ABSTRACT Liquid–liquid phase separation of disordered proteins has emerged as a ubiquitous route to membraneless compartments in living cells, and similar coacervates may have played a role

when the first cells formed. However, existing coacervates are typically made of multiple macromolecular components, and designing short peptide analogues capable of self-coacervation has

proven difficult. Here we present a short peptide synthon for phase separation, made of only two dipeptide stickers linked via a flexible, hydrophilic spacer. These small-molecule compounds

self-coacervate into micrometre-sized liquid droplets at sub-millimolar concentrations, which retain up to 75 wt% water. The design is general and we derive guidelines for the required

complexity. This provides a stepping stone for new coacervate-based protocells made of single peptide species. Access through your institution Buy or subscribe This is a preview of

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* Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS CATALYTIC PEPTIDE-BASED COACERVATES FOR ENHANCED FUNCTION

THROUGH STRUCTURAL ORGANIZATION AND SUBSTRATE SPECIFICITY Article Open access 30 October 2024 BINARY PEPTIDE COACERVATES AS AN ACTIVE MODEL FOR BIOMOLECULAR CONDENSATES Article Open access

11 March 2025 BIOMOLECULAR CONDENSATES FORMED BY DESIGNER MINIMALISTIC PEPTIDES Article Open access 26 January 2023 DATA AVAILABILITY All data supporting the findings of this study are

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chemical reactions. _Nat. Rev. Chem._ 2, 306–327 (2018). Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS This project has received funding from the European Research

Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under grant agreement number 851963, and from the Netherlands Organization for Scientific Research

(NWO-Startup to E.S.). M.A. gratefully acknowledges a Marie Skłodowska Curie Individual Fellowship (project number 839177). AUTHOR INFORMATION Author notes * These authors contributed

equally: M. Abbas, W.P. Lipiński. AUTHORS AND AFFILIATIONS * Institute for Molecules and Materials, Radboud University, Nijmegen, The Netherlands Manzar Abbas, Wojciech P. Lipiński, Karina

K. Nakashima, Wilhelm T. S. Huck & Evan Spruijt Authors * Manzar Abbas View author publications You can also search for this author inPubMed Google Scholar * Wojciech P. Lipiński View

author publications You can also search for this author inPubMed Google Scholar * Karina K. Nakashima View author publications You can also search for this author inPubMed Google Scholar *

Wilhelm T. S. Huck View author publications You can also search for this author inPubMed Google Scholar * Evan Spruijt View author publications You can also search for this author inPubMed 

Google Scholar CONTRIBUTIONS M.A. and E.S. conceived the idea and designed the experiments. M.A. and W.P.L. synthesized the peptide derivatives and performed their analysis. M.A. performed

redox, microscopy and microreactor experiments. K.K.N. performed microscopy experiments with FFssFF. All authors discussed the results and interpreted data. M.A., E.S. and W.T.S.H. wrote the

manuscript. CORRESPONDING AUTHOR Correspondence to Evan Spruijt. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. ADDITIONAL INFORMATION PEER REVIEW

INFORMATION _Nature Chemistry_ thanks Samrat Mukhopadhyay and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. PUBLISHER’S NOTE Springer Nature

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1 and 2, Figs. 1–28, discussion and Table 1. SOURCE DATA SOURCE DATA FIG. 1 Unprocessed images, Source data points SOURCE DATA FIG. 2 Unprocessed images, Source data points SOURCE DATA FIG.

3 Unprocessed images SOURCE DATA FIG. 4 Source data points and fits RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Abbas, M., Lipiński, W.P.,

Nakashima, K.K. _et al._ A short peptide synthon for liquid–liquid phase separation. _Nat. Chem._ 13, 1046–1054 (2021). https://doi.org/10.1038/s41557-021-00788-x Download citation *

Received: 17 July 2020 * Accepted: 13 August 2021 * Published: 11 October 2021 * Issue Date: November 2021 * DOI: https://doi.org/10.1038/s41557-021-00788-x SHARE THIS ARTICLE Anyone you

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