Skip to main content
SpringerLink
Log in
Book cover

RNA Biochemistry and Biotechnology pp 11–43Cite as

Algorithms and Thermodynamics for RNA Secondary Structure Prediction: A Practical Guide

  • Chapter

Part of the book series: NATO Science Series ((ASHT,volume 70))

Abstract

This article is about the current status of the mfold package for RNA and DNA secondary structure prediction using nearest neighbor thermodynamic rules. The details of the free energy rules and of the latest version 3.0 software are described. Future plans are also discussed.

The mfold software now runs on a variety of Unix platforms; specifically SGI Irix, Sun Solaris, Dec alpha Ultrix and on Linux. While the older interactive programs of version 2 still exist, they are now run by a variety of scripts that make for much easier handling. There is both a command line interface for mfold and an HTML interface that runs in a Unix environment but can be accessed by anyone with a web browser.

The thermodynamic basis for the folding model is presented in detail, with references given for both specific free energy parameters and to overview articles that have summarized the state of these nearest neighbor parameters over the past dozen years. Both RNA and DNA rules are discussed, with some mention of parameters for RNA/DNA hybridization. Although the thermodynamic model has grown in complexity to accommodate new types of information, the folding algorithm has not yet incorporated some features, such as coaxial stacking of adjacent helices, and other features will probably remain too difficult or computationally expensive to implement. For this reason, a new energy calculation program has been introduced to recompute the free energies of predicted foldings to reflect the best of our knowledge.

The most significant improvements in the mfold software are:

  1. 1.

    Folding times have been greatly reduced in recent years, partly because of faster computers and partly because of improvements in the algorithm.

  2. 2.

    Folding constraints have been expanded and are now implemented without the use of bonus energies that distort the results.

  3. 3.

    The output is significantly improved. Clear and enlargeable images of dot plots and of predicted foldings are now produced in PostScript and gif formats. Bases in structures may be annotated using different colors that reflect how well-determined they are in terms of their tendency to pair with other bases or to be single-stranded. Similarly, base pair probabilities from partition function calculations may be used for annotation. A detailed decomposition of each predicted folding into stacked pairs and loops with associated free energies is now provided.

The mfold software has a variety of parameters that may be adjusted to improve the predictions. Several examples are presented to illustrate how to interpret folding results and how to adjust these parameters to obtain better results.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. P.M. MacDonald. (1990) Bicoid mRNA localization signal, phylogenetic conservation of function and RNA secondary structure. Development, 110, 161–171.

    PubMed  CAS  Google Scholar 

  2. M.H. de Smit and J. van Duin. (1990) Control of prokaryotic translation initiation by mRNA secondary structure. Progress in Nucleic Acid Research in Molecular Biology, 38, 1–35.

    Article  Google Scholar 

  3. D.R. Mills, C. Priano, P.A. Merz, and B.D. Binderow. (1990) Qβ RNA bacteriophage, mapping cis-acting elements within an RNA genome. J. Virol., 64, 3872–3881.

    Google Scholar 

  4. C.I. Brannan, E.C. Dees, R.S. Ingram, and S.M. Tilghman. (1990) The product of the h19 gene may function as an RNA. Mol. Cell. Biol., 10, 28–36.

    PubMed  CAS  Google Scholar 

  5. C.J. Brown, A. Ballabio, J.L. Rupert, R.G. Lafreniere, M. Grompe, R. Tonlorenzi, and H.F. Willard. (1991) A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature, 349, 38–44.

    Article  PubMed  CAS  Google Scholar 

  6. T.R. Cech and B.L. Bass. (1986) Biological catalysis by RNA. Ann. Rev. Biochem., 55, 599–629.

    Article  PubMed  CAS  Google Scholar 

  7. T.R. Cech. (1990) Self-splicing of group I introns. Ann. Rev. Biochem., 59, 543–568.

    Article  PubMed  CAS  Google Scholar 

  8. S.C. Darr, J.W. Brown, and N.R. Pace. (1992) The varieties of Ribonuclease P. Trends Biochem. Sci., 17, 178–182.

    Article  PubMed  CAS  Google Scholar 

  9. S.H. Kim, F.L. Suddath, G.J. Quigley, A. McPherson, and J.L. Sussman. (1974) Three dimensional tertiary structure of yeast phenylalanine transfer RNA. Science, 185, 435–440.

    Article  PubMed  CAS  Google Scholar 

  10. J.D. Robertus, J.E. Ladner, J.T. Finch, D. Rhodes, and R.S. Brown. (1974) Structure of yeast phenylalanine tRNA at 3 Å resolution. Nature, 250, 546–551.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  12. R.R. Gutell, (1995) personal communication.

