Computer-Aided Conformational Analysis Based on NOESY Signal Intensities

  • Niels H. Andersen
  • Xiaonian Lai
  • Philip K. Hammen
  • Thomas M. Marschner
Part of the Basic Life Sciences book series (BLSC, volume 56)


The basis for the development of a suite of programs that allow the user to determine motional features (the correlation time and the significance of segmental motion) and the optimum conditions for future experiments from a NOESY signal matrix is presented. This automated evaluation of NOESY data serves as the initial step of an iterative conformational analysis which uses the molecular model manipulation capabilities of modern graphics workstations. Incorporated in these programs is NOESYSIM, a calculation subroutine which uses a set of molecular coordinates (and a correlation time estimate) together with user entered experimental parameters (acquisition time, sweep width, mixing time and cycle repetition time) to generate an accurately calculated NOESY signal matrix reflecting those conditions and the specified conformational model. Conformational refinement then consists of iterative comparisons of the experimental signal matrix with a series (or systematically sampled set) of model coordinates corresponding to a dynamics’ course, driven-minimization or torsional grid search. These procedures and developments are illustrated with examples including: solution conformations of prostanoids; studies of the folding preferences and media-dependent changes in conformation for peptide hormones; and the structure elucidation of a novel undecapeptide macrolide antibiotic (lysobactin). For larger molecules, even constrained grid searches have too high a dimensionality and one must resort to distance-constraint based minimizations. A novel procedure for deriving more accurate distance constraints (corrected for secondary NOEs) is detailed and a new strategy for conformation elucidation, based on this procedure, is outlined.


Segmental Motion NOESY Spectrum Distance Constraint Signal Matrix Nuclear Overhauser Effect 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    K. Wüthrich, 1986, NMR of Proteins and Nucleic Acids, John Wiley & Sons, New YorkGoogle Scholar
  2. 1a.
    R. Kaptein, R. Boelens, R. M. Scheek, and W. F. van Gunsteren, 1988, Biochemistry, 27:5389.PubMedCrossRefGoogle Scholar
  3. 2.
    R. E. Schirmer, and J. H. Noggle, 1972, J. Am. Chem. Soc., 94:2947, and references cited therein.CrossRefGoogle Scholar
  4. 3.a)
    G. M. Clore, and A. M. Gronenborn, 1985, J. Magn. Reson., 61:158Google Scholar
  5. 3.b)
    A. M. Gronenborn, and G. M. Clore, 1985, Investigation of the solution structure of short nucleic acid fragments by means of NOE measurements, in: “Prog, in Nuclear Magnetic Resonance Spectroscopy,” (J. W. Emsley, J. Feeney, and L. H. Sutcliffe, eds.), Pergamon, Oxford.Google Scholar
  6. 4a).
    J. W. Keepers, and T. L. James, 1984, J. Magn. Reson., 57:404Google Scholar
  7. 4b).
    E. T. Olejniczak, R. T. Gampe, Jr., and S. W. Fesik, 1986, J. Magn. Reson., 67:28Google Scholar
  8. 4c).
    B. A. Borgias, and T. L. James, J. Mag. Reson., in pressGoogle Scholar
  9. 4d).
    R. Boelens, T. M. G. Koning, and R. Kaptein, 1988, J. Molecular Struc., 173:299.CrossRefGoogle Scholar
  10. 5.
    A. Kalk, and H. J. C. Berendsen, 1976, J. Magn. Reson., 24:343.Google Scholar
  11. 6.
    I. Solomon, 1955, Phys. Rev., 99:559.CrossRefGoogle Scholar
  12. 7.
    S. Macura, and R. R. Ernst, 1980, Mol. Phys., 41:95.CrossRefGoogle Scholar
  13. 8a).
    S. W. Fesik, G. Bolis, H. L. Sham, and E. T. Olejniczak, 1987, Biochemistry, 26:1851PubMedCrossRefGoogle Scholar
  14. 8b).
    ANF -E. T. Olejniczak, R. T. Gampe, Jr., T. W. Rockway, and S. W. Fesik, 1988, Biochemistry, 27:7124PubMedCrossRefGoogle Scholar
  15. 8c).
    P. A. Mirau, 1986, 27th Experimental NMR Conference, Asilomar CA, poster WK12.Google Scholar
  16. 9a).
    M. P. Williamson, 1987, Magn. Reson. in Chem., 25:356CrossRefGoogle Scholar
  17. 9b).
    J. F. Lefevre, A. N. Lane, and O. Jardetzky, 1987, Biochemistry 26:5076PubMedCrossRefGoogle Scholar
  18. 9c).
    M. Madrid, and O. Jardetzky, 1988, Biochimica et Biophysica Acta, 953:61PubMedCrossRefGoogle Scholar
  19. 10.
