Department of Chemistry, The University of Texas at Austin, Austin, TX, USA.
School of Pharmacy, University of Nottingham, Nottingham, UK.
Nat Chem. 2022 Jul;14(7):775-785. doi: 10.1038/s41557-022-00934-z. Epub 2022 May 2.
Although it is known that RNA undergoes liquid-liquid phase separation, the interplay between the molecular driving forces and the emergent features of the condensates, such as their morphologies and dynamic properties, is not well understood. We introduce a coarse-grained model to simulate phase separation of trinucleotide repeat RNAs, which are implicated in neurological disorders. After establishing that the simulations reproduce key experimental findings, we show that once recruited inside the liquid droplets, the monomers transition from hairpin-like structures to extended states. Interactions between the monomers in the condensates result in the formation of an intricate and dense intermolecular network, which severely restrains the fluctuations and mobilities of the RNAs inside large droplets. In the largest densely packed high-viscosity droplets, the mobility of RNA chains is best characterized by reptation, reminiscent of the dynamics in polymer melts. Our work provides a microscopic framework for understanding liquid-liquid phase separation in RNA, which is not easily discernible in current experiments.
虽然人们知道 RNA 会发生液-液相分离,但分子驱动力与凝聚物的新兴特征(如形态和动态特性)之间的相互作用还不太清楚。我们引入了一个粗粒化模型来模拟三核苷酸重复 RNA 的相分离,这些 RNA 与神经紊乱有关。在确定模拟能够重现关键的实验结果之后,我们表明,一旦被招募到液滴内,单体就会从发夹样结构转变为伸展状态。凝聚物中的单体相互作用导致形成一个错综复杂且密集的分子间网络,这严重限制了 RNA 在大液滴内的波动和迁移。在最大的高密度高粘度液滴中,RNA 链的迁移可以最好地通过蠕动来描述,类似于聚合物熔体中的动力学。我们的工作为理解 RNA 的液-液相分离提供了一个微观框架,这在当前的实验中不易察觉。