    Google Scholar 

  13. F. Michel and E. Westhof. (1990) Modelling of the three-dimensional architecture of group I catalytic introns based on comparative sequence analysis. J. Mol. Biol., 216, 585–610.

    Article  PubMed  CAS  Google Scholar 

  14. F. Major, M. Turcotte, D. Gautheret, G. Lapalme, E. Fillion, and R.J. Cedergren. (1991) The combination of symbolic and numerical computation for three-dimensional modeling of RNA. Science, 253, 1255–1260.

    Article  PubMed  CAS  Google Scholar 

  15. F. Major, D. Gautheret, and R. Cedergren. (1993) Reproducing the three-dimensional structure of a tRNA molecule from structural constraints. Proc. Natl. Acad. Sci. USA, 90, 9408–9412.

    Article  PubMed  CAS  Google Scholar 

  16. M. Zuker. (1989) On finding all suboptimal foldings of an RNA molecule. Science, 244, 48–52.

    Article  PubMed  CAS  Google Scholar 

  17. J.A. Jaeger, D.H. Turner, and M. Zuker. (1989) Improved predictions of secondary structures for RNA. Proc. Natl. Acad. Sci. USA., 86, 7706–7710.

    Article  PubMed  CAS  Google Scholar 

  18. J.A. Jaeger, D.H. Turner, and M. Zuker. (1990) Predicting optimal and suboptimal secondary structure for RNA. Meth. Enzymol., 183, 281–306.

    Article  PubMed  CAS  Google Scholar 

  19. M. Zuker. (1994) Prediction of RNA Secondary Strcture by Energy Minimization., volume 25 of Computer Analysis of Sequence Data, Part II, A.M. Griffin & H.G Griffin, Eds., chapter 23, pages 267–294. CRC Press, Inc., Totowa, NJ.

    Chapter  Google Scholar 

  20. D.H. Mathews, T.C. Andre, J. Kim, D.H. Turner, and M. Zuker. (1998) An Updated Recursive Algorithm for RNA Secondary Structure Prediction with Improved Free Energy Parameters., chapter 15, pages 246–257. American Chemical Society Symposium Series 682. American Chemical Society, Washington, DC.

    Google Scholar 

  21. D. Sankoff, J.B. Kruskal, S. Mainville, and R.J. Cedergren. (1983) Fast algorithms to determine RNA secondary structures containing multiple loops., chapter 3, pages 93–120. Time warps, string edits, and macromolecules: the theory and practice of sequence comparison, Sankoff D., Kruskal J.B., Eds. Addison-Wesley, Reading, MA.

    Google Scholar 

  22. M. Zuker and D. Sankoff. (1984) RNA secondary structures and their prediction. Bull. Math. Biol., 46, 591–621.

    CAS  Google Scholar 

  23. M. Zuker. (1986) RNA folding prediction: The continued need for interaction between biologists and mathematicians. Lectures on Mathematics in the Life Sciences, 17, 86–123.

    Google Scholar 

  24. C.W. Pleij and L. Bosch. (1989) RNA pseudoknots: structure, detection, and prediction. Meth. Enzymol., 180, 289–303.

    Article  PubMed  CAS  Google Scholar 

  25. J.P. Abrahams, M. van den Berg, E. van Batenburg, and C.W. Pleij. (1990) Prediction of RNA secondary structure, including pseudoknotting, by computer simulation. Nucleic Acids Res., 18, 3035–3044.

    Article  PubMed  CAS  Google Scholar 

  26. R.R. Gutell and C.R. Woese. (1990) Higher order structural elements in ribosomal RNAs: Pseudo-knots and the use of noncanonical pairs. Proc. Natl. Acad. Sci. USA, 87, 663–667.

    Article  PubMed  CAS  Google Scholar 

  27. E. Dam, K. Pleij, and D. Draper. (1992) Structural and functional aspects of RNA pseudoknots. Biochemistry, 31, 11665–11676.

    Article  PubMed  CAS  Google Scholar 

  28. C.W. Pleij. (1994) RNA pseudoknots. Curr. Opin. Struct. Biol., 4, 337–344.

    Article  CAS  Google Scholar 

  29. Z. Du, D.P. Giedroc, and D.W. Hoffman. (1996) Structure of the autoregulatory pseudoknot within the gene 32 messenger RNA of bacteriophages T2 and T6: A model for a possible family of structurally related RNA pseudoknots. Biochemistry,35 (13), 4187–4198.

