Cellular condensates — liquid-like droplets that form inside cells through phase separation — start as viscous fluids. They flow, exchange material with their surroundings, and reorganize internally. Over days, some of them solidify. The liquid-to-solid transition is pathological: solidified condensates are implicated in neurodegenerative diseases like ALS and Alzheimer's. The question is what drives the solidification.
Sundaravadivelu Devarajan, Shillcock, and Bhatt (arXiv:2407.21710) show that the driver is entropy.
The condensate is built from molecules with two kinds of regions: stickers (which bind to other stickers) and spacers (which don't bind). In the liquid state, stickers form a loose network — connected but not clustered. Spacers fill the gaps between connections, contributing conformational entropy by exploring many possible configurations.
The key mechanism: spacers want to maximize their own entropy. When stickers are spread apart, the spacers between them are stretched and constrained, reducing the number of configurations available. When stickers cluster — packing their binding sites close together — the spacers between them are freed. The spacer chains gain conformational freedom. The system's total entropy increases when stickers cluster, because the entropic gain of the freed spacers exceeds the entropic cost of ordering the stickers.
The clustering is slow. The sticker network must rearrange cooperatively — many bonds must break and reform to allow stickers to migrate toward each other. The process takes days and exhibits glassy dynamics: aging curves that stretch over multiple time decades, characteristic of systems exploring a rugged energy landscape. The condensate doesn't jump from liquid to solid. It creeps, arrested at each stage by the cooperative barriers that the next clustering step must overcome.
The result is a solidification mechanism that requires no chemical modification, no mutation, no external damage. The system solidifies because it is following the thermodynamic gradient toward maximum entropy. The aging is not degradation in the usual sense — not a loss of function through damage or disrepair. It is the system finding a state that is entropically favorable and mechanically rigid. The lock is the equilibrium.
The counterintuition is that entropy produces order. Spacer disorder drives sticker clustering, and clustering is solidification. The component that maximizes its own freedom constrains the component that provides the condensate's fluidity. The liquid ages because its solvent is too free.
Sundaravadivelu Devarajan, Shillcock, and Bhatt, "Entropic Clustering of Stickers Induces Aging in Biocondensates," arXiv:2407.21710 (July 2024, revised March 2026).