Skip to main content
SpringerLink
Log in
SpringerLink
Log in

NMR Relaxation Analysis of Pharmaceutically Active Peptides

  • Living reference work entry
  • First Online:
Modern Magnetic Resonance

  • 193 Accesses

Abstract

Nuclear spin relaxation (NSR) is a powerful approach for studying dynamics at the ps-ns timescale, and is typically used to characterize fundamental biophysical phenomena such as bond vibrations and fluctuations, which affect the activity of the molecule in question. Here, this chapter will look to the application of NSR to study peptides, which are short chains of amino acids and have shown promise as modalities in drug design. This chapter will begin with a brief description of theoretical and practical aspects related to the use of NSR, such as experimental considerations during data acquisition and processing. As an example of this approach for studying peptide dynamics, this chapter will step through a case study that examines the effect of backbone cyclization on the dynamics of polycyclic disulfide-rich peptides. This case study will focus on a cyclic and linear variant of a promising drug scaffold isolated from sunflower seeds called SFTI-1 (sunflower trypsin inhibitor-1), which is a naturally backbone-cyclic peptide that comprises one cross-bracing disulfide bond.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  1. Kleckner IR, Foster MP. An introduction to NMR-based approaches for measuring protein dynamics. Biochim Biophys Acta. 2011;1814:942–68.

    Google Scholar 

  2. Palmer 3rd AG. A dynamic look backward and forward. J Magn Reson. 2016;266:73–80.

    Google Scholar 

  3. Palmer 3rd AG. Nmr probes of molecular dynamics: overview and comparison with other techniques. Annu Rev Biophys Biomol Struct. 2001;30:129–55.

    Google Scholar 

  4. Rule GS, Hitchens TK. Nuclear Spin Relaxation and Molecular Dynamics. In: Fundamentals of Protein NMR Spectroscopy. Netherlands: Springer; 2006. p. 431–74.

    Google Scholar 

  5. Choy WY, Kay LE. Probing residual interactions in unfolded protein states using NMR spin relaxation techniques: an application to delta131delta. J Am Chem Soc. 2003;125:11988–92.

    Article  Google Scholar 

  6. Horne J, d'Auvergne EJ, Coles M, Velkov T, Chin Y, Charman WN, Prankerd R, Gooley PR, Scanlon MJ. Probing the flexibility of the DsbA oxidoreductase from Vibrio cholerae--a 15N - 1H heteronuclear NMR relaxation analysis of oxidized and reduced forms of DsbA. J Mol Biol. 2007;371:703–16.

    Article  Google Scholar 

  7. Craik DJ, Fairlie DP, Liras S, Price D. The future of peptide-based drugs. Chem Biol Drug Des. 2013;81:136–47.

    Article  Google Scholar 

  8. Brady RM, Baell JB, Norton RS. Strategies for the development of conotoxins as new therapeutic leads. Mar Drugs. 2013;11:2293–313.

    Article  Google Scholar 

  9. Daly NL, Seymour J, Wilson D. Exploring the therapeutic potential of jellyfish venom. Future Med Chem. 2014;6:1715–24.

    Article  Google Scholar 

  10. Nguyen LT, Haney EF, Vogel HJ. The expanding scope of antimicrobial peptide structures and their modes of action. Trends Biotechnol. 2011;29:464–72.

    Article  Google Scholar 

  11. Porter CJ, Matthews JM, Mackay JP, Pursglove SE, Schmidberger JW, Leedman PJ, Pero SC, Krag DN, Wilce MC, Wilce JA. Grb7 SH2 domain structure and interactions with a cyclic peptide inhibitor of cancer cell migration and proliferation. BMC Struct Biol. 2007;7:58.

    Article  Google Scholar 

  12. Wang G, Drinkwater N, Drew DR, MacRaild CA, Chalmers DK, Mohanty B, Lim SS, Anders RF, Beeson JG, Thompson PE, McGowan S, Simpson JS, Norton RS, Scanlon MJ. Structure-Activity Studies of beta-Hairpin Peptide Inhibitors of the Plasmodium falciparum AMA1-RON2 Interaction. J Mol Biol. 2016;428:3986–98.

    Article  Google Scholar 

  13. Strandberg E, Horn D, Reisser S, Zerweck J, Wadhwani P, Ulrich AS. 2H-NMR and MD Simulations Reveal Membrane-Bound Conformation of Magainin 2 and Its Synergy with PGLa. Biophys J. 2016;111:2149–61.

    Article  Google Scholar 

  14. Klint JK, Chin YK, Mobli M. Rational Engineering Defines a Molecular Switch That Is Essential for Activity of Spider-Venom Peptides against the Analgesics Target NaV1.7. Mol Pharmacol. 2015;88:1002–10.

    Article  Google Scholar 

  15. Korzhnev DM, Bocharov EV, Zhuravlyova AV, Orekhov VY, Ovchinnikova TV, Billeter M, Arseniev AS. Backbone dynamics of the channel-forming antibiotic zervamicin IIB studied by 15N NMR relaxation. FEBS Lett. 2001;495:52–5.

