Biochemistry (Moscow)

, Volume 79, Issue 7, pp 643–652 | Cite as

Cation-pi interactions at non-redundant protein-RNA interfaces

  • Honggucun Zhang
  • Chunhua Li
  • Feng Yang
  • Jiguo Su
  • Jianjun Tan
  • Xiaoyi Zhang
  • Cunxin Wang


Cation-pi interactions have proved to be important in proteins and protein-ligand complexes. Here, cation-pi interactions are analyzed for 282 non-redundant protein-RNA interfaces. The statistical results show that this kind of interactions exists in 65% of the interfaces. The four RNA bases are ranked as Gua > Ade > Ura > Cyt according to their propensity to participate in cation-pi interactions. The corresponding ranking for the involved amino acid residues is: Arg > Lys > Asn > Gln. The same trends are obtained based on the empirical energy calculation. The Arg-Gua pairs have the greatest stability and are also most frequently observed. The number of cation-pi pairs involving unpaired bases is 2.5 times as many as those involving paired bases. Hence, cation-pi interactions show sequence and structural specificities. For the bicyclic bases, Gua and Ade, their 5-atom rings participate in cation-pi interactions somewhat more than the 6-atom rings, with percentages of 54 and 46%, respectively, which is due to the higher cation-pi participation proportion (63%) of 5-atom rings in the paired bases. These results give a general view of cation-pi interactions at protein-RNA interfaces and are helpful in understanding the specific recognition between protein and RNA.

Key words

cation-pi interactions protein-RNA interfaces sequence and structural specificities electrostatic energy ab initio 













