Interplay between Short-Range Attraction and Long-Range Repulsion Controls Reentrant Liquid Condensation of Ribonucleoprotein–RNA Complexes

In
eukaryotic cells, ribonucleoproteins (RNPs) form mesoscale condensates
by liquid–liquid phase separation that play essential roles
in subcellular dynamic compartmentalization. The formation and dissolution
of many RNP condensates are finely dependent on the RNA-to-RNP ratio,
giving rise to a windowlike phase separation behavior. This is commonly
referred to as reentrant liquid condensation (RLC). Here, using ribonucleoprotein-inspired
polypeptides with low-complexity RNA-binding sequences as well as
an archetypal disordered RNP, fused in sarcoma, as model systems,
we investigate the molecular driving forces underlying this nonmonotonous
phase transition. We show that an interplay between short-range cation−π
attractions and long-range electrostatic forces governs the heterotypic
RLC behavior of RNP–RNA complexes. Short-range attractions,
which can be encoded by both polypeptide chain primary sequence and
nucleic acid base sequence, control the two-phase coexistence regime,
regulate material properties of polypeptide–RNA condensates,
and oppose condensate reentrant dissolution. In the presence of excess
RNA, a competition between short-range attraction and long-range electrostatic
repulsion drives the formation of a colloidlike cluster phase. With
increasing short-range attraction, the fluid dynamics of the cluster
phase is arrested, leading to the formation of a colloidal gel. Our
results reveal that phase behavior, supramolecular organization, and
material states of RNP–RNA assemblies are controlled by a dynamic
interplay between molecular interactions at different length scales.