    This distinction between small and large molecule systems has long been recognized, but the 2D disadvantage for small molecules was mistakenly overstated: J. K. M. Sanders, and J. D. Mersh, 1982, Prog. in NMR Spetroscopy, 15:353.CrossRefGoogle Scholar
  20. 11.
    N. H. Andersen, H. L. Eaton, and C. Lai, “Quantitative Small olecule NOESY: A Practical Guide for Derivation of Cross-Relaxation Rates and Internuclear Distances,” Magn. Res. in Chem., in press.Google Scholar
  21. 12.
    M. P. Williamson, and D. Neuhaus, 1987, J. Magn. Reson., 72:369Google Scholar
  22. 12a.
    O. W. Sorensen, C. Griesinger, and R. R. Ernst, 1987, Chemical Phys. Letters, 135:313.CrossRefGoogle Scholar
  23. 13.a)
    N. H. Andersen, K. T. Nguyen, C. J. Hartzell, and H. L. Eaton, 987, J. Magn. Reson., 74:195Google Scholar
  24. 13.b)
    H. L. Eaton, and N. H. Andersen, 1987, J. Magn. Reson., 74:212.Google Scholar
  25. 14.
    H. L. Eaton, N. H. Anderson, and X. Lai, “Recent Extensions of OESYSIM, A Program for Rapid Computation of NOESY Intensity Matrices from Atomic Coordinates and Experimental Conditions,” paper #112, 29th ENC (4/88; Rochester, N.Y.).Google Scholar
  26. 15.
    S. Macura, B. T. Farmer, II, and L. R. Brown, 1986, J. Magn. Reson., 70:493.Google Scholar
  27. 16a).
    J. Bremer, G. L. Mendz, and W. J. Moore, 1984, J. Amer. Chem. oc., 106:4691CrossRefGoogle Scholar
  28. 16b).
    C. L. Perrin, and R. F. Gipe, 1984, J. Amer. Chem. Soc., 106:4036CrossRefGoogle Scholar
  29. 16c).
    E. R. Johnston, M. T. Dellwo, and J. Hendrix, 1986, J. Magn. Reson., 66:399Google Scholar
  30. 16d).
    S. W. Fesik, T. J. O’Donnell, R. T. Gampe, Jr., and E. T. Olehniczak, 1986, J. Amer. Chem. Soc., 108:3165.CrossRefGoogle Scholar
  31. 17.
    DISGE0 is a metric matrix distance geometry program [T. F. Havel, D. Kuntz, and G. M. Crippen, 1979, Biopolymers, 18:73; 1983, Bull. Math. Biol., 45:665]CrossRefGoogle Scholar
  32. 17a.
    T. F. Havel, and K. Wüthrich, 1984, Bull. Math. Biol., 46:673; 1985, J. Mol. Biol. 182:281.Google Scholar
  33. 18.a)
    a) W. Braun, and Go, N., 1985, J. Mol. Biol., 186:611PubMedCrossRefGoogle Scholar
  34. 18.b)
    program ISMAN -A. D. Kline, W. Braun, and K. Wüthrich, 1986, J. Mol. Biol., 189:377.PubMedCrossRefGoogle Scholar
  35. 19.
    T. A. Holak, J. H. Prestegard, and J. D. Forman, 1987, Biochemistry, 6:4652.CrossRefGoogle Scholar
  36. 20.
    The CHARMm MM and dynamics program was developed by M. Karplus, and ssociates [Brooks et al., 1983, J. Comput. Chem, 4:187]CrossRefGoogle Scholar
  37. 20a.
    G. M. Clore, A. M. Gronenborn, A. T. Brunger, and M. Karplus, 1985, J. Mol. Biol., 186:435PubMedCrossRefGoogle Scholar
  38. 20b.
    G. M. Clore, A. M. Gronenborn, G. Carlson, and E. F. Meyer, 1986, J. Mol. Biol., 190:259.PubMedCrossRefGoogle Scholar
  39. 21.
    M. Nilges, G. M. Clore, and A. M. Gronenborn, 1988, FEBS Letters, 29:317.CrossRefGoogle Scholar
  40. 22.
    E. Suzuki, N. Pattabiraman, G. Zon, and T. L. James, 1986, iochemistry, 25:6854CrossRefGoogle Scholar
  41. 22a.
    N. Zhou, A. M. Bianucci, N. Pattabiraman, and T. L. James, 1987, ibid, 26:7905Google Scholar
  42. 22b.
    V. J. Basus, M. Billeter, R. A. Love, R. M. Stroud, and I. D. Kuntz, 1988, Biochemistry, 27:2763.PubMedCrossRefGoogle Scholar
  43. 23.