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  1. 1.
    Perez-Canadillas, J. M., and Varani, G. (2001) Recent advances in RNA-protein recognition, Curr. Opin. Struct. Biol., 11, 53–58.PubMedCrossRefGoogle Scholar
  2. 2.
    Draper, D. E. (1999) Themes in RNA-protein recognition, J. Mol. Biol., 293, 255–270.PubMedCrossRefGoogle Scholar
  3. 3.
    Salonen, L. M., Ellermann, M., and Diederich, F. (2011) Aromatic rings in chemical and biological recognition: energetics and structures, Angew. Chem. Int. Ed. Engl., 50, 4808–4842.PubMedCrossRefGoogle Scholar
  4. 4.
    Singh, N. J., Min, S. K., Kim, D. Y., and Kim, K. S. (2009) Comprehensive energy analysis for various types of π-interaction, J. Chem. Theory Comput., 5, 515–529.Google Scholar
  5. 5.
    Kumpf, R. A., and Dougherty, D. A. (1993) A mechanism for ion selectivity in potassium channels: computational studies of cation-π interactions, Science, 261, 1708–1710.PubMedCrossRefGoogle Scholar
  6. 6.
    Priyakumar, U. D., Punnagai, M., Krishna Mohan, G. P., and Sastry, G. N. (2004) A computational study of cation-π interactions in polycyclic systems: exploring the dependence on the curvature and electronic factors, Tetrahedron, 60, 3037–3043.CrossRefGoogle Scholar
  7. 7.
    Dougherty, D. A. (1996) Cation-pi interactions in chemistry and biology: a new view of benzene, Phe, Tyr, and Trp, Science, 271, 163–168.PubMedCrossRefGoogle Scholar
  8. 8.
    Dougherty, D. A. (2007) Cation-pi interactions involving aromatic amino acids, J. Nutr., 137(Suppl. 1), 1504S–1508S; discussion 1516S–1517S.PubMedGoogle Scholar
  9. 9.
    Gromiha, M. M. (2005) Distinct roles of conventional noncovalent and cation-π interactions in protein stability, Polymer, 46, 983–990.CrossRefGoogle Scholar
  10. 10.
    Pless, S. A., Hanek, A. P., Price, K. L., Lynch, J. W., Lester, H. A., Dougherty, D. A., and Lummis, S. C. (2011) A cation-π interaction at a phenylalanine residue in the glycine receptor binding site is conserved for different agonists, Mol. Pharmacol., 79, 742–748.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Michael, L. A., Chenault, J. A., Miller, III, B. R., Knolhoff, A. M., and Nagan, M. C. (2009) Water, shape recognition, salt bridges, and cation-pi interactions differentiate peptide recognition of the HIV Rev-responsive element, J. Mol. Biol., 392, 774–786.PubMedCrossRefGoogle Scholar
  12. 12.
    Yamashita, S., Nagata, T., Kawazoe, M., Takemoto, C., Kigawa, T., Guntert, P., Kobayashi, N., Terada, T., Shirouzu, M., Wakiyama, M., Muto, Y., and Yokoyama, S. (2011) Structures of the first and second double-stranded RNA-binding domains of human TAR RNA-binding protein, Protein Sci., 20, 118–130.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Lummis, S. C. R., McGonigle, I., Ashby, J. A., and Dougherty, D. A. (2011) Two amino acid residues contribute to a cation-π binding interaction in the binding site of an insect GABA receptor, J. Neurosci., 31, 12371–12376.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Xiu, X., Puskar, N. L., Shanata, J. A. P., Lester, H. A., and Dougherty, D. A. (2009) Nicotine binding to brain receptors requires a strong cation-pi interaction, Nature, 458, 534–537.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Tantry, S., Ding, F. X., Dumont, M., Becker, J. M., and Naider, F. (2010) Binding of fluorinated phenylalanine alpha-factor analogues to Ste2p: evidence for a cation-pi binding interaction between a peptide ligand and its cognate G protein-coupled receptor, Biochemistry, 49, 5007–5015.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Dougherty, D. A. (2013) The cation-π interaction, Acc. Chem. Res., 46, 885–893.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Mahadevi, A. S., and Sastry, G. N. (2013) Cation-π interaction: its role and relevance in chemistry, biology, and material science, Chem. Rev., 113, 2100–2138.PubMedCrossRefGoogle Scholar
  18. 18.
    Okada, A., Miura, T., and Takeuchi, H. (2001) Protonation of histidine and histidine-tryptophan interaction in the activation of the M2 ion channel from influenza a virus, Biochemistry, 40, 6053–6060.PubMedCrossRefGoogle Scholar
  19. 19.
    Boks, G. J., Tollenaere, J. P., and Kroon, J. (1997) Possible ligand-receptor interactions for NK1 antagonists as observed in their crystal structures, Bioorg. Med. Chem., 5, 535–547.PubMedCrossRefGoogle Scholar
  20. 20.
    Ma, J. C., and Dougherty, D. A. (1997) The cation-π interaction, Chem. Rev., 97, 1303–1324.PubMedCrossRefGoogle Scholar
  21. 21.
    Gallivan, J. P., and Dougherty, D. A. (1999) Cation-pi interactions in structural biology, Proc. Natl. Acad. Sci. USA, 96, 9459–9464.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Mecozzi, S., West, A. P., Jr., and Dougherty, D. A. (1996) Cation-pi interactions in simple aromatics: electrostatics provide a predictive tool, J. Am. Chem. Soc., 118, 2307–2308.CrossRefGoogle Scholar
  23. 23.
    Wintjens, R., Lievin, J., Rooman, M., and Buisine, E. (2000) Contribution of cation-π interactions to the stability of protein-DNA complexes, J. Mol. Biol., 302, 395–410.PubMedCrossRefGoogle Scholar
  24. 24.
    Gromiha, M. M., Santhosh, C., and Suwa, M. (2004) Influence of cation-pi interactions in protein-DNA complexes, Polymer, 45, 633–639.CrossRefGoogle Scholar
  25. 25.
    Borozan, S. Z., Dimitrijevic, B. P., and Stojanovic, S. D. (2013) Cation-π interactions in high resolution protein-RNA complex crystal structures, Comput. Biol. Chem., 47, 105–112.PubMedCrossRefGoogle Scholar
  26. 26.
    Frisch, M. J., Trucks, G. W., Schlegel, H. B., et al. (2003) Gaussian 03, Revision B.05, Gaussian, Inc., Pittsburgh, PA.Google Scholar
  27. 27.
    Case, D. A., Darden, T. A., Cheatham, III, T. E., Simmerling, C. L., Wang, J., Duke R. E., Luo, R., Crowley, M., Walker, R. C., Zhang, W., Merz, K. M., Wang, B., Hayik, S., Roitberg, A., Seabra, G., Kolossvary, I., Wong, K. F., Paesani, F., Vanicek, J., Wu, X., Brozell, S. R., Steinbrecher, T., Gohlke, H., Yang, L., Tan, C., Mongan, J., Hornak, V., Cui, G., Mathews, D. H., Seetin, M. G., Sagui, C., Babin, V., and Kollman, P. A. (2008) AMBER 10, University of California, San Francisco, CA.Google Scholar
  28. 28.
    Gray, J. J., Moughan, S. E., Wang, C., Schueler-Furman, O., Kuhlman, B., Rohl, C. A., and Baker, D. (2003) Protein-protein docking with simultaneous optimization of rigid body displacement and side chain conformations, J. Mol. Biol., 331, 281–299.PubMedCrossRefGoogle Scholar
  29. 29.
    Kuhlman, B., and Baker, D. (2000) Native protein sequences are close to optimal for their structures, Proc. Natl. Acad. Sci. USA, 97, 10383–10388.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Perez-Cano, L., and Fernandez-Recio, J. (2010) Optimal protein-RNA area, OPRA: A propensity-based method to identify RNA-binding sites on proteins, Proteins, 78, 25–35.PubMedCrossRefGoogle Scholar
  31. 31.
    Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., Shindyalov, I. N., and Bourne, P. E. (2000) The Protein Data Bank, Nucleic Acids Res., 28, 235–242.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Minoux, H., and Chipot, C. (1999) Cation-pi interactions in proteins: can simple models provide an accurate description? J. Am. Chem. Soc., 121, 10366–10372.CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2014

Authors and Affiliations

  1. 1.College of Life Science and BioengineeringBeijing University of TechnologyBeijingChina
  2. 2.College of ScienceYanshan UniversityQinhuangdaoChina

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