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. 1995 Jan;68(1):13–24. doi: 10.1016/S0006-3495(95)80181-5

Probability assessment of conformational ensembles: sugar repuckering in a DNA duplex in solution.

N B Ulyanov 1, U Schmitz 1, A Kumar 1, T L James 1
PMCID: PMC1281656  PMID: 7711233

Abstract

Conformational flexibility of molecules in solution implies that different conformers contribute to the NMR signal. This may lead to internal inconsistencies in the 2D NOE-derived interproton distance restraints and to conflict with scalar coupling-based torsion angle restraints. Such inconsistencies have been revealed and analyzed for the DNA octamer GTATAATG.CATATTAC, containing the Pribnow box consensus sequence. A number of subsets of distance restraints were constructed and used in the restrained Monte Carlo refinement of different double-helical conformers. The probabilities of conformers were then calculated by a quadratic programming algorithm, minimizing a relaxation rate-base residual index. The calculated distribution of conformers agrees with the experimental NOE data as an ensemble better than any single structure. A comparison with the results of this procedure, which we term PARSE (Probability Assessment via Relaxation rates of a Structural Ensemble), to an alternative method to generate solution ensembles showed, however, that the detailed multi-conformational description of solution DNA structure remains ambiguous at this stage. Nevertheless, some ensemble properties can be deduced with confidence, the most prominent being a distribution of sugar puckers with minor populations in the N-region and major populations in the S-region. Importantly, such a distribution is in accord with the analysis of independent experimental data--deoxyribose proton-proton scalar coupling constants.

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17FIGURE 1
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18FIGURE 3
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Selected References

