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Thermodynamic origins of two-component multiphase condensates of proteins.

ABSTRACT: Intracellular condensates are highly multi-component systems in which complex phase behaviour can ensue, including the formation of architectures comprising multiple immiscible condensed phases. Relying solely on physical intuition to manipulate such condensates is difficult because of the complexity of their composition, and systematically learning the underlying rules experimentally would be extremely costly. We address this challenge by developing a computational approach to design pairs of protein sequences that result in well-separated multilayered condensates and elucidate the molecular origins of these compartments. Our method couples a genetic algorithm to a residue-resolution coarse-grained protein model. We demonstrate that we can design protein partners to form multiphase condensates containing naturally occurring proteins, such as the low-complexity domain of hnRNPA1 and its mutants, and show how homo- and heterotypic interactions must differ between proteins to result in multiphasicity. We also show that in some cases the specific pattern of amino-acid residues plays an important role. Our findings have wide-ranging implications for understanding and controlling the organisation, functions and material properties of biomolecular condensates.

SUBMITTER: Chew PY

PROVIDER: S-EPMC9931050 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Thermodynamic origins of two-component multiphase condensates of proteins.

Chew Pin Yu PY Joseph Jerelle A JA Collepardo-Guevara Rosana R Reinhardt Aleks A

Chemical science 20230125 7

Intracellular condensates are highly multi-component systems in which complex phase behaviour can ensue, including the formation of architectures comprising multiple immiscible condensed phases. Relying solely on physical intuition to manipulate such condensates is difficult because of the complexity of their composition, and systematically learning the underlying rules experimentally would be extremely costly. We address this challenge by developing a computational approach to design pairs of p ...[more]

PMID: 36819870

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Project description: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.

Project description:Biomolecular condensates, thought to form via liquid-liquid phase separation of intracellular mixtures, are multicomponent systems that can include diverse types of proteins and RNAs. RNA is a critical modulator of RNA-protein condensate stability, as it induces an RNA concentration-dependent reentrant phase transition-increasing stability at low RNA concentrations and decreasing it at high concentrations. Beyond concentration, RNAs inside condensates can be heterogeneous in length, sequence, and structure. Here, we use multiscale simulations to understand how different RNA parameters interact with one another to modulate the properties of RNA-protein condensates. To do so, we perform residue/nucleotide resolution coarse-grained molecular dynamics simulations of multicomponent RNA-protein condensates containing RNAs of different lengths and concentrations, and either FUS or PR25 proteins. Our simulations reveal that RNA length regulates the reentrant phase behavior of RNA-protein condensates: increasing RNA length sensitively rises the maximum value that the critical temperature of the mixture reaches, and the maximum concentration of RNA that the condensate can incorporate before beginning to become unstable. Strikingly, RNAs of different lengths are organized heterogeneously inside condensates, which allows them to enhance condensate stability via two distinct mechanisms: shorter RNA chains accumulate at the condensate's surface acting as natural biomolecular surfactants, while longer RNA chains concentrate inside the core to saturate their bonds and enhance the density of molecular connections in the condensate. Using a patchy particle model, we additionally demonstrate that the combined impact of RNA length and concentration on condensate properties is dictated by the valency, binding affinity, and polymer length of the various biomolecules involved. Our results postulate that diversity on RNA parameters within condensates allows RNAs to increase condensate stability by fulfilling two different criteria: maximizing enthalpic gain and minimizing interfacial free energy; hence, RNA diversity should be considered when assessing the impact of RNA on biomolecular condensates regulation.

Dataset Information

Thermodynamic origins of two-component multiphase condensates of proteins.

Publications

Thermodynamic origins of two-component multiphase condensates of proteins.

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