BPS2026 – Designing enzymatic regulation of biomolecular condensates

Biomolecular condensates form and dissolve dynamically in cells and participate in diverse processes including RNA metabolism, signal transduction, and stress responses. Yet, the physical rules by which enzymes regulate these transitions remain unclear. We address this by introducing susceptibility , a dimensionless measure of the dilute-phase response to solutes, which admits a natural thermodynamic interpretation. Screening diverse solutes across condensates with distinct driving forces of LLPS yields susceptibility spectra that reflect the molecular driving forces of condensation, including specific ion effects, amino acid regulation, and nucleotide sensitivity. We then examine how this framework extends to mixtures of solutes, showing that susceptibilities add linearly for independent solutes, while deviations uncover cooperative or antagonistic interactions. Building on this principle, we define a reaction susceptibility that predicts whether an enzymatic reaction promotes or disrupts LLPS from the susceptibilities of its substrates and products. Using ATPase, we deliberately design enzymatic control of a condensate to induce phase separation and dynamically modify condensate viscosity. These results establish design rules for enzyme-controlled condensates, opening a route to program their formation, dissolution, and material properties.