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

  1. Baikalov I., Grzeskowiak K., Yanagi K., Quintana J., Dickerson R. E. The crystal structure of the trigonal decamer C-G-A-T-C-G-6meA-T-C-G: a B-DNA helix with 10.6 base-pairs per turn. J Mol Biol. 1993 Jun 5;231(3):768–784. doi: 10.1006/jmbi.1993.1325. [DOI] [PubMed] [Google Scholar]
  2. Bishop K. D., Blocker F. J., Egan W., James T. L. Hepatitis B virus direct repeat sequence: imino proton exchange rates and distance and torsion angle restraints from NMR. Biochemistry. 1994 Jan 18;33(2):427–438. doi: 10.1021/bi00168a006. [DOI] [PubMed] [Google Scholar]
  3. Blackledge M. J., Brüschweiler R., Griesinger C., Schmidt J. M., Xu P., Ernst R. R. Conformational backbone dynamics of the cyclic decapeptide antamanide. Application of a new multiconformational search algorithm based on NMR data. Biochemistry. 1993 Oct 19;32(41):10960–10974. doi: 10.1021/bi00092a005. [DOI] [PubMed] [Google Scholar]
  4. Borgias B. A., James T. L. Two-dimensional nuclear Overhauser effect: complete relaxation matrix analysis. Methods Enzymol. 1989;176:169–183. doi: 10.1016/0076-6879(89)76011-0. [DOI] [PubMed] [Google Scholar]
  5. Brünger A. T., Clore G. M., Gronenborn A. M., Saffrich R., Nilges M. Assessing the quality of solution nuclear magnetic resonance structures by complete cross-validation. Science. 1993 Jul 16;261(5119):328–331. doi: 10.1126/science.8332897. [DOI] [PubMed] [Google Scholar]
  6. Brüschweiler R., Blackledge M., Ernst R. R. Multi-conformational peptide dynamics derived from NMR data: a new search algorithm and its application to antamanide. J Biomol NMR. 1991 May;1(1):3–11. doi: 10.1007/BF01874565. [DOI] [PubMed] [Google Scholar]
  7. Celda B., Widmer H., Leupin W., Chazin W. J., Denny W. A., Wüthrich K. Conformational studies of d-(AAAAATTTTT)2 using constraints from nuclear overhauser effects and from quantitative analysis of the cross-peak fine structures in two-dimensional 1H nuclear magnetic resonance spectra. Biochemistry. 1989 Feb 21;28(4):1462–1471. doi: 10.1021/bi00430a006. [DOI] [PubMed] [Google Scholar]
  8. Davies D. B., Danyluk S. S. Nuclear magnetic resonance studies of 2'- and 3'-ribonucleotide structures in solution. Biochemistry. 1975 Feb 11;14(3):543–554. doi: 10.1021/bi00674a013. [DOI] [PubMed] [Google Scholar]
  9. Hagerman P. J. Flexibility of DNA. Annu Rev Biophys Biophys Chem. 1988;17:265–286. doi: 10.1146/annurev.bb.17.060188.001405. [DOI] [PubMed] [Google Scholar]
  10. Hagerman P. J. Sequence-directed curvature of DNA. Annu Rev Biochem. 1990;59:755–781. doi: 10.1146/annurev.bi.59.070190.003543. [DOI] [PubMed] [Google Scholar]
  11. Jardetzky O. On the nature of molecular conformations inferred from high-resolution NMR. Biochim Biophys Acta. 1980 Feb 27;621(2):227–232. doi: 10.1016/0005-2795(80)90174-9. [DOI] [PubMed] [Google Scholar]
  12. Kennedy M. A., Nuutero S. T., Davis J. T., Drobny G. P., Reid B. R. Mobility at the TpA cleavage site in the T3A3-containing AhaIII and PmeI restriction sequences. Biochemistry. 1993 Aug 10;32(31):8022–8035. doi: 10.1021/bi00082a025. [DOI] [PubMed] [Google Scholar]
  13. Kim Y., Prestegard J. H. A dynamic model for the structure of acyl carrier protein in solution. Biochemistry. 1989 Oct 31;28(22):8792–8797. doi: 10.1021/bi00448a017. [DOI] [PubMed] [Google Scholar]
  14. Macaya R., Wang E., Schultze P., Sklenár V., Feigon J. Proton nuclear magnetic resonance assignments and structural characterization of an intramolecular DNA triplex. J Mol Biol. 1992 Jun 5;225(3):755–773. doi: 10.1016/0022-2836(92)90399-5. [DOI] [PubMed] [Google Scholar]
  15. Mujeeb A., Kerwin S. M., Egan W., Kenyon G. L., James T. L. A potential gene target in HIV-1: rationale, selection of a conserved sequence, and determination of NMR distance and torsion angle constraints. Biochemistry. 1992 Oct 6;31(39):9325–9338. doi: 10.1021/bi00154a002. [DOI] [PubMed] [Google Scholar]
  16. Mujeeb A., Kerwin S. M., Kenyon G. L., James T. L. Solution structure of a conserved DNA sequence from the HIV-1 genome: restrained molecular dynamics simulation with distance and torsion angle restraints derived from two-dimensional NMR spectra. Biochemistry. 1993 Dec 14;32(49):13419–13431. doi: 10.1021/bi00212a007. [DOI] [PubMed] [Google Scholar]
  17. Pearlman D. A., Kollman P. A. Are time-averaged restraints necessary for nuclear magnetic resonance refinement? A model study for DNA. J Mol Biol. 1991 Jul 20;220(2):457–479. doi: 10.1016/0022-2836(91)90024-z. [DOI] [PubMed] [Google Scholar]
