Aging can transform single-component protein condensates into multiphase architectures.

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Phase-separated biomolecular condensates that contain multiple coexisting phases are widespread in vitro and in cells. Multiphase condensates emerge readily within multicomponent mixtures of biomolecules (e.g., proteins and nucleic acids) when the different components present sufficient physicochemical diversity (e.g., in intermolecular forces, structure, and chemical composition) to sustain separate coexisting phases. Because such diversity is highly coupled to the solution conditions (e.g., temperature, pH, salt, composition), it can manifest itself immediately from the nucleation and growth stages of condensate formation, develop spontaneously due to external stimuli or emerge progressively as the condensates age. Here, we investigate thermodynamic factors that can explain the progressive intrinsic transformation of single-component condensates into multiphase architectures during the nonequilibrium process of aging. We develop a multiscale model that integrates atomistic simulations of proteins, sequence-dependent coarse-grained simulations of condensates, and a minimal model of dynamically aging condensates with nonconservative intermolecular forces. Our nonequilibrium simulations of condensate aging predict that single-component condensates that are initially homogeneous and liquid like can transform into gel-core/liquid-shell or liquid-core/gel-shell multiphase condensates as they age due to gradual and irreversible enhancement of interprotein interactions. The type of multiphase architecture is determined by the aging mechanism, the molecular organization of the gel and liquid phases, and the chemical makeup of the protein. Notably, we predict that interprotein disorder to order transitions within the prion-like domains of intracellular proteins can lead to the required nonconservative enhancement of intermolecular interactions. Our study, therefore, predicts a potential mechanism by which the nonequilibrium process of aging results in single-component multiphase condensates.

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biomolecular condensates, hollow condensates, liquid–liquid phase separation, multiscale modeling multiphase condensates, Aging, Biomolecular Condensates, Models, Biological, Molecular Dynamics Simulation, Protein Conformation, beta-Strand, RNA-Binding Protein FUS, Thermodynamics
Journal Title
Proc Natl Acad Sci U S A
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Proceedings of the National Academy of Sciences
European Research Council (803326)
European Research Council (337969)
Engineering and Physical Sciences Research Council (EP/P020259/1)
Wellcome Trust (203249/Z/16/Z)
European Commission Horizon 2020 (H2020) Future and Emerging Technologies (FET) (766972)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (841466)
Adiran Garaizar acknowledges funding from the EPRSC (EP/N509620)