The Generation of Three-Dimensional Structures from NMR-Derived Constraints

  • Denise D. Beusen
  • Garland R. Marshall
Part of the NATO ASI Series book series (NSSA, volume 183)


NMR is capable of providing many types of information about ligands, macromolecules, and their complexes. In recent years, the generation of solution structures based on NMR observations has become widespread. While these methods hold the promise of providing nearly as precise information for molecules in solution as X-ray methods do for crystals, they differ from X-ray in that the experimental observations do not reveal the ensemble of positions of all the heavy atoms, but rather the distances between certain pairs of atoms. Consequently, one needs to find tools that enable transformation from a set of pairwise distances [distance space] to Cartesian coordinate space in order to build usable structural models. These tools rely on an existing body of knowledge that describes reasonable geometries for covalently bonded atoms in amino acids and nucleotides. Most methods currently in use have their roots in molecular modeling, where computational methods have been developed to study the conformation of molecules and the relationship of conformation to biological activity.


Distance Constraint Nuclear Overhauser Effect Distance Geometry Bovine Pancreatic Trypsin Inhibitor Protein Structure Determination 
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. Barry, C.D., North, A.C.T., Glasel, J.A., Williams, R.J.P. and Xavier, A.V., 1971, Nature 232:236.ADSCrossRefGoogle Scholar
  2. Bassolino, D.A., Hirata, F., Kitchen, D.B., Kominos, D., Pardi, A. and Levy, R.M., 1988, Determination of protein structures in solution using NMR data and impact, Int. J. Supercomputer Applications 2:41.CrossRefGoogle Scholar
  3. Beusen, D.D., Iijima, H. and Marshall, G.R., Structures from NMR distance constraints, Biochem. Pharm., in press.Google Scholar
  4. Billeter, M., Havel, T.F. and Wiithrich, K., 1987, The ellipsoid algorithm as a method for the determination of polypeptide conformations from experimental distance constraints and energy minimization, J. Comp. Chem. 8:132.CrossRefGoogle Scholar
  5. Boelens, R., Koning, T.M.G., van der Marel, G.A., van Boom, J.H. and Kaptein, R., 1989, Iterative procedure for structure determination from proton-proton NOEs using a full relaxation matrix approach. Application to a DNA octamer, J. Magn. Resort. 82:290.Google Scholar
  6. Borgias, B.A. and James, T.L., 1988, COMATOSE, a method for constrained refinement of macromolecular structure based on two-dimensional nuclear Overhauser effect spectra, J. Magn. Resort. 79:493.Google Scholar
  7. Braun, W., 1987, Distance geometry and related methods for protein structure determination from NMR data, Quarterly Reviews of Biophysics 19:115.CrossRefGoogle Scholar
  8. Braun, W. and Go, N., 1985, Calculation of protein conformations by proton-proton distance constraints, J. Mol. Biol. 186:611.CrossRefGoogle Scholar
  9. Braun, W., Bosch, C., Brown, L.R., Go, N. and Wiithrich, K., 1981, Combined use of proton-proton Overhauser enhancements and a distance geometry algorithm for determination of polypeptide conformations, Biochim. Biophys. Acta 667:377.CrossRefGoogle Scholar
  10. Braun, W., Wagner, G., Wörgötter, E., Vasak, M., Kagi, J. and Wiithrich, K., 1985, J. Mol Biol. 186:611.CrossRefGoogle Scholar
  11. Brinkley, J.F., Altman, R.B., Duncan, B.S., Buchanan, B.G. and Jardetzky, O., 1988, Heuristic refinement method for the derivation of protein solution structures: Validation on cytochrome b562, J. Chem. Inf. Comput. Sci. 28:194.CrossRefGoogle Scholar
  12. Clore, G.M. and Gronenborn, A.M., 1987, Determination of three-dimensional structures of proteins in solution by nuclear magnetic resonance spectroscopy, Prot. Eng. 1:275.CrossRefGoogle Scholar
  13. Clore, G.M., Brünger, A.T., Karplus, M. and Gronenborn, A.M., 1986, Application of molecular dynamics with interproton distance restraints to three-dimensional protein structure determination, J. Mol. Biol. 191:523.CrossRefGoogle Scholar
