Fundamental Aspects of Phase-Separated Biomolecular Condensates

Chemical Reviews, Год журнала: 2024, Номер 124(13), С. 8550 - 8595

Опубликована: Июнь 17, 2024

Biomolecular condensates, formed through phase separation, are upending our understanding in much of molecular, cell, and developmental biology. There is an urgent need to elucidate the physicochemical foundations behaviors properties biomolecular condensates. Here we aim fill this by writing a comprehensive, critical, accessible review on fundamental aspects phase-separated We introduce relevant theoretical background, present basis for computation experimental measurement condensate properties, give mechanistic interpretations terms interactions at molecular residue levels.

Язык: Английский

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Active learning of the thermodynamics-dynamics trade-off in protein condensates

Science Advances, Год журнала: 2024, Номер 10(1)

Опубликована: Янв. 5, 2024

Phase-separated biomolecular condensates exhibit a wide range of dynamic properties, which depend on the sequences constituent proteins and RNAs. However, it is unclear to what extent condensate dynamics can be tuned without also changing thermodynamic properties that govern phase separation. Using coarse-grained simulations intrinsically disordered proteins, we show thermodynamics homopolymer are strongly correlated, with increased stability being coincident low mobilities high viscosities. We then apply an “active learning” strategy identify heteropolymer break this correlation. This data-driven approach accompanying analysis reveal how heterogeneous amino acid compositions nonuniform sequence patterning map independently tunable condensates. Our results highlight key molecular determinants governing physical establish design rules for development stimuli-responsive biomaterials.

Язык: Английский

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Disordered regions of condensate-promoting proteins have distinct molecular signatures associated with cellular function

Journal of Molecular Biology, Год журнала: 2025, Номер unknown, С. 168953 - 168953

Опубликована: Янв. 1, 2025

Язык: Английский

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Differential Effects of Sequence-Local versus Nonlocal Charge Patterns on Phase Separation and Conformational Dimensions of Polyampholytes as Model Intrinsically Disordered Proteins

The Journal of Physical Chemistry Letters, Год журнала: 2024, Номер 15(32), С. 8248 - 8256

Опубликована: Авг. 6, 2024

Conformational properties of intrinsically disordered proteins (IDPs) are governed by a sequence-ensemble relationship. To differentiate the impact sequence-local versus sequence-nonlocal features an IDP's charge pattern on its conformational dimensions and phase-separation propensity, "blockiness" κ nonlocality-weighted sequence decoration (SCD) parameters compared for their correlations with isolated-chain radii gyration (Rgs) upper critical solution temperatures (UCSTs) polyampholytes modeled random phase approximation, field-theoretic simulation, coarse-grained molecular dynamics. SCD is superior to in predicting Rg because accounts effects contact order, i.e., nonlocality, isolated chains. In contrast, comparably good, though nonideal, predictors UCST frequencies interchain contacts multiple-chain condensed less sensitive positions than intrachain chain, as reflected correlating better condensed-phase interaction energy SCD.

Язык: Английский

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Predicting Heteropolymer Interactions: Demixing and Hypermixing of Disordered Protein Sequences

Physical Review X, Год журнала: 2024, Номер 14(3)

Опубликована: Июль 18, 2024

Cells contain multiple condensates which spontaneously form due to the heterotypic interactions between their components. Although proteins and disordered region sequences that are responsible for condensate formation have been extensively studied, rule of components allow demixing, i.e., coexistence condensates, is yet be elucidated. Here, we construct an effective theory interaction heteropolymers by fitting it molecular dynamics simulation results obtained more than 200 sampled from regions human proteins. We find sum amino acid pair across two predicts Boyle temperature qualitatively well, can quantitatively improved dimer approximation, where incorporate effect neighboring acids in sequences. The theory, combined with finding a metric captures strength distinct sequences, allowed selection up three demix each other multicomponent simulations, as well generation artificial given sequence. points generic sequence design strategy or hypermix thanks low-dimensional nature space identify. As consequence geometric arguments interactions, number strongly constrained, irrespective choice coarse-grained model. Altogether, theoretical basis methods estimate heteropolymers, utilized predicting phase separation properties rules assignment localization functions Published American Physical Society 2024

Язык: Английский

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Emergence of Multiphase Condensates from a Limited Set of Chemical Building Blocks

Journal of Chemical Theory and Computation, Год журнала: 2024, Номер 20(15), С. 6881 - 6889

