A tunable aqueous architecture modulates functional output in biomolecular condensates

Area of Science:

• Cell Biology
• Biophysics
• Biochemistry

Background:

• Biomolecular condensates organize cellular biochemistry.
• Current models often overlook internal solvent organization, treating it as a uniform background.
• Understanding condensate solvent architecture is crucial for cell function and drug development.

Purpose of the Study:

• To introduce a novel method for mapping solvent polarity within biomolecular condensates.
• To investigate the spatial organization and properties of the solvent environment inside condensates.
• To explore how small molecules interact with and are influenced by the condensate solvent landscape.

Main Methods:

• Development and application of Condensate Spatial Topography via Emission Lifetimes (ConSTEL).
• Utilizing Nile Red fluorescence lifetimes to report on local solvent polarity.
• Employing PopZ as a model system for condensate studies.

Main Results:

• ConSTEL revealed a persistent, tunable mosaic of aqueous environments within condensates.
• Solvent polarity is organized by thermodynamic state and chemical cues, creating distinct rheological regimes.
• Small molecules partition non-uniformly, and exceeding solubility limits induces "reciprocal sculpting" of the solvent architecture.

Conclusions:

• Internal solvent organization is an active determinant of condensate properties, transport, and partitioning.
• The microphase-separated solvent architecture influences molecular motion and rheology.
• Predictive models of condensate function and pharmacology should incorporate spatial solvent arrangements.