揭示ATP对FUS溶液相分离双重作用的分子机理
Uncovering the molecular mechanism for dual effect of ATP on phase separation in FUS solution
摘要：
最近的研究表明，三磷酸腺苷（ATP）可以抑制和增强朊病毒样蛋白的相分离。这种令人困惑的现象背后的分子机制仍然难以捉摸。本文以肉瘤融合蛋白（FUS）溶液为例，结合半经验量子力学方法、平均场论和分子模拟，全面揭示了ATP调控相分离的内在机制.在微观水平上，ATP作为二价或三价粘合剂;在宏观水平上，在稀释的FUS溶液中确实发生了可重入相分离，这是由于在不同条件下ATP浓度依赖性的结合能力。重要的是，溶解蛋白质浓缩物的ATP浓度约为10 mM，与实验结果一致。此外，从动力学的角度来看，ATP对相分离的影响也是非单调的。本工作提供了一个清晰的物理描述的微观相互作用和宏观相图的ATP调制相分离。
英文摘要：
Recent studies reported that adenosine triphosphate (ATP) could inhibit as well as enhance the phase separation in prion-like proteins. The molecular mechanism underlying such a puzzling phenomenon remains elusive. Here, taking the fused in sarcoma (FUS) solution as an example, we comprehensively reveal the underlying mechanism by which ATP regulates phase separation by combining the semiempirical quantum mechanical method, mean-field theory, and molecular simulation. At the microscopic level, ATP acts as a bivalent or trivalent binder; at the macroscopic level, the reentrant phase separation indeed occurs in dilute FUS solutions, resulting from the ATP-concentration--dependent binding ability under different conditions. Importantly, the ATP concentration for dissolving the protein condensates is about 10 mM, agreeing with experimental results. Furthermore, from a dynamic point of view, the effect of ATP on phase separation is also non-monotonic. This work provides a clear physical description of the microscopic interaction and macroscopic phase diagram of the ATP-modulated phase separation.
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