Entropy–Driven Conformations Controlling DNA Functions

  • A. R. BishopEmail author
  • K. Ø. Rasmussen
  • A. Usheva
  • Boian S. Alexandrov
Part of the Springer Series in Materials Science book series (SSMATERIALS, volume 148)


In memory of Jim Krumhansl we summarize our growing level of understanding of the origins and functional roles of specific nonlinear conformational excitations (“bubbles”) in DNA. We present a number of results that point toward the conclusion that DNA is capable of directing major aspects of its own lifecycle, governed by the laws of equilibrium thermodynamics.First, we discuss a series of experimental and theoretical research results that demonstrate a correlation between DNA bubbles and essential biological processes such as DNA transcription and DNA–protein binding. Specifically, we discuss how, through a synergetic combination of modeling and experiments, we have developed an extended version of the Peyrard–Bishop–Dauxois model, and used it to predict specific properties, such as bubble location, size, and duration, of DNA breathing. Applying this framework, we show a number of examples that demonstrate that specific breathing properties lead to enhancements in transcription activity and DNA–protein binding efficiency.Second, we show that DNA may be able to apply its complex conformational dynamics to facilitate its own repair. We demonstrate this in the context of specific DNA damage that has been documented to arise from exposure to UV radiation.Finally, we discuss our ongoing attempts to harness our knowledge of DNA conformation and dynamics and their impact on function to help predict transcription initiation sites in entire genomes. We apply techniques from bioinformatics and statistical learning to incorporate the above features into a more predictive framework.


Transcription Factor Binding Site Core Promoter Markov Chain Monte Carlo Simulation Promoter Prediction Dinucleotide Step 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We gratefully acknowledge all our collaborators with whom we have coauthored the original works summarized here. This work was carried out under the auspices of the National Nuclear Security Administration of the US Department of Energy at Los Alamos National Laboratory under Contract No. DE-AC52–06NA25396.


  1. 1.
    D.K. Campbell, A.C. Newell, R.J. Schrieffer, H. Segur (eds.), Solitons and coherent structures. Phys. D 18, (North-Holland, Amsterdam, 1986)Google Scholar
  2. 2.
    A.R. Bishop, J.A. Krumhansl, S.E. Trullinger, Solitons in condensed matter: a paradigm. Phys. D 1, 1 (1980)CrossRefGoogle Scholar
  3. 3.
    J.A. Krumhansl, J.R. Schrieffer, Dynamics and statistical-mechanics of a one-dimensional model Hamiltonian for structural phase-transitions. Phys. Rev. B, 11(9), 3535 (1975)Google Scholar
  4. 4.
    B. Horovitz, J.A. Krumhansl, Solitons in the Peierls condensate – phase solitons. Phys. Rev. B 29, 2109 (1984)CrossRefGoogle Scholar
  5. 5.
    G.R. Barsch, J.A. Krumhansl, Twin boundaries in ferroelastic media without interface dislocations. Phys. Rev. Lett. 53(11) 1069 (1984)Google Scholar
  6. 6.
    A.E. Garcia, J.A. Krumhansl, H. Frauenfelder, Variations on a theme by Debye and Waller: From simple crystals to proteins. Proteins - Struct. Funct. Bioin. 29(2) 153 (1997)Google Scholar
  7. 7.
    S.W. Englander, N.R. Kallenbach, A.J. Heeger, J.A. Krumhansl, S. Litwin, Nature of the open state in long polynucleotide double helices: possibility of soliton excitations. Proc. Natl. Acad. Sci. U S A 77, 7222 (1980)CrossRefGoogle Scholar
  8. 8.
    A.E. Garcia, C.S. Tung, J.A. Krumhansl, Low-frequency collective motions of DNA double helices – A reduced set of coordinates approach. Biophys. J. 49(2) A123 (1986)Google Scholar
  9. 9.
    A.E. Garcia, J.A. Krumhansl, Density of states of single and double helical DNA. Biophys. J. 51, A420 (1987)Google Scholar
  10. 10.
    B. Horovitz, G.R. Barsch, J.A. Krumhansl, Twin bands in Martensites – statics and dynamics. Phys. Rev.B 43(1), 1021 (1991)Google Scholar
  11. 11.
