Biomolecular condensates are essential in various cellular processes, and their misregulation has been demonstrated to underlie disease. Small molecules that modulate condensate stability and material properties offer promising therapeutic approaches, but mechanistic insights into their interactions with condensates remain largely lacking. We employ a multiscale approach to enable long-time, equilibrated all-atom simulations of various condensate-ligand systems. Systematic characterization of the ligand binding poses reveals that condensates can form diverse and heterogeneous chemical environments with one or multiple chains to bind small molecules. Unlike traditional protein-ligand interactions, these chemical environments are dominated by nonspecific hydrophobic interactions. Nevertheless, the chemical environments feature unique amino acid compositions and physicochemical properties that favor certain small molecules over others, resulting in varied ligand partitioning coefficients within condensates. Notably, different condensates share similar sets of chemical environments but at different populations. This population shift drives ligand selectivity toward specific condensates. Our approach can enhance the interpretation of experimental screening data and may assist in the rational design of small molecules targeting specific condensates.

中文翻译：

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非特异性但选择性的相互作用有助于小分子凝聚物结合。


生物分子凝聚物在各种细胞过程中都是必不可少的，它们的失调已被证明是疾病的基础。调节凝聚物稳定性和材料特性的小分子提供了有前途的治疗方法，但在很大程度上仍然缺乏对它们与凝聚物相互作用的机制见解。我们采用多尺度方法来实现各种凝聚态配体系统的长期、平衡全原子模拟。配体结合姿势的系统表征表明，缩合物可以形成多种多样的异质化学环境，具有一条或多条链来结合小分子。与传统的蛋白质-配体相互作用不同，这些化学环境以非特异性疏水相互作用为主。然而，化学环境具有独特的氨基酸组成和物理化学性质，有利于某些小分子而不是其他小分子，从而导致凝聚物内的配体分配系数不同。值得注意的是，不同的凝聚态具有相似的化学环境，但处于不同的群体中。这种群体变化推动了配体对特定缩合物的选择性。我们的方法可以增强对实验筛选数据的解释，并可能有助于合理设计针对特定凝聚物的小分子。