Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Insight
  • Published:

Calculating the electrostatic properties of RNA provides new insights into molecular interactions and function

Nature Structural Biology volume 6, pages 1055–1061 (1999)Cite this article

Abstract

Solutions to the nonlinear Poisson-Boltzmann equation were used to obtain the electrostatic potentials of RNA molecules that have known three-dimensional structures. The results are described in terms of isopotential contours and surface electrostatic potential maps. Both representations have unexpected features: 'cavities' within isopotential contours and areas of enhanced negative potential on molecular surfaces. Intriguingly, the sites of unusual electrostatic features correspond to functionally important regions, suggesting that electrostatic properties play a key role in RNA recognition and stabilization. These calculations reveal that the electrostatic potentials generated by RNA molecules have a variety of functionally important characteristics that cannot be discerned by simple visual inspection of the molecular structure.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Isopotential contours of a GNRA tetraloop and its receptor.
Figure 2: Three-dimensional isopotential contours of various RNA structures.
Figure 3: Surface potentials of standard forms of nucleic acids with identical sequences.
Figure 4: Surface potentials of helices containing internal base pair mismatches.
Figure 5: Surface potentials of large RNAs with known metal binding sites.
Figure 6: Surface potentials of the tetraloop–receptor interaction.

References

  1. Sharp, K.A. & Honig, B. Electrostatic interactions in macromolecules: theory and applications. Annu. Rev. Biophys. Biophys. Chem. 19, 301–332 (1990).

    Article  CAS  PubMed  Google Scholar 

  2. Honig, B. & Nicholls, A. Classical electrostatics in biology and chemistry. Science 268, 1144– 1149 (1995).

    Article  CAS  PubMed  Google Scholar 

  3. Uhlenbeck, O.C., Pardi, A. & Feigon, J. RNA structure comes of age. Cell 90, 833–840 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Madura, J.D. et al. Biological applications of electrostatic calculations and Brownian dynamics simulations. Rev. Comput. Chem. 5, 229–267 (1994).

    CAS  Google Scholar 

  5. Sharp, K.A., Honig, B. & Harvey, S.C. Electrical potential of transfer RNAs: codon-anticodon recognition. Biochemistry 29, 340– 346 (1990).

    Article  CAS  PubMed  Google Scholar 

  6. Sharp, K.A. & Honig, B. Salt effects on nucleic acids. Curr. Opin. Struct. Biol. 5, 323–328 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Sharp, K.A., Friedman, R.A., Misra, V., Hecht, J. & Honig, B. Salt effects on polyelectrolyte-ligand binding: comparison of Poisson-Boltzmann, and limiting law/counterion binding models. Biopolymers 36, 245– 262 (1995).

    Article  CAS  PubMed  Google Scholar 

  8. Misra, V.K., Sharp, K.A., Friedman, R.A. & Honig, B. Salt effects on ligand-DNA binding. Minor groove binding antibiotics. J. Mol. Biol. 238, 245–263 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Misra, V.K., Hecht, J.L., Sharp, K.A., Friedman, R.A. & Honig, B. Salt effects on protein–DNA interactions. The λcI repressor and EcoRI endonuclease. J. Mol. Biol. 238, 264–280 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Misra, V.K., Hecht, J.L., Yang, A. & Honig, B. Electrostatic contributions to the binding free energy of the λcI repressor to DNA. Biophys. J. 75, 2262–2273 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Westhof, E. & Sundaralingam, M. Restrained refinement of the monoclinic form of yeast phenylalanine transfer RNA. Temperature factors and dynamics, coordinated waters, and base-pair propeller twist angles. Biochemistry 25, 4868–4878 (1986).

    Article  CAS  PubMed  Google Scholar 

  12. Jucker, F.M. & Pardi, A. GNRA tetraloops make a U-turn. RNA 1, 219–222 ( 1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Cate, J.H. et al. Crystal structure of a Group I ribozyme domain: Principles of RNA packing. Science 273, 1678– 1685 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Cornell, W.D. et al. A second generation force field for the simulation of proteins, nucleic acids, and organic molecules. J. Am. Chem. Soc. 117, 5179–5197 (1995).

    Article  CAS  Google Scholar 

  15. Klapper, I., Hagstrom, R., Fine, R., Sharp, K. & Honig, B. Focusing of electric fields in the active site of Cu-Zn superoxide dismutase: effects of ionic strength and amino-acid modification. Proteins 1, 47–59 (1986).

    Article  CAS  PubMed  Google Scholar 

  16. Gilson, M. & Honig, B. The dielectric constant of a folded protein. Biopolymers 25, 2097– 2119 (1986).

    Article  CAS  PubMed  Google Scholar 

  17. Yang, L., Weerasinghe, S., Smith, P.E. & Pettitt, B.M. Dielectric response of triplex DNA in ionic solution from simulations. Biophys. J. 69, 1519–1527 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Shen, L.X. & Tinoco, I. The structure of an RNA pseudoknot that causes efficient frameshifting in mouse mammary-tumor virus. J. Mol. Biol. 247, 963–978 (1995).

    Article  CAS  PubMed  Google Scholar 

  19. Kang, H. & Tinoco, I. A mutant RNA pseudoknot that promotes ribosomal frameshifting in mouse mammary tumor virus. Nucleic Acids Res. 25, 1943–1949 ( 1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Szewczak, A.A., Moore, P.B., Chan, Y. & Wool, I.G. The conformation of the sarcin/ricin loop from 28S ribosomal RNA. Proc. Natl. Acad. Sci. USA 90, 9581–9585 ( 1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cate, J.H. et al. RNA tertiary structure mediation by adenosine platforms. Science 273, 1696–1699 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Legault, P., Li, J., Mogridge, J., Kay, L.E. & Greenblatt, J. NMR structure of the bacteriophage lambda N peptide/box B RNA complex: Recognition of a GNRA fold by an arginine-rich motif. Cell 93, 289–299 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  23. Monzingo, A.F. & Robertus, J.D. X-ray analysis of substrate analogs in the ricin A-chain active site. J. Mol. Biol. 227, 1136–1145 ( 1992).

    Article  CAS  PubMed  Google Scholar 

  24. Strobel, S.A. & Doudna, J.A. RNA seeing double: close-packing of helices in RNA tertiary structure. Trends Biochem. Sci. 22, 262–266 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Chen, X. et al. A characteristic bent conformation of RNA pseudoknots promotes -1 frameshifting during translation of retroviral RNA. J. Mol. Biol. 260, 479–483 ( 1996).

    Article  CAS  PubMed  Google Scholar 

  26. Gilson, M.K., Rashin, A., Fine, R. & Honig, B. On the calculation of electrostatic interactions in proteins. J. Mol. Biol. 184, 503–516 (1985).

    Article  CAS  PubMed  Google Scholar 

  27. Peterson, R.D. & Feigon, J. Structural change in rev responsive element RNA of HIV-1 on binding rev peptide. J. Mol. Biol. 264, 863–877 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Nicholls, A., Sharp, K.A. & Honig, B. Protein folding and association: insights from the interfacial and thermodynamic properties of hydrocarbons. Proteins 11, 281–296 (1991).

    Article  CAS  PubMed  Google Scholar 

  29. Pullman, B. Electrostatics of polymorphic DNA. J. Biomol. Struct. Dynam. 1, 773–794 (1983).

    Article  CAS  Google Scholar 

  30. Young, M.A., Ravishanker, G. & Beveridge, D.L. A 5-nanosecond molecular dynamics trajectory for B-DNA: analysis of structure, motions, and solvation. Biophys J. 73, 2313–2336 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zakrzewska, K. & Pullman, B. Spermine–nucleic acid interactions: a theoretical study. Biopolymers 25, 375–392 (1986).

