The physical origin of ageing at biomolecular condensate interfaces

The interface separating a biomolecular condensate from its surroundings is increasingly recognised as a unique physical and chemical environment that actively regulates condensate behaviour. It controls surface tension, molecular organisation and chemical reactivity, and is also where pathological ageing often begins, with several proteins nucleating cross-β-sheet fibrils preferentially at condensate surfaces. But does ageing emerge there because of protein-specific chemistry, or a more general physical mechanism? Using coarse-grained molecular dynamics simulations, we show that cross-β-sheet nucleation generically occurs preferentially at condensate interfaces across systems of increasing chemical complexity, from simple homopolymers to patterned amphiphilic sequences. In all systems studied, interface-driven ageing has a common physical origin and can be further modulated, but not driven, by protein sequence. Specifically, terminal domains at the condensate interface gain mobility while remaining densely packed and mutually aligned, creating favourable conditions for β-sheet nucleation. Ageing is amplified in amphiphilic sequences, where hydrophilic regions act as surfactants facing the dilute phase, while aggregation-prone hydrophobic domains cluster just beneath the surface, concentrating the nucleation there. This surfactant-like organisation lowers the interfacial free energy, which falls systematically as sequence asymmetry grows. By linking molecular interactions to mesoscale behaviour, these results cast the interface as a central regulator of ageing and reveal a sequence-independent physical mechanism for the liquid-to-solid transition underlying pathological aggregation in biomolecular condensates.