Charged peptides enriched in aromatic residues decelerate condensate ageing driven by cross-β-sheet formation

Abstract

Abstract Biomolecular condensates play wide-ranging roles in cellular compartmentalization and biological processes. However, their transition from a functional liquid-like phase into a solid-like state—usually termed as condensate ageing—represents a hallmark associated with the onset of multiple neurodegenerative diseases. In this study, we design a computational pipeline to explore potential candidates, in the form of small peptides, to regulate ageing kinetics in biomolecular condensates. By combining equilibrium and non-equilibrium simulations of a sequence-dependent residue-resolution force field, we investigate the impact of peptide insertion—with different composition, patterning, and net charge—in the condensate phase diagram and ageing kinetics of archetypal proteins driving condensate ageing: TDP-43 and FUS. We reveal that small peptides composed of a specific balance of aromatic and charged residues can substantially decelerate ageing over an order of magnitude. The mechanism is controlled through condensate density reduction induced by peptide self-repulsive electrostatic interactions that specifically target protein regions prone to form cross- β -sheet fibrils. Our work proposes an efficient computational framework to rapidly scan the impact of small molecule insertion in condensate ageing and develop novel pathways for controlling phase transitions relevant to disease prevention.