Molecular Mechanisms of Amyloid Formation inside Phase-Separated Droplets

通过液-液相分离形成生物分子凝聚体是细胞划分其大量组分的最广泛机制。生物分子凝聚物实现的生物功能正在以惊人的速度增加，从基因激活、沉默和缓冲细胞噪音，到加速化学反应。然而，冷凝物也会老化，逐渐失去其液体状特性，并产生具有病理意义的固体状状态。淀粉样蛋白纤维的形成在一些神经退行性疾病中起着重要作用，比如帕金森氏症和阿尔茨海默氏症，这些疾病的发病实际上现在被假设与病理相分离有关。理解和最终恢复病理性相分离的一个关键挑战是获得对凝析物内淀粉形成的机制理解。该项目将开发一种新的多尺度分子模拟方法来解决这一挑战，并提供冷凝物内部相互作用分子的前所未有的分子视图。该模型将连接三个分辨率尺度：原子，序列依赖的粗粒度模型，以及淀粉蛋白的最小模型。与Vendruscolo团队合作，我们将测试小分子（由他们设计）抑制相分离液滴内淀粉形成的机制。

Formation of biomolecular condensates via liquid-liquid phase separation is the most widespread mechanism used by cells to compartmentalize their large number of components. The number of identified biological functions fulfilled by biomolecular condensates is increasing at incredible speed, ranging from gene activation and silencing and buffering cellular noise, to speeding up chemical reactions. However, condensates can also age, progressively losing their liquid-like properties and giving rise to solid-like states with pathological implications. The onset of some neurodegenerative diseases where amyloid fibril formation play an important role, like Parkinson's and Alzheimer's, is actually now hypothesised to have a link to pathological phase separation. A key challenge to understand and eventually revert pathological phase separation is obtaining a mechanistic understanding of amylogenesis inside condensates. This project will develop a novel multiscale molecular simulations approach to address this challenge and provide unprecedented molecular views of interacting molecules inside condensates. The model will bridge three scales of resolution: atomistic, sequence-dependent coarse-grained modelling, and a minimal model of amylogenic proteins. In collaboration with the Vendruscolo group, we will test the mechanism by which small molecules (designed by them) act to inhibit amylogenesis inside phase-separated droplets.