    B. A. Borgias, and T. L. James, Methods in Enzymology in press.Google Scholar
  44. 24.a)
    N. H. Andersen, H. L. Eaton, and K. T. Nguyen, 1987, Magn. Reson. n Chem., 25:1025CrossRefGoogle Scholar
  45. 24.b)
    N. H. Andersen, H. L. Eaton, K. T. Nguyen, and P. Hammen, 1987, Adv. Prostaglandin Thromboxane and Leukotriene Res., 17:794.Google Scholar
  46. 25.
    N. H. Andersen, P. Hammen, K. Banks, M. A. Porubcan, and A. A. ymiak, ACS Nat’l Mtg, Denver (4/87), Abstracts, paper 0RGN-57; b) N. H. Andersen, P. Hammen, K. Banks, T. Pratum, M. A. Porubcan, and A. A. Tymiak, J. Am. Chem. Soc., submitted.Google Scholar
  47. 26.
    P. W. Sprague, J. E. Heikes, D. N. Harris, and R. Greenberg, 1983, dv. Prostaglandin Thromboxane and Leukotriene Res., 11:337.Google Scholar
  48. 27a).
    O. Jardetzky, 1980, Biochem. Biophys. Acta, 621:227PubMedGoogle Scholar
  49. 27b).
    A. Marqusee, and R. L. Baldwin, 1987, Proc. Natl. Acad. Sci., USA, 84:8898PubMedCrossRefGoogle Scholar
  50. 27c).
    S. Mammi, N. J. Mammi, and E. Peggion, 1988, Biochemistry, 27:1374PubMedCrossRefGoogle Scholar
  51. 27d).
    N. Zhou, and W. A. Gibbons, 1986, J. Chem Soc. Perkin Traus. II, 637.CrossRefGoogle Scholar
  52. 28.
    K. V. Chary, S. Srivastava, R. V. Hosur, K. B. Roy, and G. Govil, 1986, Eur. J. Biochem., 158:323.PubMedCrossRefGoogle Scholar
  53. 29.
    A. A. Tymiak, T. J. McCormick, and S. E. Unger, 193rd Nat’l Mtg. of Amer. Chem. Soc. (Denver, 4/87), Abstracts, paper 0RGN-56; b) A. A. Tymiak, T. J. McCormick, and S. E. Unger, J. Org. Chem., submitted.Google Scholar
  54. 30.
    M. P. Williamson, T. F. Havel, and K. Wüthrich, 1985, J. Mol. Biol., 182:295PubMedCrossRefGoogle Scholar
  55. 30a.
    J. M. Moore, D. A. Case, W. J. Chazin, G. P. Gippert, T. F. Havel, R. Powls, and P. E. Wright, 1988, Science, 240:314PubMedCrossRefGoogle Scholar
  56. 30b.
    G. M. Clore, A. M. Gronenborn, M. Nilges, and C. A. Ryan, 1987, Biochemistry, 26:8012PubMedCrossRefGoogle Scholar
  57. 31.
    Katanosin B appears to be identical to lysobactin, it was recently assigned a similar structure, differing in being the [D-Arg, D-allo-Thr]-form: T. Kato, H. Hinoo, Y. Terui, J. Kikuchi, and J. Shoji, 1988, J. Antibiotics, XLI:719.CrossRefGoogle Scholar
  58. 32.
    Model 3 is the L-allo-Thr form. To date, our less extensive attempts to carry-out a similar sequence of refinement using a [D-allo-Thr]-fragment(7-ll) unit have failed to afford cyclic models which fit the NMR data.Google Scholar
  59. 33.a)
    T. K. Pratum, P. K. Hammen, and N. H. Andersen, 1988, paper #140, 29th E.N.C., Rochester, NY (4/88)Google Scholar
  60. 33.b)
    T. K. Pratum, P. K. Hammen, and N. H. Andersen, 1988, J. Magn. Reson., 78:376.Google Scholar
  61. 34.
    A distance geometry program from Hare Research, Inc. -for recent applications see: A. Pardi, D. R. Hare, M. E. Selsted, R. D. Morrison, D. A. Bassolino, and A. C. Bach, II, 1988, J. Mol. Biol., 201:625PubMedCrossRefGoogle Scholar
  62. 34a.
    W. Nerdal, D. R. Hare, and B. R. Reid, 1988, ibid, 717Google Scholar
  63. 34b.
    J. H. B. Pease, and D. E. Wemmer, 1988, Biochemistry, 27:8491, -the last gives a more detailed description of the program.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • Niels H. Andersen
    • 1
  • Xiaonian Lai
    • 1
  • Philip K. Hammen
    • 1
  • Thomas M. Marschner
    • 1
  1. 1.Department of ChemistryUniversity of WashingtonSeattleUSA

Personalised recommendations