Department of Biochemistry, University of Toronto, Medical Sciences Building-5th Floor, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
Molecular Medicine, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
J Phys Chem B. 2021 May 6;125(17):4337-4358. doi: 10.1021/acs.jpcb.1c00954. Epub 2021 Apr 23.
Biomolecular condensates such as membraneless organelles, underpinned by liquid-liquid phase separation (LLPS), are important for physiological function, with electrostatics, among other interaction types, being a prominent force in their assembly. Charge interactions of intrinsically disordered proteins (IDPs) and other biomolecules are sensitive to the aqueous dielectric environment. Because the relative permittivity of protein is significantly lower than that of water, the interior of an IDP condensate is expected to be a relatively low-dielectric regime, which aside from its possible functional effects on client molecules should facilitate stronger electrostatic interactions among the scaffold IDPs. To gain insight into this LLPS-induced dielectric heterogeneity, addressing in particular whether a low-dielectric condensed phase entails more favorable LLPS than that posited by assuming IDP electrostatic interactions are uniformly modulated by the higher dielectric constant of the pure solvent, we consider a simplified multiple-chain model of polyampholytes immersed in explicit solvents that are either polarizable or possess a permanent dipole. Notably, simulated phase behaviors of these systems exhibit only minor to moderate differences from those obtained using implicit-solvent models with a uniform relative permittivity equals to that of pure solvent. Buttressed by theoretical treatments developed here using random phase approximation and polymer field-theoretic simulations, these observations indicate a partial compensation of effects between favorable solvent-mediated interactions among the polyampholytes in the condensed phase and favorable polyampholyte-solvent interactions in the dilute phase, often netting only a minor enhancement of overall LLPS propensity from the very dielectric heterogeneity that arises from the LLPS itself. Further ramifications of this principle are discussed.
生物分子凝聚体，如无膜细胞器，由液-液相分离（LLPS）支撑，对于生理功能很重要，其中静电相互作用是其组装的主要力。固有无序蛋白质（IDP）和其他生物分子的电荷相互作用对水介质环境敏感。由于蛋白质的介电常数显著低于水，因此 IDP 凝聚体的内部预计处于相对低介电状态，除了对客户分子可能具有功能影响外，还应该促进支架 IDP 之间更强的静电相互作用。为了深入了解这种由 LLPS 诱导的介电各向异性，特别是考虑到低介电凝聚相是否比假设 IDP 静电相互作用均匀调制的纯溶剂具有更高的介电常数更有利于 LLPS，我们考虑了一个简化的多链模型聚电解质在极性或具有永久偶极子的显溶剂中。值得注意的是，这些系统的模拟相行为与使用具有等于纯溶剂的均匀相对介电常数的隐式溶剂模型获得的相行为仅略有差异。通过这里使用随机相位近似和聚合物场论模拟开发的理论处理得到支持，这些观察结果表明，在凝聚相中聚电解质之间有利的溶剂介导相互作用与稀相中有利的聚电解质-溶剂相互作用之间的影响部分补偿，通常仅从 LLPS 本身产生的非常介电各向异性中略微增强整体 LLPS 倾向。进一步讨论了这一原则的其他影响。
