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<p>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<sub>ion</sub>]~0.15 M, dissolve at higher salt concentration, and again phase separate at even higher salt concentrations such as [C<sub>ion</sub>]~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<sub>ion</sub>], 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<sub>ion</sub>] increases, the correlation length in the ionic plasma decreases, and the condensate dissolves. Second LLPS at high [C<sub>ion</sub>] 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.</p><p></p>

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Origin of the ionic-strength dependent reentrant behavior in the liquid-liquid phase separation of uncharged intrinsically disordered proteins

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月11日

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  • Sayantan Mondal,
  • Eugene Shakhnovich

摘要

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]~0.15 M, dissolve at higher salt concentration, and again phase separate at even higher salt concentrations such as [Cion]~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 [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 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.