Thermodynamics and kinetics of phase separation of protein-RNA mixtures by a minimal model

Joseph, Jerelle A.; Espinosa, Jorge R.; Sanchez-Burgos, Ignacio; Garaizar, Adiran; Frenkel, Daan; Collepardo-Guevara, Rosana

doi:10.1016/j.bpj.2021.01.031

Cited by 70 publications

(105 citation statements)

References 115 publications

(100 reference statements)

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“…Various levels of molecular resolution can be achieved with CG models; encompassing mean field models 49,50 , lattice-based simulations 51,52 , minimal models 44,45,[53][54][55][56] , and coarse-grained sequence-dependent simulations 42,[57][58][59][60][61] . Here, we employ our minimal protein model 43 , which has been previously applied to unveil the role of protein multivalency in multicomponent condensates 62 and multilayered condensate organization 63 , as well as to investigate the role of RNA in RNA-binding protein nucleation and stability 64 . In this model, proteins are described by a pseudo hard-sphere potential 65 that accounts for their excluded volume, and by short-range potentials for modeling the different protein binding sites, and thereby mimicking protein multivalency 43 (Fig.…”

Section: A Minimal Protein Model For Scaffold and Client Mixturesmentioning

confidence: 99%

Size Conservation Emerges Spontaneously in Biomolecular Condensates Formed by Scaffolds and Surfactant Clients

Sanchez-Burgos

Joseph

Collepardo-Guevara

et al. 2021

Preprint

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Biomolecular condensates are liquid-like membraneless compartments that contribute to the spatiotemporal organization of proteins, RNA, and other biomolecules inside cells. Some membraneless compartments, such as nucleoli, are dispersed as different condensates that do not grow beyond a certain size, or do not present coalescence over time. In this work, using a minimal protein model, we show that phase separation of binary mixtures of scaffolds and low-valency clients that can act as surfactants—i.e., that significantly reduce the droplet surface tension—can yield either a single drop or multiple droplets that conserve their sizes on long timescales (herein ‘multidroplet size-conserved’), depending on the scaffold to client ratio. Our simulations demonstrate that protein connectivity and condensate surface tension regulate the balance between these two scenarios. Multidroplet size-conserved behavior spontaneously arises at increasing surfactant-to-scaffold concentrations, when the interfacial penalty for creating small liquid droplets is sufficiently reduced by the surfactant proteins that are preferentially located at the interface. In contrast, low surfactant-to-scaffold concentrations enable continuous growth and fusion of droplets without restrictions. Overall, our work proposes one potential thermodynamic mechanism to help rationalize how size-conserved coexisting condensates can persist inside cells—shedding light on the roles of general biomolecular features such as protein connectivity, binding affinity, and droplet composition in this process.

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Section: A Minimal Protein Model For Scaffold and Client Mixturesmentioning

confidence: 99%

Size Conservation Emerges Spontaneously in Biomolecular Condensates Formed by Scaffolds and Surfactant Clients

Sanchez-Burgos

Joseph

Collepardo-Guevara

et al. 2021

Preprint

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“…22,23 The presence of nucleotides can give rise to a scaffold-client mechanism to drive the phase separation of IDPs that do not aggregate on their own. 24,25 The stability of the formed condensates exhibits nonmonotonic dependence on nucleotide concentration, giving rise to the so-called reentrant phase separation. 26,27 Further, multiple component phase separation supports novel outcomes not present in binary polymer-solvent mixtures.…”

Section: Introductionmentioning

confidence: 99%

On the stability and layered organization of protein-DNA condensates

Latham

Zhang

2021

Preprint

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Multi-component phase separation is emerging as a key mechanism for the formation of biological condensates that play essential roles in signal sensing and transcriptional regulation. The molecular factors that dictate these condensates’ stability and spatial organization are not fully understood, and it remains challenging to predict their microstructures. Using a near-atomistic, chemically accurate force field, we studied the phase behavior of chromatin regulators that are crucial for heterochromatin organization and their interactions with DNA. Our computed phase diagrams recapitulated previous experimental findings on different proteins. They revealed a strong dependence of condensate stability on the protein-DNA mixing ratio as a result of balancing protein-protein interactions and charge neutralization. Notably, a layered organization was observed in condensates formed by mixing HP1, histone H1, and DNA. This layered organization may be of biological relevance as it enables cooperative DNA packaging between the two chromatin regulators: histone H1 softens the DNA to facilitate the compaction induced by HP1 droplets. Our study supports near atomistic models as a valuable tool for characterizing the structure and stability of biological condensates.

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“…and high-resolution sequence-dependent approaches [54,[62][63][64][65]109], are becoming the go-to simulation methods for characterizing the mechanistic and molecular details of biomolecular condensates. Here, we employ two protein/RNA coarse-grained models of different resolutions, previously developed by us, to elucidate the role of RNA length in modulating LLPS of RBPs: (1) the Mpipi sequence-dependent residue-resolution coarsegrained force field for proteins and RNA [55], and (2) a minimal model in which proteins are represented as patchy particles, and RNA as self-repulsive flexible polymers [67,88] (Figure 1 (a)).…”

Section: Resultsmentioning

confidence: 99%

RNA length has a non-trivial effect in the stability of biomolecular condensates formed by RNA-binding proteins

Sanchez-Burgos

Espinosa

Joseph

et al. 2021

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Biomolecular condensates formed via liquid-liquid phase separation (LLPS) play a crucial role in the spatiotemporal organization of the cell material. Nucleic acids can act as critical modulators in the stability of these protein condensates. Here, we present a multiscale computational strategy, exploiting the advantages of both a sequence-dependent coarse-grained representation of proteins and a minimal coarse-grained model that represent proteins as patchy colloids, to unveil the role of RNA length in regulating the stability of RNA-binding protein (RBP) condensates. We find that for a constant RNA/protein ratio in which phase separation is enhanced, the protein fused in sarcoma (FUS), which can phase separate on its own-i.e., via homotypic interactions-only exhibits a mild dependency on the RNA strand length, whereas, the 25-repeat proline-arginine peptide (PR25), which does not undergo LLPS on its own at physiological conditions but instead exhibits complex coavervation with RNA-i.e., via heterotypic interactions-shows a strong dependence on the length of the added RNA chains. Our minimal patchy particle simulations, where we recapitulate the modulation of homotypic protein LLPS and complex coacervation by RNA length, suggest that the strikingly different effect of RNA length on homotypic LLPS versus complex coacervation is general. Phase separation is RNA-length dependent as long as the relative contribution of heterotypic interactions sustaining LLPS is comparable or higher than that committed by protein homotypic interactions. Taken together, our results contribute to illuminate the intricate physicochemical mechanisms that influence the stability of RBP condensates through RNA inclusion.

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Thermodynamics and kinetics of phase separation of protein-RNA mixtures by a minimal model

Cited by 70 publications

References 115 publications

Size Conservation Emerges Spontaneously in Biomolecular Condensates Formed by Scaffolds and Surfactant Clients

Size Conservation Emerges Spontaneously in Biomolecular Condensates Formed by Scaffolds and Surfactant Clients

On the stability and layered organization of protein-DNA condensates

RNA length has a non-trivial effect in the stability of biomolecular condensates formed by RNA-binding proteins

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