Separation of sticker-spacer energetics governs the coalescence of metastable biomolecular condensates.
Separation of sticker-spacer energetics governs the coalescence of metastable biomolecular condensates.
复制标题
粘着物-间隔物能量学的分离控制着亚稳态生物分子凝聚体的聚结。
DOI：
10.1101/2023.10.03.560747
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Shakhnovich,EugeneI
中科院分区：
文献类型：
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作者：
Chattaraj,Aniruddha;Shakhnovich,EugeneI
生物聚合物冷凝物通常以多液滴状态出现，并且在实验时间跨度内从未聚结成一个大液滴。这与经典聚合物物理学的预测相矛盾，经典聚合物物理学的预测表明在相变之外存在一个大液滴。先前的工作表明，生物聚合物的粘附-间隔结构可以动态地稳定多液滴状态。在这里，我们模拟冷凝聚结使用metadaptics方法，揭示了两个不同的物理机制下的液滴融合。当粘着剂表现出缓慢的交换时，由粘着剂-间隔物聚合物制成的缩合物容易经历动力学停滞，而在类似的饱和度水平下快速交换粘着剂允许合并到平衡状态。另一方面，由均聚物组成的冷凝物容易熔融，直到它们达到阈值密度。我们还表明，链的相互凝聚交换提供了一个一般的机制，驱动融合。我们映射的范围内的动力学逮捕的机制，从缓慢的贴纸交换动力学密度介导的精力充沛的分离的贴纸和间隔。我们的预测似乎是在最近的实验探测动态性质的蛋白质-RNA condensates.Significance statementA关键难题的生物冷凝物是共存的多个液滴，在直接方差与经典的预测的平均场理论的聚合物solutions。我们系统地研究了这种由粘合剂-间隔物聚合物制成的冷凝物的聚结趋势，并发现即使在低密度下，这些液滴也显示出动力学停滞的亚稳态，这与由均聚物制成的冷凝物相比是一种独特的行为。耦合的贴纸间相互作用强度和有限价性质的贴纸，使动力学逮捕。我们的预测与最近在体外和体内对蛋白质-RNA缩合物的实验结果完全相关，突出了动力学和热力学相互作用的生物相关性。
Biopolymer condensates often emerge as a multi-droplet state and never coalesce into one large droplet within the experimental timespan. This contradicts the prediction of classical polymer physics which suggests the existence of one large droplet beyond the phase transition. Previous work revealed that the sticker-spacer architecture of biopolymers may dynamically stabilize the multi-droplet state. Here, we simulate the condensate coalescence using metadynamics approach and reveal two distinct physical mechanisms underlying the fusion of droplets. Condensates made of sticker-spacer polymers readily undergo a kinetic arrest when stickers exhibit slow exchange while fast exchanging stickers at similar levels of saturation allow merger to equilibrium states. On the other hand, condensates composed of homopolymers fuse readily until they reach a threshold density. We also show that the inter-condensate exchange of chains offers a general mechanism that drives the fusion. We map the range of mechanisms of kinetic arrest from slow sticker exchange dynamics to density mediated in terms of energetic separation of stickers and spacers. Our predictions appear to be in excellent agreement with recent experiments probing dynamic nature of protein-RNA condensates.Significance statementA key conundrum of biological condensates is the coexistence of multiple droplets, in direct variance with classical predictions of mean-field theories of polymer solutions. We systematically investigated the coalescence tendency of such condensates made of sticker-spacer polymers and discovered that, even at a low density, these droplets show a kinetically arrested metastable state which is a distinct behavior compared to condensates made of homopolymers. Coupling of inter-sticker interaction strength and the finite valence nature of stickers enables kinetic arrest. Our prediction starkly correlates with recent experimental findings on protein-RNA condensates in vitro and in vivo, highlighting the biological relevance of the interplay of kinetics and thermodynamics.