Decoding optimal ligand design for multicomponent condensates.

Biomolecular condensates are essential for cellular processes and are linked to human diseases when dysregulated. These condensates are hypothesized to assemble via phase transitions of a few key driver macromolecules and are further modulated by the interactions with ligands. Previous work showed that monovalent ligands inhibit driver phase transitions whereas multivalent ligand hubs comprising several identical binding sites to drivers promote phase transitions. Here, using a library of designed ligand hubs with decreasing or increasing spacings between binding sites and altered binding affinities with drivers, we employ theory and experiments to establish a new set of rules that govern how ligand hubs affect driver phase transitions. Our findings reveal that effects of macromolecules can be manipulated through emergent properties.