Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Shaping quaternary assemblies of water-soluble non-peptide helical foldamers by sequence manipulation

Nature Chemistry volume 7, pages 871–878 (2015)Cite this article

Subjects

Abstract

The design and construction of biomimetic self-assembling systems is a challenging yet potentially highly rewarding endeavour that contributes to the development of new biomaterials, catalysts, drug-delivery systems and tools for the manipulation of biological processes. Significant progress has been achieved by engineering self-assembling DNA-, protein- and peptide-based building units. However, the design of entirely new, completely non-natural folded architectures that resemble biopolymers (‘foldamers’) and have the ability to self-assemble into atomically precise nanostructures in aqueous conditions has proved exceptionally challenging. Here we report the modular design, formation and structural elucidation at the atomic level of a series of diverse quaternary arrangements formed by the self-assembly of short amphiphilic α-helicomimetic foldamers that bear proteinaceous side chains. We show that the final quaternary assembly can be controlled at the sequence level, which permits the programmed formation of either discrete helical bundles that contain isolated cavities or pH-responsive water-filled channels with controllable pore diameters.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Quaternary assemblies formed from short water-soluble oligourea foldamers.
Figure 2: Solution and solid-state studies of the formation of the oligourea helical bundle.
Figure 3: Solution and solid-state studies of channel-forming oligourea foldamers H2 and H5.
Figure 4: Control of the quaternary arrangement of oligourea foldamers through manipulation of the primary sequence.

Similar content being viewed by others

References

  1. Zhang, F., Nangreave, J., Liu, Y. & Yan, H. Structural DNA nanotechnology: state of the art and future perspective. J. Am. Chem. Soc. 136, 11198–11211 (2014).

    Article  CAS  Google Scholar 

  2. Lai, Y.-T., King, N. P. & Yeates, T. O. Principles for designing ordered protein assemblies. Trends Cell Biol. 22, 653–661 (2012).

    Article  CAS  Google Scholar 

  3. King, N. P. et al. Computational design of self-assembling protein nanomaterials with atomic level accuracy. Science 336, 1171–1174 (2012).

    Article  CAS  Google Scholar 

  4. Lai, Y.-T., Cascio, D. & Yeates, T. O. Structure of a 16-nm cage designed by using protein oligomers. Science 336, 1129 (2012).

    Article  CAS  Google Scholar 

  5. Gradišar, H. & Jerala, R. Self-assembled bionanostructures: proteins following the lead of DNA nanostructures. J. Nanobiotechnol. 12, 4 (2014).

    Article  Google Scholar 

  6. Lai, Y.-T. et al. Structure of a designed protein cage that self-assembles into a highly porous cube. Nature Chem. 6, 1065–1071 (2014).

    Article  CAS  Google Scholar 

  7. King, N. P. et al. Accurate design of co-assembling multi-component protein nanomaterials. Nature 510, 103–108 (2014).

    Article  CAS  Google Scholar 

  8. Fletcher, J. M. et al. Self-assembling cages from coiled-coil peptide modules. Science 340, 595–599 (2013).

    Article  CAS  Google Scholar 

  9. Tebo, A. G. & Pecoraro, V. L. Artificial metalloenzymes derived from three-helix bundles. Curr. Opin. Chem. Biol. 25C, 65–70 (2015).

    Article  Google Scholar 

  10. Gradišar, H. et al. Design of a single-chain polypeptide tetrahedron assembled from coiled-coil segments. Nature Chem. Biol. 9, 362–366 (2013).

    Article  Google Scholar 

  11. Bromley, E. H. C., Channon, K., Moutevelis, E. & Woolfson, D. N. Peptide and protein building blocks for synthetic biology: from programming biomolecules to self-organized biomolecular systems. ACS Chem. Biol. 3, 38–50 (2008).

    Article  CAS  Google Scholar 

  12. Gellman, S. H. Foldamers: a manifesto. Acc. Chem. Res. 31, 173–180 (1998).

    Article  CAS  Google Scholar 

  13. Goodman, C. M., Choi, S., Shandler, S. & DeGrado, W. F. Foldamers as versatile frameworks for the design and evolution of function. Nature Chem. Biol. 3, 252–262 (2007).

