Department of Chemical and Biomolecular Engineering, Lehigh University, Bethlehem, Pennsylvania, USA.
Center for Materials Physics and Technology, Naval Research Laboratory, Washington, District of Columbia, USA.
Protein Sci. 2021 Jul;30(7):1371-1379. doi: 10.1002/pro.4094. Epub 2021 May 24.
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.
我们对用于模拟无规卷曲蛋白质（IDP）序列特异性行为的亲水性尺度（HPS）粗粒化（CG）模型进行了改进，包括它们的液-液相分离（LLPS）。之前基于 Kapcha 和 Rossky（KR 尺度）的原子亲水性尺度的模型无法捕捉到一些众所周知的 LLPS 趋势，例如突变（R 到 K 和 Y 到 F）会降低相分离倾向。在这里，我们建议使用 Urry 亲水性尺度，它是从带有侧基 X 的模型多肽的逆温度转变中推导出来的。我们引入了两个自由参数Δ和µ，用于调整新模型（HPS-Urry）的整体相互作用强度，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 的相行为仅可通过这些模型中的一个来很好地描述，这突出了需要基于多种蛋白质的仔细验证策略。CG HPS-Urry 模型应该能够准确模拟蛋白质的 LLPS，并提供分子相互作用的微观详细视图。
