Interplay between self-assembly and phase separation in a polymer-complex model

Spatiotemporal organization of biological processes can be achieved both by assembling molecules into stoichiometric complexes and by demixing via liquid–liquid phase separation. Interestingly, in the case of biomolecules with low-complexity domains, self-assembly and phase separation can arise from the same set of multivalent interactions. In this work, we introduce a theoretical model inspired by a DNA nanostar system, where single-stranded DNA can either assemble into nanostars through hybridization or undergo liquid–liquid phase separation. We derive a mean-field free energy in terms of experimentally measurable parameters assuming two-state self-assembly kinetics. Our model exhibits rich phase behavior, which we study by calculating "master phase diagrams" for the complete parameter space. Parameterizing the model as a function of temperature or ionic strength yields a predicted phase diagram for a specific biomolecular system. Our model not only explains the re-entrant phase behavior observed in experiments on DNA nanostar systems, but also provides a theoretical framework for understanding the interplay between complex assembly and liquid–liquid phase separation in naturally occurring biomolecules with low-complexity domains.