Skip to main content
NCBI home page
Biophysical Journal logoLink to Biophysical Journal
. 2000 Aug;79(2):656–669. doi: 10.1016/S0006-3495(00)76324-7

Bending and adaptability to proteins of the cAMP DNA-responsive element: molecular dynamics contrasted with NMR.

S Derreumaux 1, S Fermandjian 1
PMCID: PMC1300966  PMID: 10920000

Abstract

DNA bending is assumed to play a crucial role during recognition of the cAMP-responsive element (CRE) by transcription factors. However, diverging results have been obtained for the bending direction of the unbound double helix. The refined NMR structures present a bend directed toward the minor groove, while biochemical methods conclude that there is a bend toward the major groove. The present 10-ns molecular dynamics (MD) simulation of d(GAGATGACGTCATCTC)(2), which contains the octamer CRE in its center, was carried out with AMBER in explicit water and counterions. It shows that CRE is a flexible segment, although it is bent slightly toward the major groove (7 degrees -8 degrees ) on the average. The MD structure agrees with both the biochemical results and unrefined NMR data. The divergence with the NMR refined structures suggests an improper electrostatic parameterization in the refinement software. The malleability of the central CpG is certainly the major contribution to the curving of the whole CRE segment in both the unbound and bound states. Comparison with the crystal structure of CRE bound to GCN4 shows that the deformation induced by the protein is concentrated mainly on the CpG step, rendering the bound structure of CRE closer to the structure of the 12-0 tetradecanoylphorbol-beta-acetate-responsive element.

