Sequence dependence of biomolecular condensates*

Cells are home to a host of biomolecular condensates – phase-separated droplets that lack a membrane – which organize intracellular processes in space and time. For example, ribosomes are produced in liquid droplets called nucleoli, and there is increasing evidence that droplets condense at specific regions of DNA to regulate gene expression. In addition to nonspecific interactions, phase separation depends on specific binding motifs between constituent molecules. But few rules have been established for how these specific, heterotypic interactions drive phase separation. Using lattice-polymer simulations and mean-field theory, we show that the sequence of binding motifs strongly affects a polymer's ability to phase separate, influencing both phase boundaries and condensate properties (e.g. viscosity and polymer extension). Notably, sequence primarily acts by determining the conformational entropy of self-bonding by single polymers. This establishes a new physical paradigm for biological control of phase separation.