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用来分隔大量组分的最广泛的机制。从基因激活、沉默和缓冲细胞噪音，到加速化学反应，生物分子缩合物所完成的已识别生物功能的数量正在以令人难以置信的速度增加。然而，凝析油也会老化，逐渐失去其类似液体的性质，并产生具有病理意义的类似固体的状态。一些神经退行性疾病的发病，其中淀粉样原纤维形成起重要作用，如帕金森氏症和阿尔茨海默氏症，现在实际上被假设与病理时相分离有关。理解并最终逆转病理性相分离的一个关键挑战是从机制上理解凝析油中的淀粉样变。该项目将开发一种新的多尺度分子模拟方法来应对这一挑战，并提供前所未有的凝析油中相互作用分子的分子视图。该模型将架起三个分辨率尺度的桥梁：原子学的、依赖于序列的粗粒度模型，以及淀粉样蛋白的最小模型。在与Vendruscolo小组的合作下，我们将测试小分子(由他们设计)抑制相分离液滴中淀粉形成的机制。

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.