蛋白质液-液相分离的模拟研究

液-液相分离（比如水油混合后的液滴）是自然界普遍存在的现象。直到最近，研究人员才发现细胞内参与许多重要生理病理过程的无膜细胞器是由生物大分子的液-液相分离形成。随着研究的不断深入，越来越多的蛋白被证实参与不同无膜细胞器的形成。体外实验对相分离现象的重构揭示了生物大分子的多价相互作用是相分离发生的主要驱动力。但各种可以形成多价相互作用的分子间作用如静电、阳离子-π、π-π、疏水的贡献大小如何，可形成液-液相分离的蛋白质有什么样的序列分布特征，目前还没有系统的研究。本项目拟FUS和TDP-43的功能区片段为体系，通过粗粒化模型模拟相分离发生的过程，并结合对蛋白质相分离数据库的统计分析，揭示蛋白质液-液相分离的分子机制。同时，通过全原子模拟方法，探讨相分离中液态凝聚体内部的蛋白质分子结构和构象分布。该研究有助于相关疾病的理解，并可为其预防或治疗，以及相关生物材料的设计和应用提供理论指导。

Liquid–liquid phase separation (LLPS) is a pervasive phenomenon in nature, such as mixing of water and oil leads to the formation of droplets. Until recent years, researchers discovered that LLPS underlies the formation of membraneless organelles (MLOs) in cell, which play important roles in both physiology and pathology. More and more proteins have been indicated to intermediate the formation of various MLOs through LLPS. The in vitro experiments indicate multi-valent interactions, such as electrostatic interaction, cation-π、π-π and hydrophobic interaction are the driving forces of biomolecular LLPS. However, how these different kinds of interaction contribute to LLPS, as well as what’s the sequence distribution feature of proteins which intermediate LLPS, are not clear yet. In this project, using the functional regions of FUS and TDP-43 as model systems, their LLPS will be simulated based on coarse-grained model. Further, by combing with the statistical analysis of LLPS related databases, the molecular mechanism of protein LLPS will be investigated thoroughly. Meantime, the intrinsic structure and conformation distribution of proteins within the condensates will be discovered through all-atomic simulations. This project would provide new insights into the understanding of related diseases, and could provide theoretical basis for the prevention or treatment of them, as well as for the rational design of related biomolecular materials.