Origin of the ionic-strength dependent reentrant behavior in the liquid-liquid phase separation of uncharged...

The effect of salt on coacervation of synthetic or biological polyelectrolytes and polyampholytes is well-studied. However, recent experiments showed that largely uncharged IDPs (like FUS) also undergo LLPS at physiological salt concentrations such as [C_ion]~0.15 M, dissolve at higher salt concentration, and again phase separate at even higher salt concentrations such as [C_ion]~3 M. Here we use analytical theory and explicit solvent coarse-grained simulations to reveal the mechanism of these transitions, which is significantly different than that of highly charged IDPs with net charge neutrality. At low [C_ion], the ionic solution acts as a highly correlated medium conferring long-range effective attractive interactions between spatially distant monomers. In this regime, the ion concentration inside the condensate is higher than in the bulk solution. As [C_ion] increases, the correlation length in the ionic plasma decreases, and the condensate dissolves. Second LLPS at high [C_ion] is due to the entropy-driven crowding, and the ion concentration inside the condensate is lower than in the bulk. Our study unravels a general physical mechanism of salt-dependent reentrant behavior in LLPS in uncharged IDPs.