Conformational dynamics of RNA plays important roles in a variety of cellular functions such as transcriptional regulation, catalysis, scaffolding, and sensing. Recently, RNAs with low-complexity sequences have been shown to phase separate and form condensate phases similar to lowcomplexity protein domains. The affinity for phase separation and the material characteristics of RNA condensates are strongly dependent on sequence composition and patterning. We hypothesize that differences in the affinities for RNA phase separation can be uncovered by studying sequence-dependent conformational dynamics of single RNA chains. To this end, we have employed atomistic simulations and deep dimensionality reduction techniques to map temperature-dependent conformational free energy landscapes for 20 base-long homopolymeric RNA sequences: poly(U), poly(G), poly(C), and poly(A). The energy landscapes of homopolymeric RNAs reveal a plethora of metastable states with qualitatively different populations stemming from differences in base chemistry. Through detailed analysis of base, phosphate, and sugar interactions, we show that experimentally observed temperature-driven shifts in metastable state populations align with experiments on RNA phase transitions. Specifically, we find that the thermodynamics of unfolding of homopolymeric RNA follows the poly(G) > poly(A) > poly(C) > poly(U) order of stability, mirroring the propensity of RNA to form condensates. To conclude, this work shows that at least for homopolymeric RNA sequences the single-chain conformational dynamics contains sufficient information for predicting and quantifying condensate forming affinities of RNAs. Thus, we anticipate that atomically detailed studies of temeprature -dependent energy landscapes of RNAs will be a useful guide for understanding the propensity of various RNA molecules to form condensates.

中文翻译：

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深度无监督学习揭示同聚 RNA 的能量景观


RNA 的构象动力学在转录调控、催化、支架和传感等多种细胞功能中发挥着重要作用。最近，具有低复杂性序列的 RNA 已被证明可以相分离并形成类似于低复杂性蛋白质结构域的凝聚相。 RNA 凝聚物的相分离亲和力和材料特性强烈依赖于序列组成和图案。我们假设通过研究单条 RNA 链的序列依赖性构象动力学可以揭示 RNA 相分离亲和力的差异。为此，我们采用原子模拟和深度降维技术来绘制 20 个碱基长的均聚物 RNA 序列的温度依赖性构象自由能图谱：poly(U)、poly(G)、poly(C) 和 poly( A）。同聚 RNA 的能量景观揭示了过多的亚稳态，其群体由于基础化学的差异而具有质的不同。通过对碱基、磷酸盐和糖相互作用的详细分析，我们表明实验观察到的亚稳态群体中温度驱动的变化与 RNA 相变实验一致。具体来说，我们发现同聚 RNA 解折叠的热力学遵循聚（G）>聚（A）>聚（C）>聚（U）稳定性顺序，反映了 RNA 形成缩合物的倾向。总之，这项工作表明，至少对于同聚 RNA 序列，单链构象动力学包含足够的信息来预测和量化 RNA 的缩合物形成亲和力。 因此，我们预计，对 RNA 温度依赖性能量景观的原子详细研究将有助于了解各种 RNA 分子形成凝聚物的倾向。