    Article  CAS  Google Scholar 

  14. Guichard, G. & Huc, I. Synthetic foldamers. Chem. Commun. 47, 5933–5941 (2011).

    Article  CAS  Google Scholar 

  15. Johnson, L. M. & Gellman, S. H. α-Helix mimicry with α/β-peptides. Methods Enzymol. 523, 407–429 (2013).

    Article  CAS  Google Scholar 

  16. Frackenpohl, J., Arvidsson, P. I., Schreiber, J. V. & Seebach, D. The outstanding biological stability of β- and λ-peptides toward proteolytic enzymes: an in vitro investigation with fifteen peptidases. ChemBioChem 2, 445–455 (2001).

    Article  CAS  Google Scholar 

  17. Daniels, D. S., Petersson, E. J., Qiu, J. X. & Schepartz, A. High-resolution structure of a β-peptide bundle. J. Am. Chem. Soc. 129, 1532–1533 (2007).

    Article  CAS  Google Scholar 

  18. Wang, P. S. P., Nguyen, J. B. & Schepartz, A. Design and high-resolution structure of a β3-peptide bundle catalyst. J. Am. Chem. Soc. 136, 6810–6813 (2014).

    Article  CAS  Google Scholar 

  19. Pizzey, C. L. et al. Characterization of nanofibers formed by self-assembly of β-peptide oligomers using small angle X-ray scattering. J. Chem. Phys. 129, 095103 (2008).

    Article  Google Scholar 

  20. Pomerantz, W. C. et al. Nanofibers and lyotropic liquid crystals from a class of self-assembling β-peptides. Angew. Chem. Int. Ed. 47, 1241–1244 (2008).

    Article  CAS  Google Scholar 

  21. Horne, W. S., Price, J. L., Keck, J. L. & Gellman, S. H. Helix bundle quaternary structure from α/β-peptide foldamers. J. Am. Chem. Soc. 129, 4178–4180 (2007).

    Article  CAS  Google Scholar 

  22. Giuliano, M. W., Horne, W. S. & Gellman, S. H. An α/β-peptide helix bundle with a pure β3-amino acid core and a distinctive quaternary structure. J. Am. Chem. Soc. 131, 9860–9861 (2009).

    Article  CAS  Google Scholar 

  23. Burgess, K., Shin, H. & Linthicum, D. S. Solid-phase syntheses of unnatural biopolymers containing repeating urea units. Angew. Chem. Int. Ed. Engl. 34, 907–909 (1995).

    Article  CAS  Google Scholar 

  24. Douat-Casassus, C., Pulka, K., Claudon, P. & Guichard, G. Microwave-enhanced solid-phase synthesis of N,N′-linked aliphatic oligoureas and related hybrids. Org. Lett. 14, 3130–3133 (2012).

    Article  CAS  Google Scholar 

  25. Fischer, L. et al. The canonical helix of urea oligomers at atomic resolution: insights into folding-induced axial organization. Angew. Chem. Int. Ed. 49, 1067–1070 (2010).

    Article  CAS  Google Scholar 

  26. Violette, A. et al. N,N′-linked oligoureas as foldamers: chain length requirements for helix formation in protic solvent investigated by circular dichroism, NMR spectroscopy, and molecular dynamics. J. Am. Chem. Soc. 127, 2156–2164 (2005).

    Article  CAS  Google Scholar 

  27. Nelli, Y. R., Fischer, L., Collie, G. W., Kauffmann, B. & Guichard, G. Structural characterization of short hybrid urea/carbamate (U/C) foldamers: a case of partial helix unwinding. Biopolymers 100, 687–697 (2013).

    Article  CAS  Google Scholar 

  28. Hill, R. B., Raleigh, D. P., Lombardi, A. & DeGrado, W. F. De novo design of helical bundles as models for understanding protein folding and function. Acc. Chem. Res. 33, 745–754 (2000).

    Article  CAS  Google Scholar 

  29. Woolfson, D. N. The design of coiled-coil structures and assemblies. Adv. Protein Chem. 70, 79–112 (2005).

    Article  CAS  Google Scholar 

  30. Fremaux, J., Fischer, L., Arbogast, T., Kauffmann, B. & Guichard, G. Condensation approach to aliphatic oligourea foldamers: helices with N-(pyrrolidin-2-ylmethyl)ureido junctions. Angew. Chem. Int. Ed. 50, 11382–11385 (2011).

