AI 中文总结
研究内在无序蛋白序列模式对生物分子凝聚物亚区室化及缓冲浓度波动的影响，用RPA聚合物理论和分子动力学建模，发现大尺寸时三元LLPS在噪声缓冲上优于二元LLPS，小尺寸时情况更复杂，为生物分子凝聚物研究提供新见解。
AI 中文摘要
分子物种的特定混合或分离是细胞内无膜凝聚区室的一个特征。本文通过使用随机相位近似（RPA）聚合物理论和分子动力学（MD）对两性聚电解质序列对的液-液相分离（LLPS）进行建模，研究了内在无序蛋白（IDP）的序列模式如何从根本上影响生物分子凝聚物的亚区室化及其在缓冲浓度波动方面的作用。RPA理论以温度敏感的方式预测二元和三元LLPS。我们观察到，具有不同序列电荷模式的序列对会发生由三元LLPS支持的分离，而具有相似序列电荷模式的序列对则不会。值得注意的是，当用界面张力和/或与MD模型系统的典型小尺寸相称的有限尺寸形式对RPA进行增强时，MD证实了预测的行为，这支持了我们的观点，即当有限尺寸效应不太显著时，RPA理论是一种用于模拟更大、更现实尺寸的生物分子凝聚物的有用的序列特异性建模工具。原则上，当凝聚物尺寸足够大时，三元LLPS在噪声缓冲方面优于二元LLPS，因为三元LLPS中三个共存相的IDP组成在扩展的二维浓度范围内保持不变，而二元LLPS中的两个共存相仅沿系线固定。然而，当凝聚物尺寸足够小时，三元与二元LLPS的缓冲能力更为复杂，因为它们受到有限尺寸效应的不同调制。本文从天然生物分子凝聚物的大小多样性角度讨论了这种相互作用的生物物理影响。
英文摘要
Specific mixing or demixing of molecular species is a characteristic feature of condensed intracellular membraneless compartments. How sequence patterns of intrinsically disordered proteins (IDPs) fundamentally impact subcompartmentalization of biomolecular condensates and their role in buffering against concentration fluctuations are hereby addressed by modeling liquid-liquid phase separation (LLPS) of polyampholytic sequence pairs using random phase approximation (RPA) polymer theory and molecular dynamics (MD). RPA theory predicts both binary and ternary LLPS in a temperature-sensitive manner. We observe demixing underpinned by ternary LLPS for pairs with dissimilar sequence charge patterns but not for pairs with similar sequence charge patterns. Notably, the predicted behaviors are corroborated by MD when RPA is augmented with interfacial tension and/or a finite-size formalism commensurating with the typical small sizes of MD model systems, supporting our stipulation that RPA theory is a useful sequence-specific modeling tool for biomolecular condensates with larger, more realistic sizes when finite-size effects are much less significant. In principle, when the condensate size is sufficiently large, ternary LLPS is superior to binary LLPS in noise buffering because the IDP compositions of the three coexisting phases in ternary LLPS remain unchanged over an extended two-dimensional concentration regime, whereas the two coexisting phases in binary LLPS are fixed only along a tieline. However, when condensate sizes are sufficiently small, the buffering capacities of ternary versus binary LLPSs are more complex as they are modulated differently by finite-size effects. Biophysical ramifications of this interplay are discussed in view of the size diversity of natural biomolecular condensates.
Comments61 pages, 8 main-text figures, Supporting Information (containing supporting text, 1 supporting table, and 14 supporting figures), and 92 references. Submitted
