Connecting Coil-to-Globule Transitions to Full Phase Diagrams for Intrinsically Disordered Proteins
Connecting Coil-to-Globule Transitions to Full Phase Diagrams for Intrinsically Disordered Proteins
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DOI：
10.1016/j.bpj.2020.06.014
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发表时间：
2020-07-21
影响因子：
3.4
通讯作者：
Pappu, Rohit, V
中科院分区：
文献类型：
--
作者：
Zeng, Xiangze;Holehouse, Alex S.;Pappu, Rohit, V
相分离被认为是控制细胞内生化反应所需的空间和时间组织的基础。相互作用基序的多价性，也被称为贴纸，是驱动相分离的蛋白质的一个决定性特征。具有沿着线性序列均匀分布的贴纸的本质上无序的蛋白质可以作为驱动相分离的支架分子。通过计算或测量序列特定的相图，可以辨别无序蛋白质对相分离的序列内在贡献。这些有助于描绘蛋白质浓度和支持相分离的适当控制参数(如温度)的组合。在这里，我们提出了一种方法，将详细的模拟与分析的高斯簇理论的数值适应相结合，以实现特定于序列的相图的计算。我们的方法利用了稀溶液中单链崩溃的驱动力和浓溶液中相分离的驱动力之间的已知等价性。我们通过计算一组典型的内在无序的低复杂度域的相图来演示理论辅助计算的应用。我们还利用理论来计算序列特定的渗流线，从而为许多生物分子凝聚物观察到的硬化转变提供一个热力学框架。
Phase separation is thought to underlie spatial and temporal organization that is required for controlling biochemical reactions in cells. Multivalence of interaction motifs, also known as stickers, is a defining feature of proteins that drive phase separation. Intrinsically disordered proteins with stickers uniformly distributed along the linear sequence can serve as scaffold molecules that drive phase separation. The sequence-intrinsic contributions of disordered proteins to phase separation can be discerned by computing or measuring sequence-specific phase diagrams. These help to delineate the combinations of protein concentration and a suitable control parameter, such as temperature, that support phase separation. Here, we present an approach that combines detailed simulations with a numerical adaptation of an analytical Gaussian cluster theory to enable the calculation of sequence-specific phase diagrams. Our approach leverages the known equivalence between the driving forces for single-chain collapse in dilute solutions and the driving forces for phase separation in concentrated solutions. We demonstrate the application of the theory-aided computations through calculation of phase diagrams for a set of archetypal intrinsically disordered low-complexity domains. We also leverage theories to compute sequence-specific percolation lines and thereby provide a thermodynamic framework for hardening transitions that have been observed for many biomolecular condensates.