    Article  Google Scholar 

  16. Conibear AC, Wang CK, Bi T, Rosengren KJ, Camarero JA, Craik DJ. Insights into the molecular flexibility of theta-defensins by NMR relaxation analysis. J Phys Chem B. 2014;118:14257–66.

    Article  Google Scholar 

  17. Rovo P, Straner P, Lang A, Bartha I, Huszar K, Nyitray L, Perczel A. Structural insights into the Trp-cage folding intermediate formation. Chemistry. 2013;19:2628–40.

    Article  Google Scholar 

  18. Goldenberg DP, Koehn RE, Gilbert DE, Wagner G. Solution structure and backbone dynamics of an omega-conotoxin precursor. Protein Sci. 2001;10:538–50.

    Article  Google Scholar 

  19. Peto H, Stott K, Sunde M, Broadhurst RW. Backbone dynamics of oxidised and reduced forms of human atrial natriuretic peptide. J Struct Biol. 2004;148:214–25.

    Article  Google Scholar 

  20. Rogne P, Ozdowy P, Richter C, Saxena K, Schwalbe H, Kuhn LT. Atomic-level structure characterization of an ultrafast folding mini-protein denatured state. PLoS One. 2012;7:e41301.

    Article  Google Scholar 

  21. Rawat A, Kumar D. NMR investigations of structural and dynamics features of natively unstructured drug peptide - salmon calcitonin: implication to rational design of potent sCT analogs. J Pept Sci. 2013;19:33–45.

    Article  Google Scholar 

  22. Song J, Vranken W, Xu P, Gingras R, Noyce RS, Yu Z, Shen SH, Ni F. Solution structure and backbone dynamics of the functional cytoplasmic subdomain of human ephrin B2, a cell-surface ligand with bidirectional signaling properties. Biochemistry. 2002;41:10942–9.

    Article  Google Scholar 

  23. Daly NL, Thorstholm L, Greenwood KP, King GJ, Rosengren KJ, Heras B, Martin JL, Craik DJ. Structural insights into the role of the cyclic backbone in a squash trypsin inhibitor. J Biol Chem. 2013;288:36141–8.

    Article  Google Scholar 

  24. Sher I, Chang SC, Li Y, Chhabra S, Palmer 3rd AG, Norton RS, Chill JH. Conformational flexibility in the binding surface of the potassium channel blocker ShK. Chembiochem. 2014;15:2402–10.

    Article  Google Scholar 

  25. Saez NJ, Mobli M, Bieri M, Chassagnon IR, Malde AK, Gamsjaeger R, Mark AE, Gooley PR, Rash LD, King GF. Mol Pharmacol. 2011;80:796–808.

    Article  Google Scholar 

  26. Yan Y, Wang C. J Mol Biol. 2006;364:853–62.

    Article  Google Scholar 

  27. Shalom-Elazari H, Zazrin-Greenspon H, Shaked H, Chill JH. Biochim Biophys Acta. 2014;1838:2919–28.

    Article  Google Scholar 

  28. de Medeiros LN, Angeli R, Sarzedas CG, Barreto-Bergter E, Valente AP, Kurtenbach E, Almeida FC. Biochim Biophys Acta. 2010;1798:105–13.

    Article  Google Scholar 

  29. Bader R, Bettio A, Beck-Sickinger AG, Zerbe O. J Mol Biol. 2001;305:307–29.

    Article  Google Scholar 

  30. Ingolfsson HI, Li Y, Vostrikov VV, Gu H, Hinton JF, Koeppe 2nd RE, Roux B, OS Andersen. J Phys Chem B. 2011;115:7417–26.

    Google Scholar 

  31. Yushmanov VE, Mandal PK, Liu Z, Tang P, Xu Y. Biochemistry. 2003;42:3989–95.

    Article  Google Scholar 

  32. Campbell AP, Spyracopoulos L, Wong WY, Irvin RT, Sykes BD. Biochemistry. 2003;42:11334–46.

    Article  Google Scholar 

  33. Wang M, Prorok M, Castellino FJ. Biophys J. 2010;99:302–12.

    Article  Google Scholar 

  34. Puttamadappa SS, Jagadish K, Shekhtman A, Camarero JA. Angew Chem Int Ed Eng. 2010;49:7030–4.

    Article  Google Scholar 

  35. De Paula VS, Gomes NS, Lima LG, Miyamoto CA, Monteiro RQ, Almeida FC, Valente AP. J Mol Biol. 2013;425:4479–95.

    Article  Google Scholar 

  36. Bobby R, Medini K, Neudecker P, Lee TV, Brimble MA, McDonald FJ, Lott JS, Dingley AJ. Biochim Biophys Acta. 2013;1834:1632–41.

