How Hierarchical Interactions Make Membraneless Organelles Tick Like Clockwork

Biomolecular condensates appear throughout the cell, serving many different biochemical functions. We argue that condensate functionality is optimized when the interactions driving condensation vary widely in affinity. Strong interactions provide structural specificity needed to encode functional properties but carry the risk of kinetic arrest, while weak interactions allow the system to remain dynamic but do not restrict the conformational ensemble enough to sustain specific functional features. To support our opinion, we describe illustrative examples of the interplay of strong and weak interactions that are found in the nucleolus, SPOP/DAXX condensates, polySUMO/polySIM condensates, chromatin, and stress granules. The common feature of these systems is a hierarchical assembly motif in which weak, transient interactions condense structurally defined functional units. Biomolecular condensates (BMCs) perform diverse functions, including signaling, stress protection, environmental sensing, genome organization, gene expression, RNA processing, and ribosome assembly.Biomolecular condensation is driven by interactions of varying affinity, including weak interactions between individual sidechains of intrinsically disordered regions (IDRs), specific binding events involving folded domains, and nearly irreversible amyloid-like structures.Polymer-like scaffolds with discrete interaction sites, such as nucleic acids, attractive sidechains on IDRs, and proteins with multiple folded domains, form disordered, dynamic networks that can recruit other molecules.The networks stabilizing condensates often combine multiple types of interactions, and this mixture of interactions gives rise to structural features that encode specific functional characteristics.We argue that interactions within BMCs have a range of affinities to navigate the competing physical requirements of dynamics and structural specificity.