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Quantifying collective interactions in biomolecular phase separation

Author

Listed:
  • Hannes Ausserwöger

    (University of Cambridge)

  • Ella Csilléry

    (University of Cambridge)

  • Daoyuan Qian

    (University of Cambridge)

  • Georg Krainer

    (University of Graz)

  • Timothy J. Welsh

    (University of Cambridge)

  • Tomas Sneideris

    (University of Cambridge)

  • Titus M. Franzmann

    (Technische Universität Dresden)

  • Seema Qamar

    (University of Cambridge)

  • Nadia A. Erkamp

    (University of Cambridge)

  • Jonathon Nixon-Abell

    (University of Cambridge)

  • Mrityunjoy Kar

    (Max Planck Institute of Cell Biology and Genetics (MPI-CBG))

  • Peter St George-Hyslop

    (University of Toronto
    Columbia University)

  • Anthony A. Hyman

    (Max Planck Institute of Cell Biology and Genetics (MPI-CBG))

  • Simon Alberti

    (Technische Universität Dresden)

  • Rohit V. Pappu

    (Washington University in St. Louis)

  • Tuomas P. J. Knowles

    (University of Cambridge)

Abstract

Biomolecular phase separation is an emerging theme for protein assembly and cellular organisation. The collective forces driving such condensation, however, remain challenging to characterise. Here we show that tracking the dilute phase concentration of only one component suffices to quantify composition and energetics of multicomponent condensates. Applying this assay to several disease- and stress-related proteins, we find that monovalent ions can either deplete from or enrich within the dense phase in a context-dependent manner. By analysing the effect of the widely used modulator 1,6-hexanediol, we find that the compound inhibits phase separation by acting as a solvation agent that expands polypeptide chains. Extending the strategy to in cellulo data, we even quantify the relative energetic contributions of individual proteins within complex condensates. Together, our approach provides a generic and broadly applicable tool for dissecting the forces governing biomolecular condensation and guiding the rational modulation of condensate behaviour.

Suggested Citation

  • Hannes Ausserwöger & Ella Csilléry & Daoyuan Qian & Georg Krainer & Timothy J. Welsh & Tomas Sneideris & Titus M. Franzmann & Seema Qamar & Nadia A. Erkamp & Jonathon Nixon-Abell & Mrityunjoy Kar & Pe, 2025. "Quantifying collective interactions in biomolecular phase separation," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62437-y
    DOI: 10.1038/s41467-025-62437-y
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    References listed on IDEAS

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    1. William E. Arter & Runzhang Qi & Nadia A. Erkamp & Georg Krainer & Kieran Didi & Timothy J. Welsh & Julia Acker & Jonathan Nixon-Abell & Seema Qamar & Jordina Guillén-Boixet & Titus M. Franzmann & Dav, 2022. "Biomolecular condensate phase diagrams with a combinatorial microdroplet platform," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Huasong Lu & Dan Yu & Anders S. Hansen & Sourav Ganguly & Rongdiao Liu & Alec Heckert & Xavier Darzacq & Qiang Zhou, 2018. "Phase-separation mechanism for C-terminal hyperphosphorylation of RNA polymerase II," Nature, Nature, vol. 558(7709), pages 318-323, June.
    3. Joshua A. Riback & Lian Zhu & Mylene C. Ferrolino & Michele Tolbert & Diana M. Mitrea & David W. Sanders & Ming-Tzo Wei & Richard W. Kriwacki & Clifford P. Brangwynne, 2020. "Composition-dependent thermodynamics of intracellular phase separation," Nature, Nature, vol. 581(7807), pages 209-214, May.
    4. Amy R. Strom & Alexander V. Emelyanov & Mustafa Mir & Dmitry V. Fyodorov & Xavier Darzacq & Gary H. Karpen, 2017. "Phase separation drives heterochromatin domain formation," Nature, Nature, vol. 547(7662), pages 241-245, July.
    5. Georg Krainer & Timothy J. Welsh & Jerelle A. Joseph & Jorge R. Espinosa & Sina Wittmann & Ella Csilléry & Akshay Sridhar & Zenon Toprakcioglu & Giedre Gudiškytė & Magdalena A. Czekalska & William E. , 2021. "Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
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