    S. Kartha, J.A. Krumhansl, J.P. Sethna, L.K. Wickham, Disorder-driven pretransitional tweed pattern in Martensitic transformations. Phys. Rev. B, 52, 2, 803 (1995)Google Scholar
  12. 12.
    T. Lookman, S.R. Shenoy, K.Ø. Rasmussen, et al., Ferroelastic dynamics and strain compatibility. Phys. Rev. B 67, 2, 024114 (2003)Google Scholar
  13. 13.
    M. Peyrard, A.R. Bishop, Statistical mechanics of a nonlinear model for DNA denaturation. Phys. Rev. Lett. 62, 2755 (1989)CrossRefGoogle Scholar
  14. 14.
    T. Dauxois, M. Peyrard, A.R. Bishop, Entropy-driven DNA denaturation. Phys. Rev. E 47, R44 (1993)Google Scholar
  15. 15.
    H. Gohlke, M.F. Thorpe, A natural coarse graining for simulating large biomolecular motion. Biophys. J. 91, 2115 (2006)CrossRefGoogle Scholar
  16. 16.
    A. Katherine, A. Henzler-Wildman, M. Lei, V. Thai, S.J. Kerns, M. Karplus, D. Kern, A hierarchy of timescales in protein dynamics is linked to enzyme catalysis. Nature 450, 913 (2007)CrossRefGoogle Scholar
  17. 17.
    S.T. Smale, J.T. Kadonaga, The RNA polymerase II core promoter. Annu. Rev. Biochem. 72, 449 (2003)CrossRefGoogle Scholar
  18. 18.
    T. Juven-Gershon, J.T. Kadonaga, Regulation of gene expression via the core promoter and the basal transcriptional machinery. Dev. Biol. 339, 225 (2010)CrossRefGoogle Scholar
  19. 19.
    J.A. Stamatoyannopoulos, Illuminating eukaryotic transcription start sites. Nat. Methods 7, 501 (2010)CrossRefGoogle Scholar
  20. 20.
    A. Sandelin, P. Carninci, B. Lenhard, J. Ponjavic, Y. Hayashizaki, D.A. Hume, Mammalian RNA polymerase II core promoters: insights from genome-wide studies. Nat. Rev. Genet. 8, 424 (2007)CrossRefGoogle Scholar
  21. 21.
    A.F. Melnikova, R. Beabealashvilli, A.D. Mirzabekov, A study of unwinding of DNA and shielding of the DNA grooves by RNA polymerase by using methylation with dimethylsulphate. Eur. J. Biochem. 84, 301 (1978)CrossRefGoogle Scholar
  22. 22.
    U. Siebenlist, RNA polymerase unwinds an 11-base pair segment of a phage T7 promoter. Nature 279 651–652 (1979)CrossRefGoogle Scholar
  23. 23.
    M. Guéron, M. Kochoyan, J.L. Leroy, A single mode of DNA base-pair opening drives imino proton exchange. Nature, 328, 89 (1987)CrossRefGoogle Scholar
  24. 24.
    D.M.J. Lilley, DNA opens up – supercoiling and heavy breathing. Trends Genet. 4(4), 111 (1988)Google Scholar
  25. 25.
    A. Kornberg, T.A. Baker, DNA Replication, 2nd edn. (University Science Books, Sausalito, CA, 2005)Google Scholar
  26. 26.
    Y. Lin, S.Y. Dent, J.H. Wilson, R.D. Wells, M. Napierala, R-loops stimulate genetic instability of CTG.CAG repeats. Proc. Natl Acad. Sci. U. S. A. 107, 692 (2010)Google Scholar
  27. 27.
    C.H. Choi, G. Kalosakas, K.Ø. Rasmussen, M. Hiromura, A.R. Bishop, A. Usheva, DNA dynamically directs its own transcription initiation. Nucl. Acids. Res. 32, 1584 (2004)CrossRefGoogle Scholar
  28. 28.
    G. Kalosakas, K.Ø. Rasmussen, A.R. Bishop, C.H. Choi, A. Usheva, Sequence-specific thermal fluctuations identify start sites for DNA transcription. Europhys. Lett. 68, 127 (2004)CrossRefGoogle Scholar
  29. 29.
    W.C. Kerr, A.M. Hawthorne, R.J. Gooding, A.R. Bishop, J.A. Krumhansl, First-order displacive structural phase transitions studied by computer simulation. Phys. Rev. B 45, (1992)Google Scholar
  30. 30.