    Article  CAS  PubMed  Google Scholar 

  32. Le, S.Y., Chen, J.H., Pattabiraman, N. & Maizel Jr., J.V. Ion-RNA interactions in the RNA pseudoknot of a ribosomal frameshifting site: molecular modeling studies. J. Biomol. Struct. Dyn. 16, 1–11 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  33. Suga, H., Cowan, J.A. & Szostak, J.W. Unusual metal ion catalysis in an acyl-transferase ribozyme. Biochemistry 37, 10118– 10125 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Correll, C.C., Freeborn, B., Moore, P.B. & Steitz, T.A. Metals, motifs, and recognition in the crystal structure of a 5S rRNA domain. Cell 91, 705–712 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Kieft, J.S. & Tinoco, I. Solution structure of a metal-binding site in the major groove of RNA complexed with cobalt(III) hexamine. Structure 5, 713–721 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  36. Cate, J.H. & Doudna, J.A. Metal-binding sites in the major groove of a large ribozyme domain. Structure 4, 1221–1229 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. McDowell, J.A., He, L., Chen, X. & Turner, D.H. Investigation of the structural basis for thermodynamic stabilities of tandem GU wobble pairs: NMR structures of (rGGAGUUCC)2 and (rGGAUGUCC)2. Biochemistry 36, 8030–8038 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  38. Santalucia, J. & Turner, D.H. Structure of (rGGCGAGCC)2 in solution from NMR and restrained molecular dynamics. Biochemistry 32, 12612–12623 (1993).

    Article  CAS  PubMed  Google Scholar 

  39. Wu, M. & Turner, D.H. Solution structure of (rGCGGACGC)2 by two-dimensional NMR and the iterative relaxation matrix approach. Biochemistry 35, 9677–9689 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Holbrook, S.R., Sussman, J.L., Warrant, R.W., Church, G.M. & Kim, S. RNA-ligand interactions: (I) magnesium binding sites in yeast tRNAphe. Nucleic Acids Res. 4, 2811–2820 ( 1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pyle, A.M. Role of metal ions in ribozymes. Metal ions in biological systems 32, 479–520 ( 1996).

    CAS  PubMed  Google Scholar 

  42. Hermann, T. & Westhof, E. Exploration of metal ion binding sites in RNA folds with Brownian dynamics simulation. Structure 6, 1303–1314 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  43. Gilson, M.K. & Honig, B. Calculation of the total electrostatic energy of a macromolecular system: solvation energies, binding energies, and conformational analysis. Proteins 4, 7– 18 (1988).

    Article  CAS  PubMed  Google Scholar 

  44. Lavery, R. & Pullman, B. The electrostaic field of DNA: the role of nucleic acid conformation. Nucleic Acids Res. 10, 4383–4395 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Pley, H.W., Flaherty, K.M. & Mckay, D.B. Three-dimensional structure of a hammerhead ribozyme. Nature 372, 68–74 (1994).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to C. Duarte and B. Hitz for helpful discussions and to E. Jankowsky for critical review of the manuscript. We thank S. Sridharan for assistance in modifying the NLPB solver program. This work was supported by a NYI award to A.M.P. from the NSF and an NIH grant to B.H. A.M.P. is an assistant investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biophysics, Columbia University, 630 West 168th Street, Box 36, New York, 10032, New York, USA

    Kevin Chin, Barry Honig & Anna Marie Pyle

  2. Department of Biochemistry and Biophysics, University of Pennsylvania, Room 417 Anatomy Chemistry Building, Philadelphia, 19104, Pennsylvania, USA

    Kim A. Sharp

  3. Howard Hughes Medical Institute, Columbia University, New York, New York, USA

    Anna Marie Pyle

Authors
  1. Kevin Chin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kim A. Sharp
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Barry Honig
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna Marie Pyle
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Barry Honig or Anna Marie Pyle.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chin, K., Sharp, K., Honig, B. et al. Calculating the electrostatic properties of RNA provides new insights into molecular interactions and function. Nat Struct Mol Biol 6, 1055–1061 (1999). https://doi.org/10.1038/14940

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/14940

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing