Zhang Bin, Wang Cong, Kilgore Henry, Latham Andrew
Res Sq. 2024 Aug 13:rs.3.rs-4784242. doi: 10.21203/rs.3.rs-4784242/v1.
Biomolecular condensates are essential in various cellular processes, and their misregulation has been demonstrated to be underly 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 non-specific 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 towards 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.
生物分子凝聚物在各种细胞过程中至关重要，其失调已被证明是疾病的潜在原因。调节凝聚物稳定性和材料特性的小分子提供了有前景的治疗方法，但对它们与凝聚物相互作用的机制理解仍很欠缺。我们采用多尺度方法来实现对各种凝聚物-配体系统的长时间、平衡全原子模拟。对配体结合姿态的系统表征表明，凝聚物可以与一条或多条链形成多样且异质的化学环境来结合小分子。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导。然而，这些化学环境具有独特的氨基酸组成和物理化学性质，使得某些小分子比其他小分子更受青睐，从而导致凝聚物内不同的配体分配系数。值得注意的是，不同的凝聚物共享相似的化学环境集，但比例不同。这种比例变化驱动了配体对特定凝聚物的选择性。我们的方法可以增强对实验筛选数据的解释，并可能有助于针对特定凝聚物的小分子的合理设计。
