Mechanistic Pathways Leading to the Maturation of Biomolecular Condensates by Amyloid Fibrils

Biomolecular condensates, formed via liquid--liquid phase separation, are increasingly recognized as precursors of pathological amyloid fibrils in neurodegenerative disease. While condensates typically maintain liquid-like dynamics, their gradual aging often culminates in liquid-to-solid transitions and fibrillar assembly. Here, using coarse-grained molecular dynamics (CGMD) simulations, we demonstrate that rigid attractive segments embedded within phase-separating polymers modulate the aging trajectory of condensates by promoting surface-localized fibrillization. At early times, small clusters of aligned rigid segments nucleate at the condensate interface, where local anisotropy lowers entropic barriers to $\beta$-sheet like alignment. These protofilaments elongate into pilus-like fibrillar protrusions that remain anchored to the condensate surface. Growth is sustained by a continuous flux of polymers recruited from surrounding low-density regions, resulting in outward fibril extension and progressive remodeling of the condensate boundary. The interplay between rigid segment alignment, interface geometry, and molecular recruitment establishes a mechanistic framework that connects condensate aging to amyloid fibril formation. Our findings highlight how interfaces act as catalytic hubs for fibril nucleation and suggest that selective modulation of rigid segment interactions could regulate condensate stability and delay pathological aging. This work underscores the utility of CGMD simulations for bridging molecular grammar with mesoscale condensate behavior, offering predictive insight into how sequence design, solvent environment, or small-molecule modulators may reshape the landscape of condensate-to-fibril transitions.