Separation of sticker-spacer energetics governs the coalescence of metastable biomolecular condensates

Abstract

AbstractBiopolymer condensates often emerge as a multi-droplet state and never coalesce into one large droplet within the experimental timespan. This contradicts the prediction of classical polymer physics which suggests the existence of one large droplet beyond the phase transition. Previous work revealed that the sticker-spacer architecture of biopolymers may dynamically stabilize the multi-droplet state. Here, we simulate the condensate coalescence using metadynamics approach and reveal two distinct physical mechanisms underlying the fusion of droplets. Condensates made of sticker-spacer polymers readily undergo a kinetic arrest when stickers exhibit slow exchange while fast exchanging stickers at similar levels of saturation allow merger to equilibrium states. On the other hand, condensates composed of homopolymers fuse readily until they reach a threshold density. We also show that the inter-condensate exchange of chains offers a general mechanism that drives the fusion. We map the range of mechanisms of kinetic arrest from slow sticker exchange dynamics to density mediated in terms of energetic separation of stickers and spacers. Our predictions appear to be in excellent agreement with recent experiments probing dynamic nature of protein-RNA condensates.Significance statementA key conundrum of biological condensates is the coexistence of multiple droplets, in direct variance with classical predictions of mean-field theories of polymer solutions. We systematically investigated the coalescence tendency of such condensates made of sticker-spacer polymers and discovered that, even at a low density, these droplets show a kinetically arrested metastable state which is a distinct behavior compared to condensates made of homopolymers. Coupling of inter-sticker interaction strength and the finite valence nature of stickers enables kinetic arrest. Our prediction starkly correlates with recent experimental findings on protein-RNA condensates in vitro and in vivo, highlighting the biological relevance of the interplay of kinetics and thermodynamics.