To Mix, or To Demix, That Is the Question

Harmon, Tyler S.; Holehouse, Alex S.; Pappu, Rohit V.

doi:10.1016/j.bpj.2016.12.031

Cited by 18 publications

(15 citation statements)

References 10 publications

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“…By considering hypothetical intercomponent interaction strengths (contact energies), the authors found that with sufficient heterogeneity in contact energies, demixed domains are likely to segregate. This and other results of this big-picture study suggest that phase separation into cellular compartments with different compositions is a robust consequence of interaction heterogeneity among biomolecules [72,73].…”

Section: Sequence-dependent Multiple-component Idp Phase Separationsupporting

confidence: 73%

Charge pattern matching as a ‘fuzzy’ mode of molecular recognition for the functional phase separations of intrinsically disordered proteins

et al. 2017

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Biologically functional liquid-liquid phase separation of intrinsically disordered proteins (IDPs) is driven by interactions encoded by their amino acid sequences. Little is currently known about the molecular recognition mechanisms for distributing different IDP sequences into various cellular membraneless compartments. Pertinent physics was addressed recently by applying random-phaseapproximation (RPA) polymer theory to electrostatics, which is a major energetic component governing IDP phase properties. RPA accounts for charge patterns and thus has advantages over Flory-Huggins (FH) and Overbeek-Voorn mean-field theories. To make progress toward deciphering the phase behaviors of multiple IDP sequences, the RPA formulation for one IDP species plus solvent is hereby extended to treat polyampholyte solutions containing two IDP species plus solvent. The new formulation generally allows for binary coexistence of two phases, each containing a different set of volume fractions , 1 2 OPEN ACCESS RECEIVED

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Section: Sequence-dependent Multiple-component Idp Phase Separationsupporting

confidence: 73%

Charge pattern matching as a ‘fuzzy’ mode of molecular recognition for the functional phase separations of intrinsically disordered proteins

et al. 2017

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“…Multicompartment coacervates have recently been developed based on ELPs with different chain lengths (Simon et al, 2017), and different IDPs derived from nucleoli (Feric et al, 2016), in an attempt to better understand the hierarchical organization of the numerous different components found in many MLOs. A related aspect that has not been experimentally addressed yet, is how different types of coacervates or MLOs could coexist in the same cytosol, without mixing (Feric et al, 2016; Harmon et al, 2017b), as has long been known for many other multicomponent liquid mixtures (Mace et al, 2012; Torre et al, 2014). This could be connected to amphipathic biomolecules that adsorb at the liquid-liquid interface to stabilize it (Mason et al, 2017; Simon et al, 2017), or to a continuous turnover of coacervate material, away from thermodynamic equilibrium, in order to suppress Ostwald ripening (Zwicker et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Biomolecular Chemistry in Liquid Phase Separated Compartments

Nakashima

Vibhute

Spruijt

2019

Front. Mol. Biosci.

171

167

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Biochemical processes inside the cell take place in a complex environment that is highly crowded, heterogeneous, and replete with interfaces. The recently recognized importance of biomolecular condensates in cellular organization has added new elements of complexity to our understanding of chemistry in the cell. Many of these condensates are formed by liquid-liquid phase separation (LLPS) and behave like liquid droplets. Such droplet organelles can be reproduced and studied in vitro by using coacervates and have some remarkable features, including regulated assembly, differential partitioning of macromolecules, permeability to small molecules, and a uniquely crowded environment. Here, we review the main principles of biochemical organization in model membraneless compartments. We focus on some promising in vitro coacervate model systems that aptly mimic part of the compartmentalized cellular environment. We address the physicochemical characteristics of these liquid phase separated compartments, and their impact on biomolecular chemistry and assembly. These model systems enable a systematic investigation of the role of spatiotemporal organization of biomolecules in controlling biochemical processes in the cell, and they provide crucial insights for the development of functional artificial organelles and cells.

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“…Mean field theories based on interactions drawn from a statistical distribution or averaged over specific sequences account for the scenarios depicted in figures 1(a)-(e). However, the biologically relevant scenarios (figures 1(f), (g)) of spatially organized core-shell architectures cannot be described by mean field theories [33]. In this work, we show that explicit consideration of sequenceencoded solvation preferences of disordered linkers in linear multivalent proteins provides a necessary and sufficient minimalist numerical framework for modeling the emergence of spatially organized coexisting phases.…”

Section: Introductionmentioning

confidence: 90%

Differential solvation of intrinsically disordered linkers drives the formation of spatially organized droplets in ternary systems of linear multivalent proteins

2018

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Intracellular biomolecular condensates are membraneless organelles that encompass large numbers of multivalent protein and nucleic acid molecules. The bodies assemble via a combination of liquidliquid phase separation and gelation. A majority of condensates included multiple components and show multilayered organization as opposed to being well-mixed unitary liquids. Here, we put forward a simple thermodynamic framework to describe the emergence of spatially organized droplets in multicomponent systems comprising of linear multivalent polymers also known as associative polymers. These polymers, which mimic proteins and/or RNA have the architecture of domains or motifs known as stickers that are interspersed by flexible spacers known as linkers. Using a minimalist numerical model for a four-component system, we have identified features of linear multivalent molecules that are necessary and sufficient for generating spatially organized droplets. We show that differences in sequence-specific effective solvation volumes of disordered linkers between interaction domains enable the formation of spatially organized droplets. Molecules with linkers that are preferentially solvated are driven to the interface with the bulk solvent, whereas molecules that have linkers with negligible effective solvation volumes form cores in the core-shell architectures that emerge in the minimalist four-component systems. Our modeling has relevance for understanding the physical determinants of spatially organized membraneless organelles. Recent advances have helped in uncovering many of the key determinants of material properties and assembly mechanisms of well-established membraneless organelles [10,11]. Most membraneless organelles are referred to as biomolecular condensates [10,11] because they appear to be non-stoichiometric assemblies of proteins and nucleic acids that are akin to networked fluids that form via liquid-liquid phase separation (LLPS) and gelation [13][14][15][16]. Here, LLPS refers to a density transition, which leads to the formation of spherical droplets OPEN ACCESS

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To Mix, or To Demix, That Is the Question

Cited by 18 publications

References 10 publications

Charge pattern matching as a ‘fuzzy’ mode of molecular recognition for the functional phase separations of intrinsically disordered proteins

Charge pattern matching as a ‘fuzzy’ mode of molecular recognition for the functional phase separations of intrinsically disordered proteins

Biomolecular Chemistry in Liquid Phase Separated Compartments

Differential solvation of intrinsically disordered linkers drives the formation of spatially organized droplets in ternary systems of linear multivalent proteins

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