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Exploring the sequence space for (tri-)peptide self-assembly to design and discover new hydrogels

Abstract

Peptides that self-assemble into nanostructures are of tremendous interest for biological, medical, photonic and nanotechnological applications. The enormous sequence space that is available from 20 amino acids probably harbours many interesting candidates, but it is currently not possible to predict supramolecular behaviour from sequence alone. Here, we demonstrate computational tools to screen for the aqueous self-assembly propensity in all of the 8,000 possible tripeptides and evaluate these by comparison with known examples. We applied filters to select for candidates that simultaneously optimize the apparently contradicting requirements of aggregation propensity and hydrophilicity, which resulted in a set of design rules for self-assembling sequences. A number of peptides were subsequently synthesized and characterized, including the first reported tripeptides that are able to form a hydrogel at neutral pH. These tools, which enable the peptide sequence space to be searched for supramolecular properties, enable minimalistic peptide nanotechnology to deliver on its promise.

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Figure 1: Screening for self-assembling tripeptides.
Figure 2: From screening to design rules.
Figure 3: Characterization of selected tripeptides.

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Acknowledgements

The authors thank C. Irving for assistance with DOSY NMR spectroscopy and M. Mullin (Glasgow University) for help with TEM. P.W.J.M.F., N.T.H. and R.V.U. acknowledge financial support from the European Research Council (no. 334949: SPRITES-H2). R.V.U. acknowledges funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/EMERgE/ERC grant agreement no. 258775. G.G.S. acknowledges financial support by Macphie of Glenbervie. C.G.P. acknowledges financial support by Linn Products. Y.M.A. acknowledges financial support by FP7 Marie Curie Actions of the European Commission, via the initial training network ReAd (no. 289723). Results were obtained using the EPSRC-funded ARCHIE-WeSt High Performance Computer (www.archie-west.ac.uk; EPSRC grant no. EP/K000586/1).

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Contributions

P.W.J.M.F. was responsible for computational work and infrared spectroscopy. Y.M.A., D.K., C.G.P. and G.G.S. performed peptide synthesis and characterization. N.J., Y.M.A. and G.G.S. performed TEM. C.G.P. performed DOSY NMR spectroscopy. N.J. and D.K. performed DLS. N.T.H., R.V.U. and T.T. contributed to the experimental design. All authors commented on the manuscript. P.W.J.M.F., R.V.U. and T.T. wrote the paper.

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Correspondence to Rein V. Ulijn or Tell Tuttle.

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The University of Strathclyde has filed a patent application (UK Patent application no. 1417885.9) on technology related to the processes described in this article. Several authors are listed as inventors on the patent application.

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Frederix, P., Scott, G., Abul-Haija, Y. et al. Exploring the sequence space for (tri-)peptide self-assembly to design and discover new hydrogels. Nature Chem 7, 30–37 (2015). https://doi.org/10.1038/nchem.2122

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