Conformational Freedom and Topological Confinement of Proteins in Biomolecular Condensates

The emergence of biomolecular condensation and liquid–liquid phase separation (LLPS) introduces a new layer of complexity into our understanding of cell and molecular biology. Evidence steadily grows indicating that condensates are not only implicated in physiology but also human disease. Macro- and mesoscale characterization of condensates as a whole have been instrumental in understanding their biological functions and dysfunctions. By contrast, the molecular level characterization of condensates and how condensates modify the properties of the molecules that constitute them thus far remain comparably scarce. In this minireview we summarize and discuss the findings of several recent studies that have focused on structure, dynamics, and interactions of proteins undergoing condensation. The mechanistic insights they provide help us identify the relevant properties nature and scientists can leverage to modulate the behavior of condensate systems. We also discuss the unique environment of the droplet surface and speculate on effects of topological constraints and physical exclusion on condensate properties.