e5def4d93a8ddc6423a65772db Abstract]
*Sussman JL, Silman  I. Acetylcholinesterase: structure and use as a model for specific cation-protein interactions. Curr. Opin. Struct. Biol. 1992 2:721-729.  [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VS6-488FR7B-18&_user=10&_handle=V-WA-A-W-WV-MsSAYZW-UUW-U-AACCVECUCE-AACBUDCYCE-WADDYDE-WV-U&_fmt=summary&_coverDate=10%2F31%2F1992&_rdoc=12&_orig=browse&_srch=%23toc%236254%231992%23999979994%23411862!&_cdi=6254&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=311482e5def4d93a8ddc6423a65772db Abstract]
==See Also==
*[http://www.ncbi.nlm.nih.gov/pubmed?term=dougherty%20da%5Bau%5D Search PubMed for ''Dougherty DA''].
*[http://www.pdb.org/pdb/101/motm.do?momID=71 Acetyl Choline Receptor - Molecule of the Month].
*[http://www.umass.edu/microbio/chime/pe_beta/pe/protexpl/cationpi.htm The Introduction, Gallery & Tutorial for Cation-Pi Interactions from Eric Martz's Protein Explorer]
*[http://www.umass.edu/microbio/chime/pe_beta/pe/protexpl/cationpi.htm The Introduction, Gallery & Tutorial for Cation-Pi Interactions from Eric Martz's Protein Explorer]
*[http://en.wikipedia.org/wiki/Cation-pi_interaction Wikipedia Cation-pi interaction page]
*[http://en.wikipedia.org/wiki/Cation-pi_interaction Wikipedia Cation-pi interaction page]

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Wayne Decatur, Eric Martz, Michal Harel, Alexander Berchansky
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