Biomolecular condensates are currently recognized to play a key role in organizing cellular space and in orchestrating biochemical processes. Despite an increasing interest in characterizing their internal organization at the molecular scale, not much is known about how the densely crowded environment within these condensates affects the structural properties of recruited macromolecules. Here, we adopted explicit-solvent all-atom simulations based on a combination of enhanced sampling approaches to investigate how the conformational ensemble of an RNA hairpin is reshaped in a highly concentrated peptide solution that mimics the interior of a biomolecular condensate. Our simulations indicate that RNA structure is greatly perturbed by this distinctive physico-chemical environment, which weakens RNA secondary structure and promotes extended nonnative conformations. The resulting high-resolution picture reveals that RNA unfolding is driven by the effective solvation of nucleobases through hydrogen bonding and stacking interactions with surrounding peptides. This solvent effect can be modulated by the amino acid composition of the model condensate as proven by the differential RNA behavior observed in the case of arginine-rich and lysine-rich peptides.

中文翻译：

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通过原子模拟探索生物分子缩合物中 RNA 不稳定的机制


生物分子凝聚物目前被认为在组织细胞空间和协调生化过程中起关键作用。尽管人们对在分子尺度上表征它们的内部组织越来越感兴趣，但对于这些凝聚态中密集拥挤的环境如何影响募集的大分子的结构特性，人们知之甚少。在这里，我们采用了基于增强采样方法组合的显式溶剂全原子模拟，以研究 RNA 发夹的构象集合如何在模拟生物分子凝聚物内部的高浓度肽溶液中重塑。我们的模拟表明，RNA 结构受到这种独特的物理化学环境的极大扰动，这会削弱 RNA 二级结构并促进扩展的非天然构象。由此产生的高分辨率图片显示，RNA 去折叠是由核碱基的有效溶剂化驱动的，通过氢键和与周围肽的堆叠相互作用。这种溶剂效应可以通过模型缩合物的氨基酸组成来调节，在富含精氨酸和富含赖氨酸的肽段中观察到的 RNA 差异行为证明了这一点。