Temperature-Controlled Liquid-Liquid Phase Separation of Disordered Proteins
Temperature-Controlled Liquid-Liquid Phase Separation of Disordered Proteins
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DOI：
10.1021/acscentsci.9b00102
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发表时间：
2019-05-22
影响因子：
18.2
通讯作者：
Mittal, Jeetain
中科院分区：
文献类型：
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作者：
Dignon, Gregory L.;Zheng, Wenwei;Mittal, Jeetain
本质无序蛋白质（IDP）的液-液相分离（LLPS）是细胞内常见的现象，这种凝聚物对于生物材料和药物输送的应用也非常有吸引力。更好地理解序列依赖性热响应行为具有极大的意义，因为它将有助于设计具有所需特性的蛋白质序列以及理解细胞对热应激的反应。在这项工作中，我们使用可转移的粗粒度模型来直接探测 IDP 的序列依赖性热响应相行为。为了实现这一目标，我们开发了一种独特的基于知识的氨基酸势，它可以解释不同类型氨基酸的溶剂介导相互作用的温度依赖性影响。值得注意的是，我们能够在实验条件下区分超过 35 个具有较高或较低临界溶液温度的 IDP，从而提供直接证据，证明将温度依赖性溶剂介导的相互作用纳入 IDP 组件可以捕获所得相图形状的差异。鉴于该模型在预测实验行为方面取得了成功，我们将其用作高通量筛选框架来扫描数百万个无序序列，以表征蛋白质相分离的组成依赖性。
The liquid-liquid phase separation (LLPS) of intrinsically disordered proteins (IDPs) is a commonly observed phenomenon within the cell, and such condensates are also highly attractive for applications in biomaterials and drug delivery. A better understanding of the sequence-dependent thermoresponsive behavior is of immense interest as it will aid in the design of protein sequences with desirable properties and in the understanding of cellular response to heat stress. In this work, we use a transferable coarse-grained model to directly probe the sequence-dependent thermoresponsive phase behavior of IDPs. To achieve this goal, we develop a unique knowledge-based amino acid potential that accounts for the temperature-dependent effects on solvent-mediated interactions for different types of amino acids. Remarkably, we are able to distinguish between more than 35 IDPs with upper or lower critical solution temperatures at experimental conditions, thus providing direct evidence that incorporating the temperature-dependent solvent-mediated interactions to IDP assemblies can capture the difference in the shape of the resulting phase diagrams. Given the success of the model in predicting experimental behavior, we use it as a high-throughput screening framework to scan through millions of disordered sequences to characterize the composition dependence of protein phase separation.