We present improvements to the hydropathy scale (HPS) coarse-grained (CG) model for simulating sequence-specific behavior of intrinsically disordered proteins (IDPs), including their liquid–liquid phase separation (LLPS). The previous model based on an atomistic hydropathy scale by Kapcha and Rossky (KR scale) is not able to capture some well-known LLPS trends such as reduced phase separation propensity upon mutations (R-to-K and Y-to-F). Here, we propose to use the Urry hydropathy scale instead, which was derived from the inverse temperature transitions in a model polypeptide with guest residues X. We introduce two free parameters to shift (Δ) and scale (µ) the overall interaction strengths for the new model (HPS-Urry) and use the experimental radius of gyration for a diverse group of IDPs to find their optimal values. Interestingly, many possible (Δ, µ) combinations can be used for typical IDPs, but the phase behavior of a low-complexity (LC) sequence FUS is only well described by one of these models, which highlights the need for a careful validation strategy based on multiple proteins. The CG HPS-Urry model should enable accurate simulations of protein LLPS and provide a microscopically detailed view of molecular interactions.

中文翻译：

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用于研究无序蛋白质序列依赖性相分离的改进粗粒度模型

我们提出了对水力病理尺度 (HPS) 粗粒度 (CG) 模型的改进，用于模拟内在无序蛋白质 (IDP) 的序列特异性行为，包括它们的液-液相分离 (LLPS ) 。先前基于 Kapcha 和 Rossky 的原子亲水量表（KR 量表）的模型无法捕捉一些众所周知的 LLPS 趋势，例如突变时相分离倾向降低（R-to-K 和 Y-to-F）。在这里，我们建议改用 Urry 亲水量表，该量表源自具有客体残基 X 的模型多肽中的逆温度转变。我们引入了两个自由参数来偏移 (Δ) 和量表 ( µ) 新模型 (HPS-Urry) 的整体交互强度，并使用不同 IDP 组的实验回转半径来找到它们的最佳值。有趣的是，许多可能的 (Δ, µ ) 组合可用于典型的 IDP，但低复杂度 (LC) 序列 FUS 的相位行为只能由其中一个模型很好地描述，这突出了仔细验证策略的必要性基于多种蛋白质。CG HPS-Urry 模型应该能够准确模拟蛋白质 LLPS，并提供分子相互作用的微观详细视图。