Full Text

The Full Text of this article is available as a PDF (431.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arnott S., Hukins D. W. Optimised parameters for A-DNA and B-DNA. Biochem Biophys Res Commun. 1972 Jun 28;47(6):1504–1509. doi: 10.1016/0006-291X(72)90243-4. [DOI] [PubMed] [Google Scholar]
  2. Bertrand H., Ha-Duong T., Fermandjian S., Hartmann B. Flexibility of the B-DNA backbone: effects of local and neighbouring sequences on pyrimidine-purine steps. Nucleic Acids Res. 1998 Mar 1;26(5):1261–1267. doi: 10.1093/nar/26.5.1261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chaoui M., Derreumaux S., Mauffret O., Fermandjian S. An intrinsic curvature towards the minor groove in the cAMP-responsive element DNA found by combined NMR and molecular modelling studies. Eur J Biochem. 1999 Feb;259(3):877–886. doi: 10.1046/j.1432-1327.1999.00115.x. [DOI] [PubMed] [Google Scholar]
  4. Cheatham T. E., 3rd, Cieplak P., Kollman P. A. A modified version of the Cornell et al. force field with improved sugar pucker phases and helical repeat. J Biomol Struct Dyn. 1999 Feb;16(4):845–862. doi: 10.1080/07391102.1999.10508297. [DOI] [PubMed] [Google Scholar]
  5. Cheatham T. E., 3rd, Kollman P. A. Observation of the A-DNA to B-DNA transition during unrestrained molecular dynamics in aqueous solution. J Mol Biol. 1996 Jun 14;259(3):434–444. doi: 10.1006/jmbi.1996.0330. [DOI] [PubMed] [Google Scholar]
  6. Conte M. R., Lane A. N., Bloomberg G. Solution structure of the ATF-2 recognition site and its interaction with the ATF-2 peptide. Nucleic Acids Res. 1997 Oct 1;25(19):3808–3815. doi: 10.1093/nar/25.19.3808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dickerson R. E. DNA bending: the prevalence of kinkiness and the virtues of normality. Nucleic Acids Res. 1998 Apr 15;26(8):1906–1926. doi: 10.1093/nar/26.8.1906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Diekmann S. Temperature and salt dependence of the gel migration anomaly of curved DNA fragments. Nucleic Acids Res. 1987 Jan 12;15(1):247–265. doi: 10.1093/nar/15.1.247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ellenberger T. E., Brandl C. J., Struhl K., Harrison S. C. The GCN4 basic region leucine zipper binds DNA as a dimer of uninterrupted alpha helices: crystal structure of the protein-DNA complex. Cell. 1992 Dec 24;71(7):1223–1237. doi: 10.1016/s0092-8674(05)80070-4. [DOI] [PubMed] [Google Scholar]
  10. Grzeskowiak K., Yanagi K., Privé G. G., Dickerson R. E. The structure of B-helical C-G-A-T-C-G-A-T-C-G and comparison with C-C-A-A-C-G-T-T-G-G. The effect of base pair reversals. J Biol Chem. 1991 May 15;266(14):8861–8883. doi: 10.2210/pdb1d23/pdb. [DOI] [PubMed] [Google Scholar]
  11. Hai T., Curran T. Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3720–3724. doi: 10.1073/pnas.88.9.3720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hartmann B., Piazzola D., Lavery R. BI-BII transitions in B-DNA. Nucleic Acids Res. 1993 Feb 11;21(3):561–568. doi: 10.1093/nar/21.3.561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hockings S. C., Kahn J. D., Crothers D. M. Characterization of the ATF/CREB site and its complex with GCN4. Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1410–1415. doi: 10.1073/pnas.95.4.1410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hurst H. C. Transcription factors. 1: bZIP proteins. Protein Profile. 1994;1(2):123–168. [PubMed] [Google Scholar]
  15. Keller W., König P., Richmond T. J. Crystal structure of a bZIP/DNA complex at 2.2 A: determinants of DNA specific recognition. J Mol Biol. 1995 Dec 8;254(4):657–667. doi: 10.1006/jmbi.1995.0645. [DOI] [PubMed] [Google Scholar]
  16. Kim J., Struhl K. Determinants of half-site spacing preferences that distinguish AP-1 and ATF/CREB bZIP domains. Nucleic Acids Res. 1995 Jul 11;23(13):2531–2537. doi: 10.1093/nar/23.13.2531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lavery R., Parker I., Kendrick J. A general approach to the optimization of the conformation of ring molecules with an application to valinomycin. J Biomol Struct Dyn. 1986 Dec;4(3):443–462. doi: 10.1080/07391102.1986.10506361. [DOI] [PubMed] [Google Scholar]
  18. Lavery R., Sklenar H. The definition of generalized helicoidal parameters and of axis curvature for irregular nucleic acids. J Biomol Struct Dyn. 1988 Aug;6(1):63–91. doi: 10.1080/07391102.1988.10506483. [DOI] [PubMed] [Google Scholar]
  19. Lavery R., Sklenar H., Zakrzewska K., Pullman B. The flexibility of the nucleic acids: (II). The calculation of internal energy and applications to mononucleotide repeat DNA. J Biomol Struct Dyn. 1986 Apr;3(5):989–1014. doi: 10.1080/07391102.1986.10508478. [DOI] [PubMed] [Google Scholar]
  20. Lefebvre A., Fermandjian S., Hartmann B. Sensitivity of NMR internucleotide distances to B-DNA conformation: underlying mechanics. Nucleic Acids Res. 1997 Oct 1;25(19):3855–3862. doi: 10.1093/nar/25.19.3855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lefebvre A., Mauffret O., Hartmann B., Lescot E., Fermandjian S. Structural behavior of the CpG step in two related oligonucleotides reflects its malleability in solution. Biochemistry. 1995 Sep 19;34(37):12019–12028. doi: 10.1021/bi00037a045. [DOI] [PubMed] [Google Scholar]
