The structural basis for diverse nucleic acid roles in biomolecular condensates

Nucleic acids are ubiquitous components of biomolecular condensates, yet their contributions to condensate formation and properties vary considerably between protein systems. Here, we examine the diverse roles of nucleic acids in condensates through the lens of protein structure and multivalency. Proteins that interact with nucleic acids often combine folded and disordered regions, which organize interaction sites differently and thereby bias multivalent interactions toward distinct molecular partners. We propose that the collective integration of these interactions determines whether proteins readily phase separate through protein-protein interactions alone or rely substantially on nucleic acid mediated interactions. In the former regime, nucleic acids may primarily regulate condensate material properties, whereas in the latter they can provide the additional multivalency required for condensate assembly. Most biological condensates likely integrate these modes to varying degrees. Understanding how protein structure, multivalency, and nucleic acid properties dynamically reshape these patterns of intermolecular interactions presents an important challenge for both experiments and coarse-grained molecular models.