Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 26, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2119800119
Keywords
biomolecular condensates; multiscale modeling multiphase condensates; liquid-liquid phase separation; hollow condensates
Categories
Funding
- European Research Council (ERC) under the European Union [766972, 841466]
- European Union [337969]
- ERC [803326]
- Engineering and Physical Sciences Research Council (EPSRC) [EP/N509620/]
- Winton Programme
- Oppenheimer Research Fellowship
- Emmanuel College Roger Ekins Fellowship
- King's College Research Fellowship
- Herchel Smith Funds
- Wolfson College Junior Research Fellowship
- Newman Foundation
- Biotechnology and Biological Sciences Research Council
- Winton Advanced Research Fellowship
- Wellcome Trust [203249/Z/16/Z]
- EPSRC Tier-2 Capital Grant [EP/P020259/1]
- European Research Council (ERC) [803326] Funding Source: European Research Council (ERC)
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This research investigates the thermodynamic factors that contribute to the transformation of single-component biomolecular condensates into multiphase architectures during the nonequilibrium process of aging. By developing a multiscale model and performing nonequilibrium simulations, the researchers predict that single-component condensates can gradually transform into gel-core/liquid-shell or liquid-core/gel-shell multiphase condensates as they age. 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.
Phase-separated biomolecular condensates that contain multiple coexisting phases are widespread in vitro and in cells. Multiphase condensates emerge readily within multi-component 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/gelshell 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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