Small molecule properties define partitioning into biomolecular condensates

Biomolecular condensates regulate cellular function by compartmentalizing
molecules without a surrounding membrane. Condensate function arises from
specific exclusion or enrichment of molecules. Thus, understanding
condensate composition is critical to characterizing condensate function.
While principles defining macromolecular composition have been described,
understanding of small molecule composition remains limited. Here we
quantified partitioning of ~1700 biologically relevant small molecules
into condensates composed of different macromolecules. Partitioning varied
nearly a million-fold across compounds but was correlated among
condensates, indicating disparate condensates are physically similar. For
one system, enriched compounds did not generally bind macromolecules with
high affinity under conditions where condensates do not form, suggesting
partitioning is not governed by site-specific interactions.
Correspondingly, a machine learning model accurately predicts partitioning
using only computed physicochemical features of the compounds, chiefly
those related to solubility and hydrophobicity. These results suggest that
a hydrophobic environment emerges upon condensate formation, driving
enrichment and exclusion of small molecules.