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Molecular mechanisms of condensate modulation from energy-dominance analysis

Daoyuan Qian1,†, Hannes Ausserwoger1,†, William E. Arter2, Rob M. Scrutton1, Timothy J. Welsh1, Tadas Kartanas2, Niklas Ermann2, Seema Qamar2, Charlotte M. Fischer1 et al.

Tomas Sneideris1, Peter St George-Hyslop3,4, Rohit V. Pappu5, and Tuomas P.J. Knowles1,6,*

  • *Contact author: tpjk2@cam.ac.uk
  • †These authors contributed equally.
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Phys. Rev. Applied 23, 064017 – Published 6 June, 2025

DOI: https://doi.org/10.1103/PhysRevApplied.23.064017

Abstract

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.

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Phys. Rev. Applied 23, 064017– Published 6 June, 2025
  • Received 15 July 2024
  • Revised 16 December 2024
  • Accepted 29 January 2025
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