Department of Biochemistry , University of Toronto , Toronto , Ontario M5S 1A8 , Canada.
Department of Molecular Genetics , University of Toronto , Toronto , Ontario M5S 1A8 , Canada.
J Phys Chem B. 2018 May 31;122(21):5418-5431. doi: 10.1021/acs.jpcb.7b11723. Epub 2018 Feb 15.
In view of recent intense experimental and theoretical interests in the biophysics of liquid-liquid phase separation (LLPS) of intrinsically disordered proteins (IDPs), heteropolymer models with chain molecules configured as self-avoiding walks on the simple cubic lattice are constructed to study how phase behaviors depend on the sequence of monomers along the chains. To address pertinent general principles, we focus primarily on two fully charged 50-monomer sequences with significantly different charge patterns. Each monomer in our models occupies a single lattice site, and all monomers interact via a screened pairwise Coulomb potential. Phase diagrams are obtained by extensive Monte Carlo sampling performed at multiple temperatures on ensembles of 300 chains in boxes of sizes ranging from 52 × 52 × 52 to 246 × 246 × 246 to simulate a large number of different systems with the overall polymer volume fraction ϕ in each system varying from 0.001 to 0.1. Phase separation in the model systems is characterized by the emergence of a large cluster connected by intermonomer nearest-neighbor lattice contacts and by large fluctuations in local polymer density. The simulated critical temperatures, T, of phase separation for the two sequences differ significantly, whereby the sequence with a more "blocky" charge pattern exhibits a substantially higher propensity to phase separate. The trend is consistent with our sequence-specific random-phase-approximation (RPA) polymer theory, but the variation of the simulated T with a previously proposed "sequence charge decoration" pattern parameter is milder than that predicted by RPA. Ramifications of our findings for the development of analytical theory and simulation protocols of IDP LLPS are discussed.
鉴于目前人们对无序蛋白质液-液相分离（LLPS）的生物物理特性的强烈实验和理论兴趣，我们构建了具有链分子的杂多聚合物模型，这些链分子在简单立方晶格上被配置为自回避行走，以研究相行为如何取决于链上单体的序列。为了解决相关的一般原则，我们主要关注两个具有显著不同电荷模式的完全充电的 50 个单体序列。我们模型中的每个单体占据一个单独的晶格位置，所有单体通过屏蔽的成对库仑势相互作用。通过在多个温度下对 300 个链的集合进行广泛的蒙特卡罗采样，在从 52×52×52 到 246×246×246 的盒子中获得相图，以模拟具有不同整体聚合物体积分数 ϕ的大量不同系统，每个系统中的ϕ从 0.001 到 0.1 变化。模型系统中的相分离由通过单体最近邻晶格接触连接的大团簇和局部聚合物密度的大波动来表征。两种序列的模拟相分离临界温度 T 差异很大，其中具有更“块状”电荷模式的序列表现出更高的相分离倾向。这一趋势与我们的序列特异性随机相位近似（RPA）聚合物理论一致，但模拟 T 随先前提出的“序列电荷修饰”模式参数的变化比 RPA 预测的要温和。讨论了我们的发现对无序蛋白质 LLPS 的分析理论和模拟方案的发展的影响。
