scholarly journals Investigating Large Scale Liquid-Liquid Phase Separation in a Biological Membrane

2016 ◽  
Vol 110 (3) ◽  
pp. 74a
Author(s):  
Scott Rayermann ◽  
Sarah Keller
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Large Scale ◽  
Biological Membrane ◽  
Liquid Phase Separation ◽  
Liquid Liquid Phase Separation

scholarly journals Mesoscale liquid model of chromatin recapitulates nuclear order of eukaryotes

2019 ◽  
Author(s):  
Rabia Laghmach ◽  
Michele Di Pierro ◽  
Davit A Potoyan
Keyword(s):  
Phase Separation ◽  
Life Cycle ◽  
Liquid Phase ◽  
Large Scale ◽  
Surface Effects ◽  
Liquid Phase Separation ◽  
Nuclear Chromatin ◽  
Scale Morphology ◽  
Liquid Model ◽  
Liquid Liquid Phase Separation

ABSTRACTThe nuclear envelope segregates the genome of Eukaryota from the cytoplasm. Within the nucleus, chromatin is further compartmentalized into architectures that change throughout the lifetime of the cell. Epigenetic patterns along the chromatin polymer strongly correlate with chromatin compartmentalization and, accordingly, also change during the cell life cycle and at differentiation. Recently, it has been suggested that sub-nuclear chromatin compartmentalization might result from a process of liquid-liquid phase separation orchestrated by the epigenetic marking and operated by proteins that bind to chromatin. Here, we translate these observations into a diffuse interface model of chromatin, which we named MEsoscale Liquid mOdel of Nucleus (MELON). Using this streamlined continuum model of the genome, we study the large-scale rearrangements of chromatin that happen at different stages of the growth and senescence of the cell, and during nuclear inversion events. Particularly, we investigate the role of droplet diffusion, fluctuations, and heterochromatin-lamina interactions during nuclear remodeling. Our results indicate that the physical process of liquid-liquid phase separation, together with surface effects is sufficient to recapitulate much of the large-scale morphology and dynamics of chromatin along the life cycle of cells.SIGNIFICANCE STATEMENTEukaryotic chromatin occupies a few micrometers of nuclear space while remaining dynamic and accessible for gene regulation. The physical state of nuclear chromatin is shaped by the juxtaposition of complex, out of equilibrium processes on one hand and intrinsic polymeric aspect of the genome on the other. Recent experiments have revealed a remarkable ability of disordered nuclear proteins to drive liquid-liquid phase separation of chromatin domains. We have built a mesoscale liquid model of nuclear chromatin which allows dissecting the contribution of liquid behavior of chromatin to nuclear order of eukaryotes. Our results show that liquid-liquid phase separation, together with surface effects is sufficient for recapitulating large-scale morphology and dynamics of chromatin at many stages of the nuclear cycle.

scholarly journals Liquid-Liquid Phase Separation is Driven by Large-Scale Conformational Unwinding and Fluctuations of Intrinsically Disordered Protein Molecules

2019 ◽  
Author(s):  
Anupa Majumdar ◽  
Priyanka Dogra ◽  
Shiny Maity ◽  
Samrat Mukhopadhyay
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Large Scale ◽  
Intrinsically Disordered Proteins ◽  
Intrinsically Disordered Protein ◽  
Liquid Phase Separation ◽  
Disordered Proteins ◽  
Fluorescence Depolarization ◽  
Intrinsically Disordered ◽  
Liquid Liquid Phase Separation

ABSTRACTLiquid-liquid phase separation occurs via a multitude of transient, non-covalent, intermolecular interactions resulting in phase transition of intrinsically disordered proteins/regions (IDPs/IDRs) and other biopolymers into mesoscopic, dynamic, non-stoichiometric, supramolecular condensates. IDPs resemble associative polymers possessing stereospecific “stickers” and flexible “spacers” that govern the transient chain-chain interactions and fluidity in phase-separated liquid droplets. However, the fundamental molecular origin of phase separation remains elusive. Here we present a unique case to demonstrate that unusual conformational expansion events coupled with solvation and fluctuations drive phase separation of tau, an IDP associated with Alzheimer’s disease. Using intramolecular excimer emission as a powerful proximity readout, we show the unraveling of polypeptide chains within the protein-rich interior environment that can promote critical interchain contacts. Using highly-sensitive picosecond time-resolved fluorescence depolarization measurements, we directly capture rapid large-amplitude torsional fluctuations in the extended chains that can control the relay of making-and-breaking of noncovalent intermolecular contacts maintaining the internal fluidity. Our observations, together with the existing polymer theories, suggest that such an orchestra of concerted molecular shapeshifting events involving chain expansion, solvation, and fluctuations can provide additional favorable free energies to overcome the entropy of mixing term during phase separation. The interplay of these key molecular parameters can also be of prime importance in modulating the mesoscale material property of liquid-like condensates and their maturation of into pathological gel-like and solid-like aggregates.

scholarly journals Emulsion patterns in the wake of a liquid–liquid phase separation front

2018 ◽  
Vol 115 (14) ◽  
pp. 3599-3604 ◽  
Author(s):  
Pepijn G. Moerman ◽  
Pierre C. Hohenberg ◽  
Eric Vanden-Eijnden ◽  
Jasna Brujic
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Large Scale ◽  
Scaling Law ◽  
Liquid Phase Separation ◽  
Scale Free ◽  
Transport Control ◽  
Droplet Sizes ◽  
Miscible Liquids ◽  
Liquid Liquid Phase Separation

Miscible liquids can phase separate in response to a composition change. In bulk fluids, the demixing begins on molecular-length scales, which coarsen into macroscopic phases. By contrast, confining a mixture in microfluidic droplets causes sequential phase separation bursts, which self-organize into rings of oil and water to make multilayered emulsions. The spacing in these nonequilibrium patterns is self-similar and scale-free over a range of droplet sizes. We develop a modified Cahn–Hilliard model, in which an immiscibility front with stretched exponential dynamics quantitatively predicts the spacing of the layers. In addition, a scaling law predicts the lifetime of each layer, giving rise to a stepwise release of inner droplets. Analogously, in long rectangular capillaries, a diffusive front yields large-scale oil and water stripes on the time scale of hours. The same theory relates their characteristic length scale to the speed of the front and the rate of mass transport. Control over liquid–liquid phase separation into large-scale patterns finds potential material applications in living cells, encapsulation, particulate design, and surface patterning.

scholarly journals dSCOPE: a software to detect sequences critical for liquid-liquid phase separation

2021 ◽  
Author(s):  
Shihua Li ◽  
Kai Yu ◽  
Qingfeng Zhang ◽  
Zekun Liu ◽  
Jia Liu ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Large Scale ◽  
Liquid Phase Separation ◽  
Post Translational Modifications ◽  
P Bodies ◽  
Large Scale Analysis ◽  
Cancer Mutations ◽  
And Function ◽  
Liquid Liquid Phase Separation

ABSTRACTMembrane based cells are the fundamental structure and function units of organisms, while evidences were increasing that liquid-liquid phase separation (LLPS) is associated with the formation of membraneless organelles, such as P-bodies, nucleoli and stress granules. Many studies have been undertaken to explore the functions of protein phase separation, but these studies lacked an effective tool to identify the sequence segments that critical for LLPS (SCOPEs). In this study, we presented a novel software called dSCOPE (http://dscope.omicsbio.info) to predict the SCOPEs. To develop the predictor, we curated experimentally identified sequence segments that can drive LLPS from published literature. Then sliding sequence window based physiological, biochemical, structural and coding features were integrated by random forest algorithm to perform prediction. Through rigorous evaluation, dSCOPE was demonstrated to achieve satisfactory performance. Furthermore, large-scale analysis of human proteome based on dSCOPE showed that the predicted SCOPEs enriched various protein post-translational modifications and cancer mutations, and the proteins which contain predicted SCOPEs enriched critical cellular signaling pathways. Taken together, dSCOPE precisely predicted the protein sequence segments critical for LLPS, with various helpful information visualized in the webserver to facilitate LLPS related research.

scholarly journals Consistent Force Field Captures Homolog Resolved HP1 Phase Separation

2021 ◽  
Author(s):  
Andrew P. Latham ◽  
Bin Zhang
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Force Field ◽  
Large Scale ◽  
Spatial Organization ◽  
Structural Difference ◽  
Liquid Phase Separation ◽  
Coarse Grained ◽  
Disordered Proteins ◽  
Liquid Liquid Phase Separation

Many proteins have been shown to function via liquid-liquid phase separation. Computational modeling could offer much needed structural details of protein condensates and reveal the set of molecular interactions that dictate their stability. However, the presence of both ordered and disordered domains in these proteins places a high demand on the model accuracy. Here, we present an algorithm to derive a coarse-grained force field, MOFF, that can model both ordered and disordered proteins with consistent accuracy. It combines maximum entropy biasing, least-squares fitting, and basic principles of energy landscape theory to ensure that MOFF recreates experimental radii of gyration while predicting the folded structures for globular proteins with lower energy. The theta temperature determined from MOFF separates ordered and disordered proteins at 300 K and exhibits a strikingly linear relationship with amino acid sequence composition. We further applied MOFF to study the phase behavior of HP1, an essential protein for posttranslational modification and spatial organization of chromatin. The force field successfully resolved the structural difference of two HP1 homologs, despite their high sequence similarity. We carried out large scale simulations with hundreds of proteins to determine the critical temperature of phase separation and uncover multivalent interactions that stabilize higher-order assemblies. In all, our work makes significant methodological strides to connect theories of ordered and disordered proteins and provides a powerful tool for studying liquid-liquid phase separation with near-atomistic details.

scholarly journals Liquid-Liquid Phase Separation of Tau Driven by Hydrophobic Interaction Facilitates Fibrillization of Tau

2021 ◽  
Vol 433 (2) ◽  
pp. 166731
Author(s):  
Yanxian Lin ◽  
Yann Fichou ◽  
Andrew P. Longhini ◽  
Luana C. Llanes ◽  
Pengyi Yin ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Hydrophobic Interaction ◽  
Liquid Phase Separation ◽  
Liquid Liquid Phase Separation

scholarly journals Amyloid Aggregation under the Lens of Liquid–Liquid Phase Separation

2020 ◽  
pp. 368-378
Author(s):  
Yanting Xing ◽  
Aparna Nandakumar ◽  
Aleksandr Kakinen ◽  
Yunxiang Sun ◽  
Thomas P. Davis ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Amyloid Aggregation ◽  
Liquid Liquid Phase Separation

scholarly journals Observation of liquid-liquid phase separation of ataxin-3 and quantitative evaluation of its concentration in a single droplet using Raman microscopy

2021 ◽  
Author(s):  
Kazuki Murakami ◽  
Shinji Kajimoto ◽  
Daiki Shibata ◽  
Kunisato Kuroi ◽  
Fumihiko Fujii ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Quantitative Evaluation ◽  
Raman Microscopy ◽  
Liquid Phase Separation ◽  
Biological Processes ◽  
Single Droplet ◽  
Liquid Liquid Phase Separation

Liquid–liquid phase separation (LLPS) plays an important role in a variety of biological processes and is also associated with protein aggregation in neurodegenerative diseases. Quantification of LLPS is necessary to...

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