  22. Lefebvre A., Mauffret O., Lescot E., Hartmann B., Fermandjian S. Solution structure of the CpG containing d(CTTCGAAG)2 oligonucleotide: NMR data and energy calculations are compatible with a BI/BII equilibrium at CpG. Biochemistry. 1996 Sep 24;35(38):12560–12569. doi: 10.1021/bi9606298. [DOI] [PubMed] [Google Scholar]
  23. Leonard D. A., Kerppola T. K. DNA bending determines Fos-Jun heterodimer orientation. Nat Struct Biol. 1998 Oct;5(10):877–881. doi: 10.1038/2316. [DOI] [PubMed] [Google Scholar]
  24. Lyubartsev A. P., Laaksonen A. Molecular dynamics simulations of DNA in solutions with different counter-ions. J Biomol Struct Dyn. 1998 Dec;16(3):579–592. doi: 10.1080/07391102.1998.10508271. [DOI] [PubMed] [Google Scholar]
  25. McFail-Isom L., Shui X., Williams L. D. Divalent cations stabilize unstacked conformations of DNA and RNA by interacting with base pi systems. Biochemistry. 1998 Dec 8;37(49):17105–17111. doi: 10.1021/bi982201+. [DOI] [PubMed] [Google Scholar]
  26. Paolella D. N., Liu Y., Fabian M. A., Schepartz A. Electrostatic mechanism for DNA bending by bZIP proteins. Biochemistry. 1997 Aug 19;36(33):10033–10038. doi: 10.1021/bi970515b. [DOI] [PubMed] [Google Scholar]
  27. Paolella D. N., Palmer C. R., Schepartz A. DNA targets for certain bZIP proteins distinguished by an intrinsic bend. Science. 1994 May 20;264(5162):1130–1133. doi: 10.1126/science.8178171. [DOI] [PubMed] [Google Scholar]
  28. Poncin M., Hartmann B., Lavery R. Conformational sub-states in B-DNA. J Mol Biol. 1992 Aug 5;226(3):775–794. doi: 10.1016/0022-2836(92)90632-t. [DOI] [PubMed] [Google Scholar]
  29. Rouzina I., Bloomfield V. A. DNA bending by small, mobile multivalent cations. Biophys J. 1998 Jun;74(6):3152–3164. doi: 10.1016/S0006-3495(98)78021-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ryseck R. P., Bravo R. c-JUN, JUN B, and JUN D differ in their binding affinities to AP-1 and CRE consensus sequences: effect of FOS proteins. Oncogene. 1991 Apr;6(4):533–542. [PubMed] [Google Scholar]
  31. Shui X., Sines C. C., McFail-Isom L., VanDerveer D., Williams L. D. Structure of the potassium form of CGCGAATTCGCG: DNA deformation by electrostatic collapse around inorganic cations. Biochemistry. 1998 Dec 1;37(48):16877–16887. doi: 10.1021/bi982063o. [DOI] [PubMed] [Google Scholar]
  32. Sitlani A., Crothers D. M. DNA-binding domains of Fos and Jun do not induce DNA curvature: an investigation with solution and gel methods. Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1404–1409. doi: 10.1073/pnas.95.4.1404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sloan L. S., Schepartz A. Sequence determinants of the intrinsic bend in the cyclic AMP response element. Biochemistry. 1998 May 19;37(20):7113–7118. doi: 10.1021/bi972009s. [DOI] [PubMed] [Google Scholar]
  34. Sprous D., Young M. A., Beveridge D. L. Molecular dynamics studies of axis bending in d(G5-(GA4T4C)2-C5) and d(G5-(GT4A4C)2-C5): effects of sequence polarity on DNA curvature. J Mol Biol. 1999 Jan 29;285(4):1623–1632. doi: 10.1006/jmbi.1998.2241. [DOI] [PubMed] [Google Scholar]
  35. Suzuki M., Yagi N. Stereochemical basis of DNA bending by transcription factors. Nucleic Acids Res. 1995 Jun 25;23(12):2083–2091. doi: 10.1093/nar/23.12.2083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Talanian R. V., McKnight C. J., Rutkowski R., Kim P. S. Minimum length of a sequence-specific DNA binding peptide. Biochemistry. 1992 Aug 4;31(30):6871–6875. doi: 10.1021/bi00145a002. [DOI] [PubMed] [Google Scholar]
  37. Tisné C., Hantz E., Hartmann B., Delepierre M. Solution structure of a non-palindromic 16 base-pair DNA related to the HIV-1 kappa B site: evidence for BI-BII equilibrium inducing a global dynamic curvature of the duplex. J Mol Biol. 1998 May 29;279(1):127–142. doi: 10.1006/jmbi.1998.1757. [DOI] [PubMed] [Google Scholar]
  38. Ulyanov N. B., James T. L. Statistical analysis of DNA duplex structural features. Methods Enzymol. 1995;261:90–120. doi: 10.1016/s0076-6879(95)61006-5. [DOI] [PubMed] [Google Scholar]
  39. Young M. A., Beveridge D. L. Molecular dynamics simulations of an oligonucleotide duplex with adenine tracts phased by a full helix turn. J Mol Biol. 1998 Aug 28;281(4):675–687. doi: 10.1006/jmbi.1998.1962. [DOI] [PubMed] [Google Scholar]
  40. 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. 1997 Nov;73(5):2313–2336. doi: 10.1016/S0006-3495(97)78263-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Young M. A., Ravishanker G., Beveridge D. L., Berman H. M. Analysis of local helix bending in crystal structures of DNA oligonucleotides and DNA-protein complexes. Biophys J. 1995 Jun;68(6):2454–2468. doi: 10.1016/S0006-3495(95)80427-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. de Souza O. N., Ornstein R. L. Inherent DNA curvature and flexibility correlate with TATA box functionality. Biopolymers. 1998 Nov;46(6):403–415. doi: 10.1002/(SICI)1097-0282(199811)46:6<403::AID-BIP5>3.0.CO;2-A. [DOI] [PubMed] [Google Scholar]
  43. el antri S., Bittoun P., Mauffret O., Monnot M., Convert O., Lescot E., Fermandjian S. Effect of distortions in the phosphate backbone conformation of six related octanucleotide duplexes on CD and 31P NMR spectra. Biochemistry. 1993 Jul 20;32(28):7079–7088. doi: 10.1021/bi00079a003. [DOI] [PubMed] [Google Scholar]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES