Molecular Mechanisms of Amyloid Formation inside Phase-Separated Droplets

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.