整合结构模拟研究化学修饰对生物大分子凝聚物相变过程的调控

Chemical modifications of large biomolecules play critical roles in many biological processes. It would be important to study their functions and reveal the underlying mechanisms. Besides experimental techniques, computer simulation, such as multi-scale modeling, serves as a complementary tool, which enables us to simulate how a chemical modification would affect the structure of a large biomolecule and analyze how structural perturbation may regulate the function of the biomolecule. This project aims to build a platform of integrative structural modeling, which can combine experimental data from different sources and multi-scale modeling (including all-atom and coarse-grained simulations), to investigate the molecular mechanisms of chemical modifications. We are interested in membrane-less organelles (such as stress granule) in cells, which are also called biomolecular condensates. It has been recognized that posttranslational modifications of amino acids in proteins provide a means to modulate the phase transition of these biomolecular condensates. Using integrative structural modeling, two core proteins in stress granule will be investigated. The first one is the N-terminal low-complexity region of FUS that carries multiple sites of phosphorylation, and the second one is the C-terminal RGG repeats of G3BP1 that is enriched for arginine methylation. We want to know how these chemical modifications change structural ensembles of the proteins, and how they would affect protein-protein/protein-RNA interactions. Based on our studies, the possible mechanism of phosphorylation and methylation in regulating phase transition of the biomolecular condensates may be addressed in detail, which could provide a clue about how to interfere these modifications chemically.

生物大分子动态修饰与化学干预重大研究计划2019年度项目指南中提出的研究重点之一是“生物大分子化学修饰在生理过程和病理变化中的调控机制，重点关注化学修饰和干预对生物大分子凝聚和相变过程的调控作用”。本项目致力于建立一个整合结构模拟平台，有效地将各种来源的实验数据和多尺度模拟结合起来，在分子水平上研究化学修饰对生物大分子动态结构与功能的调控。我们关注细胞内存在的无膜细胞器（如应激颗粒），它们是一类生物大分子凝聚物，其核心蛋白质的翻译后修饰是调控组装/解聚相变过程的重要方式。我们拟利用整合结构模拟来研究参与形成应激颗粒的FUS蛋白N端低复杂度序列的磷酸化，以及G3BP1蛋白C端RGG重复序列的精氨酸甲基化。模拟化学修饰对蛋白质构象系综，以及蛋白-蛋白和蛋白-RNA相互作用的影响，在此基础上探讨磷酸化和甲基化调控凝聚物相变过程的分子机制，为有效地化学干预提供理论指导。

生物大分子各种类型的化学修饰调控许多重要的生理过程和病理变化。本项目拟建立一个整合结构模拟平台，有效地将各种来源的实验数据和多尺度模拟结合起来，在分子水平上研究化学修饰对生物大分子动态结构和功能的调控。我们重点关注细胞内存在的生物大分子凝聚物（如应激颗粒），其核心蛋白质的翻译后修饰是调控组装/解聚相变过程的重要方式。在本项目的资助下，我们主要完成了以下研究：（1）磷酸化对FUS蛋白（应激颗粒中核心蛋白之一）N端低复杂度序列相变过程的调控；（2）发展了一种建立化学修饰粗粒化力场参数的策略；（3）构建参与相分离的固有无序蛋白的构象系综；（4）发展了一种利用分簇指导迭代分子动力学模拟的增强采样方法；（5）YTH蛋白特异性识别腺苷酸N6位甲基化修饰的分子机制。通过模拟化学修饰对蛋白质构象系综，以及蛋白-蛋白和蛋白-RNA相互作用的影响，探讨磷酸化和甲基化等化学修饰调控生物大分子凝聚物相变过程的分子机制，为有效的化学干预提供理论指导。