Liquid–liquid phase separation occurs via a multitude of transient, noncovalent, and intermolecular interactions resulting in phase transition of intrinsically disordered proteins/regions (IDPs/IDRs) and other biopolymers into mesoscopic, dynamic, nonstoichiometric, and supramolecular condensates. Here we present a unique case to demonstrate that unusual conformational expansion events coupled with solvation and fluctuations drive phase separation of tau, an IDP associated with Alzheimer’s disease. Using intramolecular excimer emission as a powerful proximity readout, we show the unraveling of polypeptide chains within the protein-rich interior environment that can promote critical interchain contacts. Using highly sensitive picosecond time-resolved fluorescence depolarization measurements, we directly capture rapid large-amplitude torsional fluctuations in the extended chains that can control the relay of making-and-breaking of noncovalent intermolecular contacts maintaining the internal fluidity. The interplay of these key molecular parameters can be of prime importance in modulating the mesoscale material property of liquid-like condensates and their maturation into pathological gel-like and solid-like aggregates.

中文翻译：

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液相构象解旋是由大规模构象解旋和内在无序的蛋白质分子波动引起的。

液-液相分离是通过大量的瞬态，非共价和分子间相互作用而发生的，从而导致本征无序的蛋白质/区域（IDP / IDR）和其他生物聚合物发生相转变为介观，动态，非化学计量和超分子的缩合物。在这里，我们提出了一个独特的案例，以证明异常的构象扩展事件以及溶剂化和波动会驱动tau（与阿尔茨海默氏病相关的IDP）的相分离。使用分子内的受激准分子发射作为有力的邻近读出，我们显示了在富含蛋白质的内部环境中多肽链的解开，可以促进关键的链间接触。使用高灵敏度的皮秒时间分辨荧光去极化测量，我们直接捕捉到延伸链中的大振幅快速波动，可以控制非共价分子间接触的形成和破坏的传递，从而维持内部流动性。这些关键分子参数之间的相互作用在调节液体状冷凝物的中尺度材料特性以及将其成熟为病理性凝胶状和固体状聚集体方面至关重要。