    Article  CAS  Google Scholar 

  31. Harbury, P. B., Plecs, J. J., Tidor, B., Alber, T. & Kim, P. S. High-resolution protein design with backbone freedom. Science 282, 1462–1467 (1998).

    Article  CAS  Google Scholar 

  32. O'Shea, E. K., Klemm, J. D., Kim, P. S. & Alber, T. X-ray structure of the GCN4 leucine zipper, a two-stranded, parallel coiled coil. Science 254, 539–544 (1991).

    Article  CAS  Google Scholar 

  33. Zaccai, N. R. et al. A de novo peptide hexamer with a mutable channel. Nature Chem. Biol. 7, 935–941 (2011).

    Article  CAS  Google Scholar 

  34. Lear, J. D., Wasserman, Z. R. & DeGrado, W. F. Synthetic amphiphilic peptide models for protein ion channels. Science 240, 1177–1181 (1988).

    Article  CAS  Google Scholar 

  35. Hernández, H. & Robinson, C. V. Determining the stoichiometry and interactions of macromolecular assemblies from mass spectrometry. Nature Protocols 2, 715–726 (2007).

    Article  Google Scholar 

  36. Yadav, M. K. et al. Structure-based engineering of internal cavities in coiled-coil peptides. Biochemistry 44, 9723–9732 (2005).

    Article  CAS  Google Scholar 

  37. Liu, R., Loll, P. J. & Eckenhoff, R. G. Structural basis for high-affinity volatile anesthetic binding in a natural 4-helix bundle protein. FASEB J. 19, 567–576 (2005).

    Article  Google Scholar 

  38. Ghirlanda, G. et al. Volatile anesthetic modulation of oligomerization equilibria in a hexameric model peptide. FEBS Lett. 578, 140–144 (2004).

    Article  CAS  Google Scholar 

  39. Joh, N. H. et al. De novo design of a transmembrane Zn2+-transporting four-helix bundle. Science 346, 1520–1524 (2014).

    Article  CAS  Google Scholar 

  40. Tegoni, M., Yu, F., Bersellini, M., Penner-Hahn, J. E. & Pecoraro, V. L. Designing a functional type 2 copper center that has nitrite reductase activity within α-helical coiled coils. Proc. Natl Acad. Sci. USA 109, 21234–21239 (2012).

    Article  CAS  Google Scholar 

  41. Faiella, M. et al. An artificial di-iron oxo-protein with phenol oxidase activity. Nature Chem. Biol. 5, 882–884 (2009).

    Article  CAS  Google Scholar 

  42. Fremaux, J. et al. α-Peptide–oligourea chimeras: stabilization of short α-helices by non-peptide helical foldamers. Angew. Chem. Int. Ed. 34, 9816–9820 (2015).

    Article  Google Scholar 

  43. Kabsch, W. XDS. Acta Crystallogr. 66, 125–132 (2010).

    Article  CAS  Google Scholar 

  44. Winn, M. D. et al. Overview of the CCP4 suite and current developments. Acta Crystallogr. D 67, 235–242 (2011).

    Article  CAS  Google Scholar 

  45. McCoy, A. J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674 (2007).

    Article  CAS  Google Scholar 

  46. Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. 66, 486–501 (2010).

    CAS  Google Scholar 

  47. Murshudov, G. N. et al. REFMAC5 for the refinement of macromolecular crystal structures. Acta Crystallogr. 67, 355–367 (2011).

    Article  CAS  Google Scholar 

  48. Delaglio, F. et al. NMRPipe: a multidimensional spectral processing system based on UNIX pipes. J. Biomol. NMR 6, 277–293 (1995).

