Biswas Subhadip, Potoyan Davit A
Department of Chemistry, Iowa State University, Ames, Iowa, United States of America.
Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, Iowa, United States of America.
PLoS Comput Biol. 2025 Feb 10;21(2):e1012826. doi: 10.1371/journal.pcbi.1012826. eCollection 2025 Feb.
Many eukaryotic proteins and RNAs contain low-complexity domains (LCDs) with a strong propensity for binding and driving phase separation into biomolecular condensates. Mutations in LCDs frequently disrupt condensate dynamics, resulting in pathological transitions to solid-like states. Understanding how the molecular sequence grammar of LCDs governs condensate dynamics is essential for uncovering their biological functions and the evolutionary forces that shape these sequences. To this end, we present an energy landscape framework that operates on a continuous 'stickiness' energy scale rather than relying on an explicit alphabet-based sequence. Sequences are characterized by Wasserstein distance relative to thoroughly shuffled or random counterparts. Armed with an energy landscape framework, map diagrams of material and dynamical properties governed by key energy landscape features modulated by the degree of complexity in LCD arrangements, including the periodicity and local disorder in LCDs. Highly periodic LCD patterns promote elasticity-dominated behavior, while random sequences exhibit viscosity-dominated properties. Our results reveal that minimum sticker periodicity is crucial for maintaining fluidity in condensates, thereby avoiding transitions to glassy or solid-like states. Moreover, we demonstrate that the energy landscape framework explains the recent experimental findings on prion domains and predicts systematic alterations in condensate viscoelasticity. Our work provides a unifying perspective on the sequence-encoded material properties whereby key features of energy landscapes are conserved while sequences are variable.
许多真核生物蛋白质和RNA含有低复杂性结构域（LCDs），这些结构域具有很强的结合倾向，并能驱动相分离形成生物分子凝聚物。LCDs中的突变常常破坏凝聚物动力学，导致向固态的病理转变。了解LCDs的分子序列语法如何控制凝聚物动力学对于揭示它们的生物学功能以及塑造这些序列的进化力量至关重要。为此，我们提出了一个能量景观框架，该框架在连续的“粘性”能量尺度上运行，而不是依赖基于明确字母表的序列。序列通过相对于完全洗牌或随机对应物的瓦瑟斯坦距离来表征。借助能量景观框架，绘制了由LCD排列复杂性程度调节的关键能量景观特征所控制的材料和动力学特性的图谱，包括LCDs中的周期性和局部无序性。高度周期性的LCD模式促进以弹性为主导的行为，而随机序列表现出以粘性为主导的特性。我们的结果表明，最小贴纸周期性对于维持凝聚物的流动性至关重要，从而避免向玻璃态或固态的转变。此外，我们证明能量景观框架解释了最近关于朊病毒结构域的实验结果，并预测了凝聚物粘弹性中的系统性变化。我们的工作为序列编码的材料特性提供了一个统一的观点，即能量景观的关键特征是保守的，而序列是可变的。
