Complex dynamics of multicomponent biological coacervates
TL;DR: The fundamental concepts discussed in this review are widely applicable, including in the context of cellular function and development of materials with novel properties in the areas of dynamics and multicomponent systems.
Abstract: Phase transitions and coacervates play key roles in natural and synthetic soft matter. In particular, the past few years have seen a rapid expansion in studies of these phenomena in the context of dynamic cellular compartmentalization. In this brief review, we mainly focus on a few concepts and selected in vitro and cellular examples of recent developments in the areas of dynamics and multicomponent systems. Topics covered include the flexibility and conformational dynamics of polymeric species involved in phase separation, valence and non-monotonic effects, noise modulation and feedback loops, and multicomponent systems and substructure. The fundamental concepts discussed in this review are widely applicable, including in the context of cellular function and the development of materials with novel properties.
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TL;DR: In this article , the authors demonstrate the recent development of α-Syn LLPS, the underlying mechanism along with the microscopic events of aberrant phase transition, and further discuss how several intrinsic and extrinsic factors regulate the thermodynamics and kinetics of αSynLLPS and co-LLPS with other proteins, which might explain the pathophysiology of α Syn in various neurodegenerative diseases.
16 citations
TL;DR: A recent tutorial review as mentioned in this paper summarizes the recent progress on engineering coacervate protocells to reproduce the function and structure of primitive life by multiphase organization, membranization and structural hybridization.
Abstract: The origin of life on Earth remains one of the biggest open questions in science. Despite recent advances in molecular mechanism of cell biology, a large blind spot still exists between non-living matter and the emergence of life which cannot be filled by biology alone. The quest to comprehend the cell origin inspires the construction of synthetic analogs (protocells) to mimic their life-like functionality and structural complexity. Among all kinds, coacervates formed by liquid-liquid phase separation featured by their dynamic structure, molecularly crowded interior and molecular sequestration capability, have been regarded as a protocell model for exploring the origin of life. Their biological counterparts in natural cells are also found to facilitate subcellular organization and spatiotemporal regulation of biological molecules. In this tutorial review, we summarize the recent progress on engineering coacervate protocells to potentially reproduce the function and structure of primitive life by multiphase organization, membranization and structural hybridization. Routes to high-ordered protocellular system comprising spatially arranged coacervates, as well as to the construction of tissue-like structures are also described. Finally, we deduce some perspectives of coacervate engineering in the direction of the emergence of life, from molecular scale to the emergence of integrated multicellular system.
6 citations
TL;DR: Kar et al. as mentioned in this paper proposed a percolation-based model of biomolecular condensates and showed that protein clusters follow a heavytailed distribution, with low abundance of larger mesoscale clusters and distributions changing with total protein concentration.
Abstract: A rapidly growing body of work in recent years has resulted in exciting advances in our understanding of the importance of biomolecular condensates (or, more generally, various forms of mesoscale to macroscale biological matter) and their transitions in biology and disease (1–3). At first glance, the physics of how liquids percolate through porous/granular materials or related concepts in network connectivity may not seem relevant to furthering our mechanistic understanding of biomolecular condensates. Interestingly, however, percolation theory has been extensively used in the related areas of polymer physics (4, 5) and phase transitions (as well as in numerous other fields). Now, in an exciting advance, Kar et al. (6) describe a combination of experimental, conceptual, and computational work that explores the connection between percolation physics and an important class of biomolecular condensation with links to neurodegenerative diseases. Conceptual understanding in the biomolecular condensate field has been extensively guided by simple forms of nucleation and Flory–Huggins-type theories. A prediction of this type of theory is that, below a saturation concentration (csat) of a single macromolecule (e.g., protein) in a solvent, the macromolecule will exist mainly as monomers and very small clusters, because there is a size-dependent energy penalty for cluster formation. It is only above the saturation concentration that phase separation (a density transition) will occur, resulting in the formation of a dense phase (aka micrometer-sized droplets). Now, Kar et al. (6) describe a broad set of data that can provide a test of this prediction. The proteins studied in this work are FET (FUS, EWSR1, TAF15) family proteins, with links to neurodegenerative disease, which have been extensively investigated in the field. Using a combination of imaging, dynamic light scattering (DLS), and single-particle (tracking, multiparameter fluorescence, and microfluidics-based) experiments, Kar et al. (6) show that, while phase separation is not observed in solutions below an effective csat, subsaturated solutions of these proteins contain a range of nanoscale clusters. The data indicate that clusters follow a heavytailed distribution, with low abundance of larger mesoscale clusters and distributions changing with total protein concentration. It is only above csat that larger micrometer-sized bodies that display coarsening appear. Fluorescence resonance energy transfer/DLS data show that cluster formation is reversible, and that protein exchanges between clusters. Together, these data draw a sharp contrast with the predictions based on nucleation theory discussed above. The authors then go on to invoke percolation theory–based ideas to offer an explanation for these observations, building on their and other previous work (4, 5, 7, 8). In percolation theory, there exists a critical connectivity probability (pc) at which the system undergoes a connectivity (geometric) transition, forming a system-spanning network (Fig. 1A). In the present work, the proteins are represented in a stickers and spacers model of associative polymers, with stickers contributing specific protein–protein interactions and spacers contributing generalized excluded volume/ solvation effects. In the framework of the percolation model, this system can undergo a percolation-type connectivity transition (via specific sticker–sticker interactions) at a critical protein concentration cperc (Fig. 1B). Thus, specific sticker– sticker interactions give rise to an additional energy scale class that contributes to system behavior. As previously described by the Pappu laboratory (8), this scenario can give rise to an interesting coupling between density and percolation transitions if the system/conditions result in cperc being greater than csat but less than the dense phase concentration cden. Under these conditions, a density transition results in a coupled percolation transition in the dense phase, since cden is greater than cperc. How does this relate to the authors’ experimental findings of molecular clusters below csat (6)? The key result from the percolation approach is that, even below the percolation threshold, smaller network clusters are still formed (Fig. 1), and the size distribution of these clusters shifts to larger sizes as the connectivity (concentration) is increased. As noted above, this is just what was observed in the authors’ measurements. The authors then looked at ways to test the coupling between the two types of transitions. Indeed, using small-molecule solutes or mutations as perturbations, they find either coupled or differential effects on formation of clusters and macroscopic phase separation. These results are consistent with the existence of separate types of interactions governing generalized solubility and specific connectivity effects, and the idea that these can be perturbed selectively but can also be coupled. The above work is also complemented with simulations whose results are in keeping with the above model. Overall, the work serves to inspire a number of lines of thinking and inquiry.
6 citations
TL;DR: In this article, the authors summarize and discuss the findings of several recent studies that have focused on structure, dynamics, and interactions of proteins undergoing condensation and speculate on effects of topological constraints and physical exclusion on condensate properties.
1 citations
TL;DR: In this article , the authors summarize and discuss the findings of several recent studies that have focused on structure, dynamics, and interactions of proteins undergoing condensation and speculate on effects of topological constraints and physical exclusion on condensate properties.
1 citations
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TL;DR: In this paper, a statistical treatment of high polymer solutions has been carried out on the basis of an idealized model, originally proposed by Meyer, which is analogous to the one ordinarily assumed in the derivation of the ''ideal'' solution laws for molecules of equal size.
Abstract: A statistical mechanical treatment of high polymer solutions has been carried out on the basis of an idealized model, originally proposed by Meyer, which is analogous to the one ordinarily assumed in the derivation of the ``ideal'' solution laws for molecules of equal size. There is obtained for the entropy of mixing of n solvent and N linear polymer molecules (originally disoriented), ΔS=−k[(n/β) ln v1+N ln v2] where v1 and v2 are volume fractions and β is the number of solvent molecules replaceable by a freely orienting segment of the polymer chain. This expression is similar in form to the classical expression for equal‐sized molecules, mole fractions having been replaced by volume fractions. When the disparity between the sizes of the two components is great, this expression gives entropies differing widely from the classical values, which accounts for the large deviations of high polymer solutions from ``ideal'' behavior. The entropy of disorientation of a perfectly arranged linear polymer is found t...
3,513 citations
TL;DR: This work has shown that liquid–liquid phase separation driven by multivalent macromolecular interactions is an important organizing principle for biomolecular condensates and has proposed a physical framework for this organizing principle.
Abstract: In addition to membrane-bound organelles, eukaryotic cells feature various membraneless compartments, including the centrosome, the nucleolus and various granules. Many of these compartments form through liquid–liquid phase separation, and the principles, mechanisms and regulation of their assembly as well as their cellular functions are now beginning to emerge. Biomolecular condensates are micron-scale compartments in eukaryotic cells that lack surrounding membranes but function to concentrate proteins and nucleic acids. These condensates are involved in diverse processes, including RNA metabolism, ribosome biogenesis, the DNA damage response and signal transduction. Recent studies have shown that liquid–liquid phase separation driven by multivalent macromolecular interactions is an important organizing principle for biomolecular condensates. With this physical framework, it is now possible to explain how the assembly, composition, physical properties and biochemical and cellular functions of these important structures are regulated.
3,294 citations
TL;DR: It is shown that P granules exhibit liquid-like behaviors, including fusion, dripping, and wetting, which is used to estimate their viscosity and surface tension, and reflects a classic phase transition, in which polarity proteins vary the condensation point across the cell.
Abstract: In sexually reproducing organisms, embryos specify germ cells, which ultimately generate sperm and eggs In Caenorhabditis elegans, the first germ cell is established when RNA and protein-rich P granules localize to the posterior of the one-cell embryo Localization of P granules and their physical nature remain poorly understood Here we show that P granules exhibit liquid-like behaviors, including fusion, dripping, and wetting, which we used to estimate their viscosity and surface tension As with other liquids, P granules rapidly dissolved and condensed Localization occurred by a biased increase in P granule condensation at the posterior This process reflects a classic phase transition, in which polarity proteins vary the condensation point across the cell Such phase transitions may represent a fundamental physicochemical mechanism for structuring the cytoplasm
2,134 citations
1,502 citations