    B.S. Alexandrov, L.T. Wille, K.Ø. Rasmussen, A.R. Bishop, K.B. Blagoev, Bubble statistics and dynamics in double-stranded DNA. Phys. Rev. E 74, 050901 R (2006)Google Scholar
  31. 31.
    Z. Rapti, A. Smerzi, K.Ø. Rasmussen, A.R. Bishop, C.H. Choi, A. Usheva, Healing length and bubble formation in DNA. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 73, 051902 (2006)CrossRefGoogle Scholar
  32. 32.
    Z. Rapti, A. Smerzi, K.Ø. Rasmussen, A.R. Bishop, C.H. Choi, A. Usheva, Lengthscales and cooperativity in DNA bubble formation. Europhys. Lett. 74, 540 (2006)CrossRefGoogle Scholar
  33. 33.
    C.H. Chu, Z. Rapti, V. Gelev, M.R. Hacker, B.S. Alexandrov, E.J. Park, J.S. Park, N. Horikoshi, A. Smerzi, K.Ø. Rasmussen, A.R. Bishop, A. Usheva, Profiling the thermodynamic softness of adenoviral promoters. Biophys. J. 95, 597 (2008)CrossRefGoogle Scholar
  34. 34.
    B.S. Alexandrov, V. Gelev, S.W. Yoo, A.R. Bishop, K.Ø. Rasmussen, et al., Toward a detailed description of the thermally induced dynamics of the core promoter. PLoS Comput. Biol. 5(3), e1000313 (2009)Google Scholar
  35. 35.
    J. Sponer, K.E. Riley, P. Hobza, Nature and magnitude of aromatic stacking of nucleic acid bases. Phys. Chem. Chem. Phys. 10, 2595 (2008)CrossRefGoogle Scholar
  36. 36.
    B.S. Alexandrov, V. Gelev, Y. Monisova, L.B. Alexandrov, A.R. Bishop, K.Ø. Rasmussen, A. Usheva, A nonlinear dynamic model of DNA with a sequence-dependent stacking term. Nucl. Acids. Res. 37, 2405 (2009)CrossRefGoogle Scholar
  37. 37.
    R.D. Wells, J.E. Larson, R.C. Grant, B.E. Shortle, C.R. Cantor, Physicochemical studies on polydeoxyribonucleotides containing defined repeating nucleotide sequences. J. Mol. Biol. 54, 465 (1970)CrossRefGoogle Scholar
  38. 38.
    J.C. Venter, et al., The human genome. Science 291, 1304 (2001)Google Scholar
  39. 39.
    S. Ares, N.K. Voulgarakis, K.Ø. Rasmussen, A.R. Bishop, Bubble nucleation and cooperativity in DNA melting. Phys. Rev. Lett. 94, 035504 (2005)CrossRefGoogle Scholar
  40. 40.
    T. Juven-Gershon, S. Cheng, J.T. Kadonaga, Rational design of a super core promoter that enhances gene expression. Nat. Methods 3, 917 (2006)CrossRefGoogle Scholar
  41. 41.
    B.S. Alexandrov, V. Gelev, S.W. Yoo, L.B. Alexandrov, Y. Fukuyo, A.R. Bishop, K.Ø. Rasmussen, A. Usheva, DNA dynamics play a role as a basal transcription factor in the positioning and regulation of gene transcription initiation. Nucl. Acids. Res. 38(6), 1790 (2010)Google Scholar
  42. 42.
    H. Lodish, A. Berk, P. Matsudaira, C.A. Kaiser, M.P. Scott, S.L. Zipursky, J. Darnell, Molecular Biology of the Cell, 5th edn. (WH Freeman, New York, NY, 2004) p. 963Google Scholar
  43. 43.
    J. Montgomery, C.T. Wittwer, R. Palais, L. Zhou, Simultaneous mutation scanning and genotyping by high-resolution DNA melting analysis. Nat. Protoc. 2, 59 (2007)CrossRefGoogle Scholar
  44. 44.
    J. Kemmink, R. Boelens, T. Koning, et al., 1H NMR study of the exchangeable protons of the duplex d (GCGTTGCG). d (CGCAACGC) containing a thymine photodimer containing a thymine photodimer. Nucl. Acids Res. 15, 4645 (1987)Google Scholar
  45. 45.