    Article  CAS  Google Scholar 

  49. Laskowski, R. A. SURFNET: a program for visualizing molecular surfaces, cavities, and intermolecular interactions. J. Mol. Graph. 13, 323–330 (1995).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was funded in part by the CNRS and Conseil Regional d'Aquitaine (Project No. 20091102003). A pre-doctoral fellowship from the University of Bordeaux (to J.F.), CIFRE support from UREkA and ANRT (to L.M.) and Marie Curie FP7-PEOPLE-2010-IEF-273224 and FP7-PEOPLE-2012-IEF-330825 postdoctoral fellowships (to K.P.-Z. and C.M.L.) are gratefully acknowledged. We thank SOLEIL synchrotron and the ERSF for providing access to synchrotron facilities (beam lines PROXIMA 1, ID23-2 and ID29), and are grateful to P. Legrand for assistance on PROXIMA 1.

Author information

Author notes

  1. Karolina Pulka-Ziach & Juliette Fremaux

    Present address: Present addresses: Faculty of Chemistry, University of Warsaw, Pasteura 1, Warsaw 02-093, Poland (K.P.-Z.); UREkA Sarl, 2 rue Robert Escarpit, Pessac 33607, France (J.F.),

Authors and Affiliations

  1. Université de Bordeaux, CBMN, UMR 5248, Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, Pessac, 33607, France

    Gavin W. Collie, Karolina Pulka-Ziach, Caterina M. Lombardo, Juliette Fremaux, Laura Mauran & Gilles Guichard

  2. CNRS, CBMN, UMR 5248, F-33600, Pessac, France

    Gavin W. Collie, Karolina Pulka-Ziach, Caterina M. Lombardo, Juliette Fremaux, Marion Decossas, Laura Mauran, Olivier Lambert & Gilles Guichard

  3. CNRS, UMS3033/US001, Institut Européen de Chimie et Biologie, Pessac, 33607, France

    Frédéric Rosu

  4. Université de Bordeaux, CBMN, UMR 5248, All. Geoffroy Saint-Hilaire, Pessac, 33600, France

    Marion Decossas & Olivier Lambert

  5. UREkA Sarl, 2 rue Robert Escarpit, Pessac, 33607, France

    Laura Mauran

  6. Université de Bordeaux, Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, Pessac, 33607, France

    Valérie Gabelica & Cameron D. Mackereth

  7. Inserm, U869, ARNA Laboratory, 146 rue Léo Saignat, Bordeaux, 33076, France

    Valérie Gabelica & Cameron D. Mackereth

Authors
  1. Gavin W. Collie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karolina Pulka-Ziach
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Caterina M. Lombardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Juliette Fremaux
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Frédéric Rosu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marion Decossas
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Laura Mauran
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Olivier Lambert
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Valérie Gabelica
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Cameron D. Mackereth
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gilles Guichard
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G.W.C. and G.G. conceived and designed the experiments. K.P.-Z., C.M.L., J.F. and L.M. synthesized and characterized the monomers and the oligomers used in this study. G.W.C. performed the crystallization experiments, collected X-ray data, solved and refined the crystal structures and performed the CD experiments. G.W.C., F.R. and V.G. designed and performed the mass spectrometry experiments. C.D.M. designed and performed the NMR spectroscopy experiments. M.D. and O.L. designed and performed the microscopy experiments. G.W.C., F.R., M.D., O.L., V.G., C.D.M. and G.G. analysed and interpreted the experimental data. G.W.C. and G.G. prepared the manuscript. All the authors reviewed and contributed to the manuscript.

Corresponding author

Correspondence to Gilles Guichard.

Ethics declarations

Competing interests

G.G. is cofounder of UREkA SARL and has financial interests in the company. The other authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 4097 kb)

Supplementary information

Structure factors file for H1 (CIF 6443 kb)

Supplementary information

Crystallographic data for H1 (CIF 15 kb)

Supplementary information

Structure factors file for H2 (CIF 6412 kb)

Supplementary information

Crystallographic data for H2 (CIF 15 kb)

Supplementary information

Structure factors file for H4 (CIF 790 kb)

Supplementary information

Crystallographic data for H4 (CIF 14 kb)

Supplementary information

Structure factors file for H5 (CIF 10365 kb)

Supplementary information

Crystallographic data for H5 (CIF 16 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Collie, G., Pulka-Ziach, K., Lombardo, C. et al. Shaping quaternary assemblies of water-soluble non-peptide helical foldamers by sequence manipulation. Nature Chem 7, 871–878 (2015). https://doi.org/10.1038/nchem.2353

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.2353

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing