Molecular mechanisms of condensate modulation from energy-dominance analysis
Biomolecular condensates in cells underpin cellular organization but have also been implicated in disease progression. As a result, modulation of condensate formation is becoming a path of interest to ameliorate biological malfunction. However, identifying the mechanism of action of a modulator is particularly challenging. This is because condensates are typically highly multicomponent, rendering it difficult to delineate which molecular interactions a modulator is influencing to drive or oppose condensate formation. Here, we extend the theoretical framework of energy dominance to include modulation effects, allowing us to uncover mechanisms of action of small molecular modulators through measuring species energetics. Using this approach, we experimentally investigate the effect of the small molecule suramin on condensates formed by the RNA-binding protein G3BP1 and RNA. We show that suramin specifically disrupts G3BP1-RNA interactions, as independently confirmed though orthogonal binding assays. Together, this work paves the way for systematic studies of condensate modulators in the future.
Authors
- Tomas Šneideris (ORCID: https://orcid.org/0000-0001-5285-871X)
- Rohit V. Pappu (ORCID: https://orcid.org/0000-0003-2568-1378)
- Tuomas P. J. Knowles (ORCID: https://orcid.org/0000-0002-7879-0140)
- Tadas Kartanas (ORCID: https://orcid.org/0000-0002-1255-4807)
- William E. Arter (ORCID: https://orcid.org/0000-0002-3615-1885)
- Daoyuan Qian (ORCID: https://orcid.org/0000-0002-8539-3346)
- Seema Qamar (ORCID: https://orcid.org/0000-0003-1189-206X)
- Charlotte M. Fischer (ORCID: https://orcid.org/0000-0002-4693-9537)
- Peter St George‐Hyslop (ORCID: https://orcid.org/0000-0003-0796-7209)
- Hannes Ausserwӧger (ORCID: https://orcid.org/0000-0003-0762-8872)
- Niklas Ermann (ORCID: https://orcid.org/0000-0003-0280-8866)
- Timothy J. Welsh (ORCID: https://orcid.org/0000-0002-0859-1576)
- Rob Scrutton (ORCID: https://orcid.org/0009-0008-0012-0703)
Institutions
- University Health Network (CA)
- University of Toronto (CA)
- Washington University in St. Louis (US)
- University of Missouri–St. Louis (US)
- University of Cambridge (GB)
- Health Net (US)
- Transition Technologies (Poland) (PL)
- Columbia University (US)
Publication Details
- Journal
- Physical Review Applied
- Published
- 2025-06-06
- DOI
- https://doi.org/10.1103/physrevapplied.23.064017
- Citations
- 5
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- Frances and Augustus Newman Foundation
- Wellcome Trust
- Consortium canadien en neurodégénérescence associée au vieillissement
- Alzheimer Society
- European Commission
- Novo Nordisk
- Canadian Institutes of Health Research