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[http://www.ncbi.nlm.nih.gov/pubmed/10449714 Gallivan and Dougherty (1999)] reported results from a quantitative survey of cation-p (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 liklihood 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.
[http://www.ncbi.nlm.nih.gov/pubmed/10449714 Gallivan and Dougherty (1999)] reported results from a quantitative survey of cation-p (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 liklihood 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 [http://capture.caltech.edu/a server that lists text results from their program CaPTURE].
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 [http://capture.caltech.edu/a server that lists text results from their program CaPTURE].


[http://www.ncbi.nlm.nih.gov/pubmed/12084634 Zacharias and Dougherty (2002)]<ref>PMID: 12084634</ref> 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. An example is [[1l8b]], a portion of a eukaryotic translation initiation factor that recognizes N7-methylated guanosine. The ligand's heterocyclic base (cationic) is sandwiched between Trp56 and Trp102.  
[http://www.ncbi.nlm.nih.gov/pubmed/12084634 Zacharias and Dougherty (2002)]<ref>PMID: 12084634</ref> 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. An example is [[1l8b]], a portion of a eukaryotic translation initiation factor that recognizes N7-methylated guanosine. The ligand's heterocyclic base (cationic) is sandwiched between Trp56 and Trp102.


==Examples==
==Examples==

Revision as of 04:29, 20 April 2009

The flat face of an aromatic ring has a partial negative charge due to the pi orbitals. Cationic sidechains (Asp, Glu) 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 [1]. Cation-pi interactions make a significant contribution to the overall stability of most proteins. Gallivan and Dougherty (1999) conclude that "cation-pi interactions should be considered alongside the more conventional hydrogen bonds, salt bridges, and hydrophobic effects in any analysis of protein structure". Eric Martz's Protein Explorer finds and displays potential cation-pi interactions, as described here.

BackgroundBackground

Gallivan and Dougherty (1999) reported results from a quantitative survey of cation-p (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 liklihood 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)[2] 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. An example is 1l8b, a portion of a eukaryotic translation initiation factor that recognizes N7-methylated guanosine. The ligand's heterocyclic base (cationic) is sandwiched between Trp56 and Trp102.

ExamplesExamples

Examples given by Gallavan and Dougherty[3] include:

  • 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. See an image here.
  • 1bfg: a 126-amino acid chain (fibroblast growth factor) with an unusually high incidence of cation-pi interactions. Gallivan and Dougherty report 5 energetically significant interactions; Protein Explorer shows 9 rings and 8 cations; one ring interacts with two cations, making the total interactions shown equal to 10.
  • 2wea: the longest single chain (323 residues) with no energetically significant cation-pi interactions.

Interesting examples noted by Eric Martz:

  • 1axi (human growth hormone): Chain B contains an unusual string of three aromatic sidechains separated by, and capped at the ends with, 4 cationic sidechains. (Using "c" for cation and "p" for pi, the chain is "cpcpcpc".) Only the one of these six interactions is deemed energetically insignificant by CaPTURE (Lys at one end). See image here.
  • 1bl8(bacterial potassium channel): There is a single interchain cation-pi pair for each contact between chains of this homotetramer, but no intrachain cation-pi interactions.
  • 2vab (peptide bound to class I histocompatibility protein): The N-terminal Phe of the nonapeptide stacks with Trp 167 of the protein. On either side of the stacked rings are cations (Arg 170, Lys 66), forming the unusual cppc chain RWFK. See image here.
  • 1rog (peptide bound to class I histocompatibility protein): Three (of the four) cations in the 9-residue peptide interact with aromatic sidechains in the protein groove. This is a theoretical model.
  • 1dlh (peptide bound to class II histocompatibility protein): There are no cation-pi interactions for the 13-residue peptide, despite its containing three lysines and one tyrosine. A number of nearby sidechains that potentially could interact appear to be blocked by other noncovalent bonding interactions, and the peptide lysine sidechains are generally pointing away from the protein.

Literature ReferencesLiterature References

  1. ↑ Gallivan JP, Dougherty DA. Cation-pi interactions in structural biology. Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9459-64. PMID:10449714
  2. ↑ Zacharias N, Dougherty DA. Cation-pi interactions in ligand recognition and catalysis. Trends Pharmacol Sci. 2002 Jun;23(6):281-7. PMID:12084634
  3. ↑ Gallivan JP, Dougherty DA. Cation-pi interactions in structural biology. Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9459-64. PMID:10449714

Additional Literature and ResourcesAdditional Literature and Resources

[xtra 1][xtra 2][xtra 3][xtra 4][xtra 5][xtra 6][xtra 7][xtra 8]

  1. ↑ Dougherty DA. Cation-pi interactions in chemistry and biology: a new view of benzene, Phe, Tyr, and Trp. Science. 1996 Jan 12;271(5246):163-8. PMID:8539615
  2. ↑ Gromiha MM, Santhosh C, Ahmad S. Structural analysis of cation-pi interactions in DNA binding proteins. Int J Biol Macromol. 2004 Jun;34(3):203-11. PMID:15225993 doi:http://dx.doi.org/10.1016/j.ijbiomac.2004.04.003
  3. ↑ Wu R, McMahon TB. Investigation of cation-pi interactions in biological systems. J Am Chem Soc. 2008 Sep 24;130(38):12554-5. Epub 2008 Aug 29. PMID:18759391 doi:http://dx.doi.org/10.1021/ja802117s
  4. ↑ Crowley PB, Golovin A. Cation-pi interactions in protein-protein interfaces. Proteins. 2005 May 1;59(2):231-9. PMID:15726638 doi:http://dx.doi.org/10.1002/prot.20417
  5. ↑ Beene DL, Brandt GS, Zhong W, Zacharias NM, Lester HA, Dougherty DA. Cation-pi interactions in ligand recognition by serotonergic (5-HT3A) and nicotinic acetylcholine receptors: the anomalous binding properties of nicotine. Biochemistry. 2002 Aug 13;41(32):10262-9. PMID:12162741
  6. ↑ Prajapati RS, Sirajuddin M, Durani V, Sreeramulu S, Varadarajan R. Contribution of cation-pi interactions to protein stability. Biochemistry. 2006 Dec 19;45(50):15000-10. PMID:17154537 doi:http://dx.doi.org/10.1021/bi061275f
  7. ↑ Crowley PB, Golovin A. Cation-pi interactions in protein-protein interfaces. Proteins. 2005 May 1;59(2):231-9. PMID:15726638 doi:http://dx.doi.org/10.1002/prot.20417
  8. ↑ Dougherty DA. Cation-pi interactions involving aromatic amino acids. J Nutr. 2007 Jun;137(6 Suppl 1):1504S-1508S; discussion 1516S-1517S. PMID:17513416

Content AttributionContent Attribution

This was adapted from the Glossary and Introduction, Gallery & Tutorial for Cation-Pi Interactions that accompanies Eric Martz's Protein Explorer.


Category:hydrogen bonds, salt bridges, and hydrophobic effects

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Wayne Decatur, Eric Martz, Michal Harel, Alexander Berchansky
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