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bioRxiv · 10.1101/2023.10.06.561146

Merging-limited coarsening governs long-term stability of nanoscale condensates

Chen, F.·Zhang, Y.·Shum, H. C.
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Abstract

Droplet coarsening is a long-standing phenomenon widely observed in our daily life and industrial processes. This process is typically governed by classic theories, such as Brownian motion-induced coalescence and Ostwald ripening, predicting continuous and rapid droplet growth. However, recent studies revealed that nanoscale biomolecular condensates, formed by liquid-liquid phase separation (LLPS), often defy this expectation, exhibiting remarkable long-term stability in cells and in vitro systems. Here, we reveal a merging-limited coarsening mechanism that underpins this anomalously slow growth. Using experiments, theory, and simulations, we demonstrate that nanoscale coacervates formed at neutral stoichiometry remain stable over extended periods due to size-dependent merging inefficiency. This inefficiency stems from entropic charge separation caused by asymmetric chain lengths of oppositely charged polymers, which induces interfacial charge accumulation and inter-coacervate electrostatic repulsion. Our findings reframe LLPS as a kinetically constrained process evolving over a rugged energy landscape, in which merging barriers trap condensates in metastable, long-lived states. This framework offers a physical basis for condensate size control in cells and a design principle for stable synthetic biomolecular assemblies.

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Chen, F., Zhang, Y., Shum, H. C.. 2023-10-09. Merging-limited coarsening governs long-term stability of nanoscale condensates. https://doi.org/10.1101/2023.10.06.561146

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