    Article  PubMed  CAS  Google Scholar 

  30. H. Jacobson and W.H. Stockmayer. (1950) Intramolecular reaction in polycondensations. I. The theory of linear systems. J. Chem. Phys., 18, 1600–1606.

    Article  CAS  Google Scholar 

  31. S.M. Freier, R. Kierzek, J.A. Jaeger, N. Sugimoto, M.H. Caruthers, T. Neilson, and D.H. Turner. (1986) Improved free-energy parameters for predictions of RNA duplex stability. Proc. Natl. Acad. Sci. USA, 83, 9373–9377.

    Article  PubMed  CAS  Google Scholar 

  32. D.H. Turner, N. Sugimoto, J.A. Jaeger, C.E. Longfellow, S.M. Freier, and R. Kierzek. (1987) Improved parameters for prediction of RNA structure. Cold Spring Harb. Symp. Quant. Biol., 52, 123–133.

    Article  PubMed  CAS  Google Scholar 

  33. D.H. Turner, N. Sugimoto, and S.M. Freier. (1988) RNA structure prediction. Annu. Rev. Biophys. Biophys. Chem., 17, 167–192.

    Article  PubMed  CAS  Google Scholar 

  34. M. Wu, J.A. McDowell, and D.H. Turner. (1995) A periodic table of symmetric tandem mismatches in RNA. Biochemistry, 34, 3204–3211.

    Article  PubMed  CAS  Google Scholar 

  35. A.E. Walter, D.H. Turner, J. Kim, M.H. Lyttle, P. Muller, D.H. Mathews, and M. Zuker. (1994) Coaxial stacking of helixes enhances binding of oligoribonucleotides and improves predictions of RNA folding. Proc Natl Acad Sci USA, 91, 9218–9222.

    Article  PubMed  CAS  Google Scholar 

  36. J.Jr. SantaLucia. (1998) A unified view of polymer, dumbbell, and oligonucleotide DNA nearest-neighbor thermodynamics. Proc. Natl. Acad. Sci. USA, 95, 1460–1465.

    Article  PubMed  CAS  Google Scholar 

  37. N. Sugimoto, S. Nakano, M. Katoh, A. Matsumura, H. Nakamuta, T. Ohmichi, M. Yoneyama, and M. Sasaki. (1995) Thermodynamic parameters to predict stability of RNA/DNA hybrid duplexes. Biochemistry, 34, 11211–11216.

    Article  PubMed  CAS  Google Scholar 

  38. M. Zuker and A.B. Jacobson. (1998) Using Reliability Information to Annotate RNA Secondary Structures. RNA, 4, 669–679.

    Article  PubMed  CAS  Google Scholar 

  39. R.C. Beach. (1981) The Unified Graphics System for Fortran 77 Programming Manual. Stanford Linear Accelerator Center Computational Research Group, Stanford, CA, Technical Memo 203.

    Google Scholar 

  40. M. Zuker, J.A. Jaeger, and D.H. Turner. (1991) A comparison of optimal and suboptimal RNA secondary structures predicted by free energy minimization with structures determined by phylogenetic comparison. Nucleic Acids Res., 19, 2707–2714.

    Article  PubMed  CAS  Google Scholar 

  41. R.E. Bruccoleri and G. Heinrich. (1988) An improved algorithm for nucleic acid secondary structure display. Comput. Appl. Biosci., 4, 167–173.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute for Biomedical Computing, Washington University, St. Louis, MO, 63110, USA

    M. Zuker

  2. Department of Chemistry, University of Rochester, Rochester, NY, 14627-0216, USA

    D. H. Mathews & D. H. Turner

Authors
  1. M. Zuker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. H. Mathews
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. H. Turner
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Poznan, Poland

    Jan Barciszewski

  2. Institute of Molecular and Structural Biology, University of Aarhus, Denmark

    Brian F. C. Clark

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Zuker, M., Mathews, D.H., Turner, D.H. (1999). Algorithms and Thermodynamics for RNA Secondary Structure Prediction: A Practical Guide. In: Barciszewski, J., Clark, B.F.C. (eds) RNA Biochemistry and Biotechnology. NATO Science Series, vol 70. Springer, Dordrecht. https://doi.org/10.1007/978-94-011-4485-8_2

Download citation

  • DOI: https://doi.org/10.1007/978-94-011-4485-8_2

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-0-7923-5862-6

  • Online ISBN: 978-94-011-4485-8

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation