R. D. Berlin Center for Cell Analysis and Modeling, University of Connecticut School of Medicine, Farmington, Connecticut.
R. D. Berlin Center for Cell Analysis and Modeling, University of Connecticut School of Medicine, Farmington, Connecticut.
Biophys J. 2023 May 2;122(9):1678-1690. doi: 10.1016/j.bpj.2023.03.036. Epub 2023 Mar 27.
Clustering of weakly interacting multivalent biomolecules underlies the formation of membraneless compartments known as condensates. As opposed to single-component (homotypic) systems, the concentration dependence of multicomponent (heterotypic) condensate formation is not well understood. We previously proposed the solubility product (SP), the product of monomer concentrations in the dilute phase, as a tool for understanding the concentration dependence of multicomponent systems. In this study, we further explore the limits of the SP concept using spatial Langevin dynamics and rule-based stochastic simulations. We show, for a variety of idealized molecular structures, how the maximum SP coincides with the onset of the phase transition, i.e., the formation of large clusters. We reveal the importance of intracluster binding in steering the free and cluster phase molecular distributions. We also show how structural features of biomolecules shape the SP profiles. The interplay of flexibility, length, and steric hindrance of linker regions controls the phase transition threshold. Remarkably, when SPs are normalized to nondimensional variables and plotted against the concentration scaled to the threshold for phase transition, the curves all coincide independent of the structural features of the binding partners. Similar coincidence is observed for the normalized clustering versus concentration plots. Overall, the principles derived from these systematic models will help guide and interpret in vitro and in vivo experiments on the biophysics of biomolecular condensates.
弱相互作用多价生物分子的聚集是形成无膜隔间的基础,这些隔间被称为凝聚物。与单一组分(同型)系统不同,多组分(异型)凝聚物形成的浓度依赖性尚未得到很好的理解。我们之前提出了溶解度积(SP),即稀相中单分子浓度的乘积,作为理解多组分系统浓度依赖性的工具。在这项研究中,我们使用空间朗之万动力学和基于规则的随机模拟进一步探索了 SP 概念的局限性。我们展示了各种理想化的分子结构如何使最大 SP 与相变的开始(即大簇的形成)相吻合。我们揭示了内簇结合在引导自由相和簇相分子分布中的重要性。我们还展示了生物分子的结构特征如何塑造 SP 分布。连接区的灵活性、长度和空间位阻的结构特征控制着相变的阈值。值得注意的是,当 SP 被归一化为无量纲变量并绘制为与相变阈值成比例的浓度时,无论结合伴侣的结构特征如何,所有曲线都会重合。对于归一化的聚类与浓度图,也观察到类似的重合。总的来说,这些系统模型得出的原理将有助于指导和解释生物分子凝聚物的生物物理体外和体内实验。