The Origin of the Ionic-strength Dependent Reentrant Behavior in Liquid-Liquid Phase Separation of Uncharged IDPs

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 [Cion][~]0.15M, dissolve at higher salt concentration, and again phase separate at even higher salt concentrations such as, [Cion][~]3M. Here we use analytical theory and simulations to reveal the mechanism of these transitions. At low [Cion], 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 [Cion] increases, the correlation length in the ionic plasma decreases, and the condensate dissolves. Second LLPS at high [Cion] is due to the entropy-driven crowding, and 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.