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Dynamic covalent self-assembly of mechanically interlocked molecules solely made from peptides

Abstract

Mechanically interlocked molecules (MIMs), such as rotaxanes and catenanes, have captured the attention of chemists both from a synthetic perspective and because of their role as simple prototypes of molecular machines. Although examples exist in nature, most synthetic MIMs are made from artificial building blocks and assembled in organic solvents. The synthesis of MIMs from natural biomolecules remains highly challenging. Here, we report on a synthesis strategy for interlocked molecules solely made from peptides, that is, mechanically interlocked peptides (MIPs). Fully peptidic, cysteine-decorated building blocks were self-assembled in water to generate disulfide-bonded dynamic combinatorial libraries consisting of multiple different rotaxanes, catenanes and daisy chains as well as more exotic structures. Detailed NMR spectroscopy and mass spectrometry characterization of a [2]catenane comprising two peptide macrocycles revealed that this structure has rich conformational dynamics reminiscent of protein folding. Thus, MIPs can serve as a bridge between fully synthetic MIMs and those found in nature.

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Fig. 1: Strategy for a dynamic covalent self-assembly synthesis of MIPs.
Fig. 2: Synthesized Cys-decorated lasso peptide variants.
Fig. 3: Dynamic covalent self-assembly synthesis of different MIPs.
Fig. 4: Mixed DCLs and building block modifications.
Fig. 5: Structural characterization of peptide [2]catenane 3-2H by NMR spectroscopy and mass spectrometry.

Data availability

The coordinates for [2]catenane 3-2H have been deposited in the Protein Data Bank (PDB) with accession code 7LL7. The coordinates have also been deposited in the Biological Magnetic Resonance Data Bank (BMRB), the accession number is 30852. All data, including the mass spectra for all compounds, are present in the main text or the Supplementary Information. Due to the large data file size, the raw MS data underlying the figures will be provided upon request.

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Acknowledgements

We thank I. Pelczer and H. Elashal for support with the NMR experiments. This work was supported by NIH grant GM107036 to A.J.L. H.V.S. gratefully acknowledges support by the Deutsche Forschungsgemeinschaft (DFG Research Fellowship 427725459).

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H.V.S. and A.J.L. conceived the project idea. H.V.S. and Y.Z. carried out the molecular cloning experiments and peptide purification. H.V.S. carried out the MS and NMR analyses. H.V.S. and A.J.L. analysed the data. H.V.S. and A.J.L. acquired funding. H.V.S wrote the first draft of the manuscript, and it was edited by A.J.L. All the authors contributed to and approved the final version of the manuscript.

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Correspondence to A. James Link.

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Schröder, H.V., Zhang, Y. & Link, A.J. Dynamic covalent self-assembly of mechanically interlocked molecules solely made from peptides. Nat. Chem. 13, 850–857 (2021). https://doi.org/10.1038/s41557-021-00770-7

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