    Article  Google Scholar 

  37. Lipari G, Szabo A. J Am Chem Soc. 1982;104:4546–59.

    Article  Google Scholar 

  38. Lipari G, Szabo A. J Am Chem Soc. 1982;104:4559–70.

    Article  Google Scholar 

  39. Meirovitch E, Shapiro YE, Polimeno A, Freed JH. Prog Nucl Magn Reson Spectrosc. 2010;56:360–405.

    Article  Google Scholar 

  40. Clore GM, Szabo A, Bax A, Kay LE, Driscoll PC, Gronenborn AM. J Am Chem Soc. 1990;112:4989–91.

    Article  Google Scholar 

  41. Schurr JM, Babcock HP, Fujimoto BS. J Magn Reson. 1994;105:211–24.

    Article  Google Scholar 

  42. Allerhand A, Doddrell D, Glushko V, Cochran DW, Wenkert E, Lawson PJ, Gurd FR. J Am Chem Soc. 1971;93:544–6.

    Article  Google Scholar 

  43. Wagner G. Q Rev Biophys. 1983;16:1–57.

    Article  Google Scholar 

  44. Nirmala NR, Wagner G. J Am Chem Soc. 1988;110:7557–8.

    Article  Google Scholar 

  45. Price WS. NMR diffusometry. In: Webb GA, editor. Modern magnetic resonance. 2006 Dordrecht: Springer. p. 109–15.

    Google Scholar 

  46. Wang CK, Northfield SE, Swedberg JE, Harvey PJ, Mathiowetz AM, Price DA, Liras S, Craik DJ. J Phys Chem B. 2014;118:11129–36.

    Article  Google Scholar 

  47. Mandel AM, Akke M, Palmer 3rd AG. J Mol Biol. 1995;246:144–63.

    Article  Google Scholar 

  48. Palmer 3rd AG, Rance M, Wright PE. J Am Chem Soc. 1991;113:4371–80.

    Article  Google Scholar 

  49. d'Auvergne EJ, Gooley PR. J Biomol NMR. 2008;40:107–19.

    Article  Google Scholar 

  50. d'Auvergne EJ, Gooley PR. J Biomol NMR. 2008;40:121–33.

    Article  Google Scholar 

  51. Wang CK, Swedberg JE, Northfield SE, Craik DJ. J Phys Chem B. 2015;119:15821–30.

    Article  Google Scholar 

  52. d'Auvergne EJ, Gooley PR. J Biomol NMR. 2003;25:25–39.

    Article  Google Scholar 

  53. Clark RJ, Jensen J, Nevin ST, Callaghan BP, Adams DJ, Craik DJ. Angew Chem Int Ed Eng. 2010;49:6545–8.

    Article  Google Scholar 

  54. Wang CK, Northfield SE, Colless B, Chaousis S, Hamernig I, Lohman RJ, Nielsen DS, Schroeder CI, Liras S, Price DA, Fairlie DP, Craik DJ. Proc Natl Acad Sci USA. 2014;111:17504–9.

    Article  Google Scholar 

  55. Zorzi A, Deyle K, Heinis C. Curr Opin Chem Biol. 2017;38:24–9.

    Article  Google Scholar 

  56. Veber DF, Freidlinger RM, Perlow DS, Paleveda Jr WJ, Holly FW, Strachan RG, Nutt RF, Arison BH, Homnick C, Randall WC, Glitzer MS, Saperstein R, Hirschmann R. Nature. 1981;292:55–8.

    Article  Google Scholar 

  57. Luckett S, Garcia RS, Barker JJ, Konarev AV, Shewry PR, Clarke AR, Brady RL. J Mol Biol. 1999;290:525–33.

    Article  Google Scholar 

  58. Northfield SE, Wang CK, Schroeder CI, Durek T, Kan MW, Swedberg JE, Craik DJ. Eur J Med Chem. 2014;77:248–57.

    Article  Google Scholar 

  59. Wang CK, King GJ, Northfield SE, Ojeda PG, Craik DJ. Angew Chem Int Ed Eng. 2014;53:11236–41.

    Article  Google Scholar 

  60. Ortega A, Amoros D, Garcia de la Torre J. Biophys J. 2011;101:892–8.

    Article  Google Scholar 

  61. Vranken WF, Boucher W, Stevens TJ, Fogh RH, Pajon A, Llinas M, Ulrich EL, Markley JL, Ionides J, Laue ED. Proteins. 2005;59:687–96.

    Article  Google Scholar 

  62. Korsinczky ML, Schirra HJ, Rosengren KJ, West J, Condie BA, Otvos L, Anderson MA, Craik DJ. J Mol Biol. 2001;311:579–91.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia

    Conan K. Wang

Authors
  1. Conan K. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Conan K. Wang .

Editor information

Editors and Affiliations

  1. Royal Society of Chemistry, London, United Kingdom

    Graham A. Webb

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this entry

Cite this entry

Wang, C.K. (2017). NMR Relaxation Analysis of Pharmaceutically Active Peptides. In: Webb, G. (eds) Modern Magnetic Resonance. Springer, Cham. https://doi.org/10.1007/978-3-319-28275-6_115-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-28275-6_115-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-28275-6

  • Online ISBN: 978-3-319-28275-6

  • eBook Packages: Springer Reference Chemistry and Mat. ScienceReference Module Physical and Materials ScienceReference Module Chemistry, Materials and Physics

Publish with us

Policies and ethics

Search

Navigation