Biomolecular condensates assembled through liquid–liquid phase separation (LLPS) of proteins and RNAs are currently recognized to play an important role in cellular organization. Their assembly depends on the formation of a network of transient, multivalent interactions between flexible scaffold biomolecules. Understanding how protein and RNA sequences determine these interactions and ultimately regulate the phase separation is an open key challenge. Recent in vitro studies have revealed that arginine and lysine residues, which are enriched in most cellular condensates, have markedly distinct propensities to drive the LLPS of protein/RNA mixtures. Here, we employ explicit-solvent atomistic molecular dynamics simulations to shed light on the microscopic origin of this difference by investigating mixtures of polyU oligonucleotides with either polyR/polyK peptides. In agreement with experiments, our simulations indicate that arginine has a higher affinity for polyU than lysine both in highly diluted conditions and in concentrated solutions with a biomolecular density comparable to cellular condensate. The analysis of intermolecular contacts suggests that this differential behavior is due to the propensity of arginine side chains to simultaneously form a higher number of specific interactions with oligonucleotides, including hydrogen bonds and stacking interactions. Our results provide a molecular description of how the multivalency of the guanidinium group enables the coordination of multiple RNA groups by a single arginine residue, thus ultimately stabilizing protein/RNA condensates.

中文翻译：

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精氨酸多价稳定蛋白质/RNA缩合物

通过蛋白质和 RNA 的液-液相分离 (LLPS) 组装的生物分子凝聚物目前被认为在细胞组织中发挥重要作用。它们的组装取决于柔性支架生物分子之间瞬时多价相互作用网络的形成。了解蛋白质和 RNA 序列如何确定这些相互作用并最终调节相分离是一个开放的关键挑战。最近的体外研究表明，大多数细胞凝聚物中富含的精氨酸和赖氨酸残基具有明显不同的驱动蛋白质/RNA混合物的LLPS的倾向。这里，我们采用显式溶剂原子分子动力学模拟，通过研究 polyU 寡核苷酸与 polyR/polyK 肽的混合物来阐明这种差异的微观起源。与实验一致，我们的模拟表明，在高度稀释的条件下和在生物分子密度与细胞凝聚物相当的浓缩溶液中，精氨酸对 polyU 的亲和力高于赖氨酸。对分子间接触的分析表明，这种差异行为是由于精氨酸侧链倾向于同时与寡核苷酸形成更多数量的特定相互作用，包括氢键和堆积相互作用。