Folding is a ubiquitous process that nature uses to control the conformations of its molecular machines, allowing them to perform chemical and mechanical tasks. Over the years, chemists have synthesized foldamers that adopt well-defined and stable folded architectures, mimicking the control expressed by natural systems1,2. Mechanically interlocked molecules, such as rotaxanes and catenanes, are prototypical molecular machines that enable the controlled movement and positioning of their component parts3,4,5. Recently, combining the exquisite complexity of these two classes of molecules, donor–acceptor oligorotaxane foldamers have been synthesized, in which interactions between the mechanically interlocked component parts dictate the single-molecule assembly into a folded secondary structure6,7,8. Here we report on the mechanochemical properties of these molecules. We use atomic force microscopy-based single-molecule force spectroscopy to mechanically unfold oligorotaxanes, made of oligomeric dumbbells incorporating 1,5-dioxynaphthalene units encircled by cyclobis(paraquat-p-phenylene) rings. Real-time capture of fluctuations between unfolded and folded states reveals that the molecules exert forces of up to 50 pN against a mechanical load of up to 150 pN, and displays transition times of less than 10 μs. While the folding is at least as fast as that observed in proteins, it is remarkably more robust, thanks to the mechanically interlocked structure. Our results show that synthetic oligorotaxanes have the potential to exceed the performance of natural folding proteins.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $15.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Guichard, G. & Huc, I. Synthetic foldamers. Chem. Commun. 47, 5933–5941 (2011).
Le Bailly, B. A. F. & Clayden, J. Dynamic foldamer chemistry. Chem. Commun. 52, 4852–4863 (2016).
Bruns, C. J. & Stoddart, J. F. The Nature of The Mechanical Bond: From Molecules to Machines (Wiley, Hoboken, NJ, 2017).
Erbas-Cakmak, S., Leigh, D. A., McTernan, C. T. & Nussbaumer, A. L. Artificial molecular machines. Chem. Rev. 115, 10081–10206 (2015).
Kay, E. R. & Leigh, D. A. Rise of the molecular machines. Angew. Chem. Int. Ed. 54, 10080–10088 (2015).
Basu, S. et al. Donor–acceptor oligorotaxanes made to order. Chem. Eur. J. 17, 2107–2119 (2011).
Zhu, Z. et al. Synthesis and solution-state dynamics of donor–acceptor oligorotaxane foldamers. Chem. Sci. 4, 1470–1483 (2013).
Bruns, C. J. & Stoddart, J. F. Mechanically interlaced and interlocked donor–acceptor foldamers. Adv. Polym. Sci. 261, 271–294 (2013).
Fisher, T. E., Marszalek, P. E. & Fernandez, J. M. Stretching single molecules into novel conformations using the atomic force microscope. Nat. Struct. Biol. 7, 719–724 (2000).
Bustamante, C., Chemla, Y. R., Forde, N. R. & Izhaky, D. Mechanical processes in biochemistry. Annu. Rev. Biochem. 73, 705–748 (2004).
Neuman, K. C. & Nagy, A. Single-molecule force spectroscopy: optical tweezers, magnetic tweezers and atomic force microscopy. Nat. Methods 5, 491–505 (2008).
Puchner, E. M. & Gaub, H. E. Force and function: probing proteins with AFM-based force spectroscopy. Curr. Opin. Struct. Biol. 19, 605–614 (2009).
Liang, J. & Fernandez, J. M. Mechanochemistry: one bond at a time. ACS Nano 3, 1628–1645 (2009).
Duwez, A.-S. & Willet, N. Molecular Manipulation with Atomic Force Microscopy (CRC Press, Boca Raton, 2012).
Hinterdorfer, P. & Dufrene, Y. F. Detection and localization of single molecular recognition events using atomic force microscopy. Nat. Methods 3, 347–355 (2006).
Müller, D. J. & Dufrêne, Y. F. Atomic force microscopy as a multifunctional molecular toolbox in nanobiotechnology. Nat. Nanotech. 3, 261–269 (2008).
Janke, M. et al. A. Mechanically interlocked calixarene dimers display reversible bond breakage under force. Nat. Nanotech. 4, 225–229 (2009).
Lussis, P. et al. A single synthetic small molecule that generates force against a load. Nat. Nanotech. 6, 553–557 (2011).
Van Quaethem, A., Lussis, P., Leigh, D. A., Duwez, A.-S. & Fustin, C.-A. Probing the mobility of catenane rings in single molecules. Chem. Sci. 5, 1449–1452 (2014).
Odell, B. et al. Cyclobis(paraquat-p-phenylene). A tetracationic multipurpose receptor. Angew. Chem. Int. Ed. 27, 1547–1550 (1988).
Zhu, Z. et al. Oligomeric pseudorotaxanes adopting infinite-chain lattice superstructures. Angew. Chem. Int. Ed. 51, 7231–7235 (2012).
Franco, I., Schatz, G. C. & Ratner, M. A. Single-molecule pulling and the folding of donor–acceptor oligorotaxanes: phenomenology and interpretation. J. Chem. Phys. 131, 124902 (2009).
Hunter, C. A. Quantifying intermolecular interactions: guidelines for the molecular recognition toolbox. Angew. Chem. Int. Ed. 43, 5310–5324 (2004).
Beyer, M. K. & Clausen-Schaumann, H. Mechanochemistry: the mechanical activation of covalent bonds. Chem. Rev. 105, 2921–2948 (2005).
Flory, P. J. Statistical mechanics of chain molecules. Br. Polym. J. 2, 302–303 (1989).
Lee, G. et al. Nanospring behaviour of ankyrin repeats. Nature 440, 246–249 (2006).
Liphardt, J., Onoa, B., Smith, S. B., Tinoco, I. & Bustamante, C. Reversible unfolding of single RNA molecules by mechanical force. Science 292, 733–737 (2001).
Cecconi, C., Shank, E., Bustamante, C. & Marqusee, S. Direct observation of the three-state folding of a single protein molecule. Science 309, 2057–2060 (2005).
Junker, J. P. & Rief, M. Single-molecule force spectroscopy distinguishes target binding modes of calmodulin. Proc. Natl Acad. Sci. USA 106, 14361–14366 (2009).
Junker, J. P., Ziegler, F. & Rief, M. Ligand-dependent equilibrium fluctuations of single calmodulin molecules. Science 323, 633–637 (2009).
He, C. et al. Direct observation of the reversible two-state unfolding and refolding of an α/β protein by single-molecule atomic force microscopy. Angew. Chem. Int. Ed. 54, 9921–9925 (2015).
Žoldák, G., Stigler, J., Pelz, B., Li, H. & Rief, M. Ultrafast folding kinetics and cooperativity of villin headpiece in single-molecule force spectroscopy. Proc. Natl Acad. Sci. USA 110, 18156–18161 (2013).
D.S. thanks the Fonds de la Recherche Scientifique-Fonds National pour la Recherche Scientifique (FRS-FNRS) for his FRIA fellowship. The research was supported by the PDR T.0205.13 project of the FRS-FNRS at University of Liège and by the King Abdulaziz City of Science and Technology (KACST) as part of their Joint Center of Excellence in Integrated Nano-Systems (JCIN) at Northwestern University.
Supplementary Figs. 1–5
About this article
Nature Communications (2018)