  14. Clore, G.M., Nilges, M., Brünger, A.T., Karplus, M. and Gronenborn, A.M., 1987a, A comparison of the restrained molecular dynamics and distance geometry methods for determining three-dimensional structures of proteins on the basis of interproton distances, FEBS Lett. 213:269.CrossRefGoogle Scholar
  15. Clore, G.M., Sukumaran, D.K., Nilges, M., Zarbock, J. and Gronenborn, A.M., 1987b, The conformations of hirudin in solution: A study using nuclear magnetic resonance, distance geometry and restrained molecular dynamics, EMBO J. 6:529.Google Scholar
  16. Cung, M.T. and Marraud, M., 1982, Conformational dependence of the vicinal proton coupling constant for the Ca-Cß bond in peptides, Biopolymers 21:953.CrossRefGoogle Scholar
  17. DeMarco, A., Llinas, M. and Wiithrich, K., 1978, Analysis of the H — NMR spectra of ferrichrome peptides. I. The non-amide protons, Biopolymers 17:617.CrossRefGoogle Scholar
  18. Furey, W.F., Robbins, A.H., Clancy, L.L., Winge, D.R., Wand, B.C. and Stout, C.D., 1986, Science 231:704.ADSCrossRefGoogle Scholar
  19. Gullion, T. and Schaefer, J., 1989, Rotational-echo double-resonance NMR, J. Magn. Reson. 81:196.Google Scholar
  20. Havel, T. and Wiithrich, K., 1984, A distance geometry program for determining the structures of small proteins and other macromolecules from nuclear magnetic resonance measurements of intramolecular H-H proximities in solution, Bull. Math. Biol. 46:673.MATHGoogle Scholar
  21. Havel, T. and Wiithrich, K., 1985, An evaluation of the combined use of nuclear magnetic resonance and distance geometry for the determination of protein conformation in solution, J. Mol. Biol. 182:281.CrossRefGoogle Scholar
  22. Havel, T.F., Kuntz, I.D. and Crippen, G.M., 1983, The theory and practice of distance geometry, Bull. Math. Biol. 45:665.MathSciNetMATHGoogle Scholar
  23. Hendrickson, W.A., 1989, NMR structural analysis from the perspective of a protein crystallographer, J. Cell. Biochem. 13A:12.Google Scholar
  24. Holak, T.A., Prestegard, J.H. and Forman, J.D., 1987, NMR-Pseudoenergy approach to the solution structure of acyl carrier protein, Biochemistry 26:4652.CrossRefGoogle Scholar
  25. Iijima, H., Dunbar, J.B., Jr. and Marshall, G.R., 1987, The calibration of effective van der Waals atomic contact radii for proteins and peptides, Proteins: Struct. Funct. Genet. 2:330.CrossRefGoogle Scholar
  26. Jardetzky, O., 1980, On the nature of molecular conformations inferred from high-resolution NMR, Biochim.Biophys.Acta 621:227.CrossRefGoogle Scholar
  27. Karplus, M., 1959, Contact electron-spin coupling of nuclear magnetic moments, J. Chem. Phys. 30:11.ADSCrossRefGoogle Scholar
  28. Karplus, M., 1963, Vicinal proton coupling in nuclear magnetic resonance, J. Am. Chem. Soc. 85:2870.CrossRefGoogle Scholar
  29. Keepers, J.W. and James, T.L., 1984, A theoretical study of distance determinations from NMR two-dimensional nuclear Overhauser effect spectra, J. Magn. Reson. 57:404.Google Scholar
  30. Kessler, H., Loosli, H.R., Oschkinat, H. and Widmer, A., 1985, Assignment of the 1H-, 13C-and 15N-NMR spectra of cyclosporin A in CDCl3 and C6D6 by a combination of homo- and heteronuclear two-dimensional techniques, Helv. Chim. Acta 68:661.CrossRefGoogle Scholar
  31. Kessler, H., Griesinger, C. and Wagner, K., 1987, Peptide conformations. 42. Conformation of side chains in peptides using heteronuclear coupling constants obtained by two-dimensional NMR spectroscopy, J. Am. Chem. Soc. 109:6927.CrossRefGoogle Scholar
  32. Kopple, K.D., Wiley, G.R. and Tauke, R., 1973, A dihedral angle-vicinal proton coupling constant correlation for the a-ß bond of amino acid residues, Biopolymers 12:627.CrossRefGoogle Scholar
  33. Lautz, J., Kessler, H., Kaptein, R. and van Gunsteren, W.F., 1987, Molecular dynamics simulation of cyclosporin A: The crystal structure and dynamic modelling of a structure in apolar solution based on NMR data, J. Comput.-Aided Mol. Design 1:219.ADSCrossRefGoogle Scholar
  34. Loosli, H.R., Kessler, H., Oschkinat, H., Weber, H.-P., Petcher, T.J. and Widmer, A., 1985, The conformation of cyclosporin A in the crystal and in solution, Helv. Chim. Acta 68:682.CrossRefGoogle Scholar
  35. Marshall, G.R., Beusen, D.D., Kociolek, K., Redlinski, A.S., Leplawy, M.T., Pan, Y. and Schaefer, J., Determination of a precise interatomic distance in a helical peptide by REDOR NMR, J. Am. Chem. Soc., in press.Google Scholar
  36. McCammon, J.A. and Harvey, S.C., 1987, “Dynamics of Proteins and Nucleic Acids,” Cambridge University Press, Cambridge, UK.CrossRefGoogle Scholar
  37. Mildvan, A.S., 1989, NMR studies of the interaction of substrates with enzymes and their peptide fragments, FASEB J. 3:1705.Google Scholar
  38. Mildvan, A.S. and Gupta, R.K., 1978, Nuclear relaxation measurements of the geometry of enzyme-bound substrates and analogues, Methods Enzymol. 49G:322.CrossRefGoogle Scholar
  39. Montelione, G.T., Winkler, M.E., Rauenbuehler, P. and Wagner, G., 1989, Accurate measurements of long-range heteronuclear coupling constants from homonuclear 2D NMR spectra of isotope-enriched proteins, J. Magn. Reson. 82:198.Google Scholar
  40. Nikiforovich, G.V., Vesterman, B.G. and Betins, J., 1988, Combined use of spectroscopic and energy calculation methods for the determination of peptide conformation in solution, Biophys. Chem. 31:101.CrossRefGoogle Scholar
  41. Nilges, M., Clore, G.M. and Gronenborn, A.M., 1988, Determination of three-dimensional structures of proteins from interproton distance data by hybrid distance geometry-dynamical simulated annealing calculations, FEBS Lett. 229:317.CrossRefGoogle Scholar
  42. Noggle, J.H. and Schirmer, R.E., 1971, “The Nuclear Overhauser Effect,” Academic Press, New York.Google Scholar
  43. Pardi, A., Billeter, M. and Wüthrich, K., 1984, Calibration of the angular dependence of the amide proton-Ca proton coupling constants in a globular protein, J. Mol. Biol. 180:741.CrossRefGoogle Scholar
  44. Pardi, A., Hare, D.R. and Wang, G., 1988, Determination of DNA structures by NMR and distance geometry techniques: A computer simulation, Proc. Natl. Acad. Sci. USA 85:8785.ADSCrossRefGoogle Scholar
  45. Patel, D.J., Shapiro, L. and Hare, D., 1987, Nuclear magnetic resonance and distance geometry studies of DNA structures in solution, Ann. Rev. Biophys. Biophys. Chem. 16:423.CrossRefGoogle Scholar
  46. Petcher, T.J., Weber, H.-P. and Ruegger, A., 1976, Crystal and molecular structure of an iodo-derivative of the cyclic undecapeptide cyclosporin A, Helv. Chim. Acta 59:1480.CrossRefGoogle Scholar
  47. Summer, M.F., Hare, D., South, T.L. and Kim, B., 1989, Structure of a retroviral zinc finger: 2D NMR spectroscopy and distance geometry calculations on a synthetic finger from HIV-1 nucleic acid binding protein, p7, J. Cell. Biochem. 13A:17.Google Scholar
  48. Vasquez, M. and Scheraga, H.A., 1988, Calculation of protein conformation by the build-up procedure. Application to bovine pancreatic trypsin inhibitor using limited simulated nuclear magnetic resonance data, J. Biomol. Struct. Dynamics 5:705.CrossRefGoogle Scholar
  49. Wagner, G., Braun, W., Havel, T.F., Schaumann, T., Go, N. and Wüthrich, K., 1987, Protein structures in solution by nuclear magnetic resonance and distance geometry — The polypeptide fold of the basic pancreatic trypsin inhibitor determined using two different algorithms, DISGEO and DISMAN, J. Mol. Biol. 196:611.CrossRefGoogle Scholar
  50. Wüthrich, K., 1986, “NMR of Proteins and Nucleic Acids,” John Wiley and Sons, New York.Google Scholar
  51. Wüthrich, K., 1989a, Protein structure determination in solution by nuclear magnetic resonance spectroscopy, Science 243:45.ADSCrossRefGoogle Scholar
  52. Wüthrich, K., 1989b, The development of nuclear magnetic resonance spectroscopy as a technique for protein structure determination, Ace. Chem. Res. 22:36.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • Denise D. Beusen
    • 1
  • Garland R. Marshall
    • 1
  1. 1.Center for Molecular DesignWashington UniversitySt. LouisUSA

Personalised recommendations