    J. Ramstein, C. Hélène, M. Leng, A study of chemically methylated deoxyribonucleic acid. Eur. J. Biochem. 21(1), 125 (1971)Google Scholar
  46. 46.
    K.B. Blagoev, B.S. Alexandrov, E.H. Goodwin, A.R. Bishop, Ultra-violet light induced changes in DNA dynamics may enhance TT-dimer recognition. DNA Repair 7, 863 (2006)CrossRefGoogle Scholar
  47. 47.
    B.S. Alexandrov, N.K. Voulgarakis, K.Ø. Rasmussen, A. Usheva, A.R. Bishop, Pre-melting dynamics of DNA and its relation to specific functions. J. Phys.: Condens. Matter 21, 034107 (2009)Google Scholar
  48. 48.
    M. Fixman, Classical statistical mechanics of constraints: a theorem and application to polymers. Proc. Natl. Acad. Sci. U. S. A. 71, 3050 (1974)CrossRefGoogle Scholar
  49. 49.
    T. Abeel, Y. Van de Peer, Y. Saeys, Toward a gold standard for promoter prediction evaluation. Bioinformatics 25, i313 (2009)CrossRefGoogle Scholar
  50. 50.
    M. Megraw, F. Pereira, T.J. Jensen, et al., A transcription factor affinity-based code for mammalian transcription initiation. Genome Res. 19, 644 (2009)CrossRefGoogle Scholar
  51. 51.
    C.F. Frith, E. Valen, A. Krogh, et al., A code for transcription initiation in mammalian genomes. Genome Res. 18, 1 (2008)CrossRefGoogle Scholar
  52. 52.
    G. Badis, M.F. Berger, A.A. Philippaki, et al., Diversity and complexity in DNA recognition by transcription factors. Science 26, 5935 (2009)Google Scholar
  53. 53.
    F. Liu, E. Tostesen, J.K. Sundet, T.K. Jenssen, C. Bock, et al., The human genomic melting map. PLoS Comput. Biol. 3, e93 (2007)CrossRefGoogle Scholar
  54. 54.
    D.G. Dineen, A. Wilm, P. Cunningham, D.G. Higgins, High DNA melting temperature predicts transcription start site location in human and mouse. Nucl. Acids Res 37, 7360 (2009)CrossRefGoogle Scholar
  55. 55.
    C.J. Benham, Duplex destabilization in superhelical DNA is predicted to occur at specific transcriptional regulatory regions. J. Mol. Biol. 255, 425 (1996)CrossRefGoogle Scholar
  56. 56.
    T.A. Down, T.J. Hubbard, Computational detection and location of transcription start sites in mammalian genomic DNA. Genome Res. 12, 458 (2002)CrossRefGoogle Scholar
  57. 57.
    T. Abeel, Y. Saeys, E. Bonnet, P. Rouze, Y. Van de Peer, Generic eukaryotic core promoter prediction using structural features of DNA. Genome Res 18, 310 (2008)CrossRefGoogle Scholar
  58. 58.
    S. Sonnenburg, A. Zien, G. Ratsch, ARTS: accurate recognition of transcription starts in human. Bioinformatics 22, e472 (2006)CrossRefGoogle Scholar
  59. 59.
    T. Abeel, Y. Saeys, P. Rouze, Y. Van de Peer, ProSOM: core promoter prediction based on unsupervised clustering of DNA physical profiles. Bioinformatics 24, 24 (2008)CrossRefGoogle Scholar
  60. 60.
    L.B. Alexandrov, K.Ø. Rasmussen, A.R. Bishop, A. Usheva, B.S. Alexandrov, DNA breathing dynamics for genomic-scale core promoter prediction. SubmittedGoogle Scholar
  61. 61.
    A. Usheva, T. Shenk, YY1 transcriptional initiator: protein interactions and association with a DNA site containing unpaired strands. Proc. Natl. Acad. Sci. U. S. A. 93, 13571 (1996)CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • A. R. Bishop
    • 1
    Email author
  • K. Ø. Rasmussen
    • 1
  • A. Usheva
    • 2
  • Boian S. Alexandrov
    • 1
  1. 1.Theoretical DivisionLos Alamos National LaboratoryLos AlamosUSA
  2. 2.Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA

Personalised recommendations