  18. Poltev V. I., Shulyupina N. V. Simulation of interactions between nucleic acid bases by refined atom-atom potential functions. J Biomol Struct Dyn. 1986 Feb;3(4):739–765. doi: 10.1080/07391102.1986.10508459. [DOI] [PubMed] [Google Scholar]
  19. Rinkel L. J., Altona C. Conformational analysis of the deoxyribofuranose ring in DNA by means of sums of proton-proton coupling constants: a graphical method. J Biomol Struct Dyn. 1987 Feb;4(4):621–649. doi: 10.1080/07391102.1987.10507665. [DOI] [PubMed] [Google Scholar]
  20. Schmitz U., Pearlman D. A., James T. L. Solution structure of [d(GTATATAC)]2 via restrained molecular dynamics simulations with nuclear magnetic resonance constraints derived from relaxation matrix analysis of two-dimensional nuclear Overhauser effect experiments. J Mol Biol. 1991 Sep 5;221(1):271–292. doi: 10.1016/0022-2836(91)80219-k. [DOI] [PubMed] [Google Scholar]
  21. Schmitz U., Sethson I., Egan W. M., James T. L. Solution structure of a DNA octamer containing the Pribnow box via restrained molecular dynamics simulation with distance and torsion angle constraints derived from two-dimensional nuclear magnetic resonance spectral fitting. J Mol Biol. 1992 Sep 20;227(2):510–531. doi: 10.1016/0022-2836(92)90904-x. [DOI] [PubMed] [Google Scholar]
  22. Schmitz U., Ulyanov N. B., Kumar A., James T. L. Molecular dynamics with weighted time-averaged restraints for a DNA octamer. Dynamic interpretation of nuclear magnetic resonance data. J Mol Biol. 1993 Nov 20;234(2):373–389. doi: 10.1006/jmbi.1993.1593. [DOI] [PubMed] [Google Scholar]
  23. Schmitz U., Zon G., James T. L. Deoxyribose conformation in [d(GTATATAC)]2: evaluation of sugar pucker by simulation of double-quantum-filtered COSY cross-peaks. Biochemistry. 1990 Mar 6;29(9):2357–2368. doi: 10.1021/bi00461a021. [DOI] [PubMed] [Google Scholar]
  24. Steitz T. A. Structural studies of protein-nucleic acid interaction: the sources of sequence-specific binding. Q Rev Biophys. 1990 Aug;23(3):205–280. doi: 10.1017/s0033583500005552. [DOI] [PubMed] [Google Scholar]
  25. Stolarski R., Egan W., James T. L. Solution structure of the EcoRI DNA octamer containing 5-fluorouracil via restrained molecular dynamics using distance and torsion angle constraints extracted from NMR spectral simulations. Biochemistry. 1992 Aug 11;31(31):7027–7042. doi: 10.1021/bi00146a003. [DOI] [PubMed] [Google Scholar]
  26. Torda A. E., Scheek R. M., van Gunsteren W. F. Time-averaged nuclear Overhauser effect distance restraints applied to tendamistat. J Mol Biol. 1990 Jul 5;214(1):223–235. doi: 10.1016/0022-2836(90)90157-H. [DOI] [PubMed] [Google Scholar]
  27. Trifonov E. N. Curved DNA. CRC Crit Rev Biochem. 1985;19(2):89–106. doi: 10.3109/10409238509082540. [DOI] [PubMed] [Google Scholar]
  28. Ulyanov N. B., Gorin A. A., Zhurkin V. B., Chen B. C., Sarma M. H., Sarma R. H. Systematic study of nuclear Overhauser effects vis-à-vis local helical parameters, sugar puckers, and glycosidic torsions in B DNA: insensitivity of NOE to local transitions in B DNA oligonucleotides due to internal structural compensations. Biochemistry. 1992 Apr 28;31(16):3918–3930. doi: 10.1021/bi00131a005. [DOI] [PubMed] [Google Scholar]
  29. Ulyanov N. B., Schmitz U., James T. L. Metropolis Monte Carlo calculations of DNA structure using internal coordinates and NMR distance restraints: an alternative method for generating a high-resolution solution structure. J Biomol NMR. 1993 Sep;3(5):547–568. doi: 10.1007/BF00174609. [DOI] [PubMed] [Google Scholar]
  30. Weisz K., Shafer R. H., Egan W., James T. L. Solution structure of the octamer motif in immunoglobulin genes via restrained molecular dynamics calculations. Biochemistry. 1994 Jan 11;33(1):354–366. doi: 10.1021/bi00167a046. [DOI] [PubMed] [Google Scholar]
  31. Weisz K., Shafer R. H., Egan W., James T. L. The octamer motif in immunoglobulin genes: extraction of structural constraints from two-dimensional NMR studies. Biochemistry. 1992 Aug 25;31(33):7477–7487. doi: 10.1021/bi00148a007. [DOI] [PubMed] [Google Scholar]
  32. Zhurkin V. B., Lysov Y. P., Florentiev V. L., Ivanov V. I. Torsional flexibility of B-DNA as revealed by conformational analysis. Nucleic Acids Res. 1982 Mar 11;10(5):1811–1830. doi: 10.1093/nar/10.5.1811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Zhurkin V. B., Ulyanov N. B., Gorin A. A., Jernigan R. L. Static and statistical bending of DNA evaluated by Monte Carlo simulations. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7046–7050. doi: 10.1073/pnas.88.16.7046. [DOI] [PMC free article] [PubMed] [Google Scholar]

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