Опубликована: Июль 30, 2024

Biomolecules composed of a limited set chemical building blocks can colocalize into distinct, spatially segregated compartments known as biomolecular condensates. While many condensates are to form spontaneously via phase separation, it has been unclear how immiscible with precisely controlled molecular compositions assemble from small number blocks. We address this question by establishing connection between the specificity interactions and thermodynamic stability coexisting By computing minimum interaction required target compositions, we show design heteropolymer mixtures that produce compositionally complex using only monomer types. Our results provide insight compositional arises in naturally occurring multicomponent demonstrate rational algorithm for engineering artificial simple

Язык: Английский

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Active phase separation: new phenomenology from non-equilibrium physics

Reports on Progress in Physics, Год журнала: 2025, Номер 88(5), С. 056601 - 056601

Опубликована: Май 1, 2025

Abstract In active systems, whose constituents have non-equilibrium dynamics at local level, fluid-fluid phase separation is widely observed. Examples include the formation of membraneless organelles within cells; clustering self-propelled colloidal particles in absence attractive forces, and some types ecological segregation. A schematic understanding such was initially borrowed from what known for equilibrium case, which detailed balance holds microscopic level. However it has recently become clear that systems balance, although leave qualitatively unchanged regimes (for example domain growth driven by interfacial tension via Ostwald ripening), can other radically alter its phenomenology mechanistic For example, microphase be caused reverse ripening, a process hard to imagine an perspective. This new phenomena arise because, instead having single, positive like their counterparts, interfaces created several distinct tensions governing different properties, negative. These broadly understood studying continuum field theories single conserved scalar order parameter (the fluid density), supplemented with velocity cases where momentum conservation also present. More complex described multiple parameters (especially nonreciprocal interactions between these); or when undergoes both non-conserved (such combination breaks balance); support orientational long-range one more coexisting phases. this Review, we survey recent progress specific role activity separation, drawing attention many open questions. We focus primarily on theories, especially those parameter, reviewing analytical numerical work. compare predictions particle-based models, mostly been studied numerically few explicitly coarse-grained compare, possible, experimental results. latter qualitative comparisons are encouraging whereas quantitative ones hindered dynamical complexity most relative simplified (particle-level continuum) models matter.

Язык: Английский

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Phase Separation in Complex Mixtures with Many Components: Analytical Expressions for Spinodal Manifolds

ACS Omega, Год журнала: 2024, Номер 9(21), С. 22677 - 22690

Опубликована: Май 13, 2024

The phase behavior is investigated for systems composed of a large number macromolecular components

Язык: Английский

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Reaction-Driven Diffusiophoresis of Liquid Condensates: Potential Mechanisms for Intracellular Organization

ACS Nano, Год журнала: 2024, Номер 18(26), С. 16530 - 16544

Опубликована: Июнь 14, 2024

The cellular environment, characterized by its intricate composition and spatial organization, hosts a variety of organelles, ranging from membrane-bound ones to membraneless structures that are formed through liquid–liquid phase separation. Cells show precise control over the position such condensates. We demonstrate organelle movement in external concentration gradients, diffusiophoresis, is distinct one colloids because fluxes can remain finite inside liquid-phase droplets latter arises incompressibility. Within domains diffusiophoresis naturally biochemical reactions driven chemical fuel produce waste. Simulations analytical arguments within minimal model reaction-driven separation reveal directed stems two contributions: Fuel waste refilled or extracted at boundary, resulting which (i) induce product via incompressibility (ii) result an asymmetric forward reaction droplet's surroundings (as well as backward droplet), thereby shifting position. former contribution dominates sets direction movement, toward away source sink, depending on molecules' affinity waste, respectively. mechanism thus provides simple means organize condensates with different composition. Particle-based simulations systems more complex cycles corroborate robustness universality this mechanism.

Язык: Английский

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Beyond pairwise: Higher-order physical interactions affect phase separation in multicomponent liquids

Physical Review Research, Год журнала: 2024, Номер 6(3)

Опубликована: Июль 1, 2024

Phase separation, crucial for spatially segregating biomolecules in cells, is well-understood the simple case of a few components with pairwise interactions. Yet, biological cells challenge picture at least two ways: First, biomolecules, like proteins and nucleic acids, exhibit complex, higher-order interactions, where single molecule may interact multiple others simultaneously. Second, comprise myriad different that form various droplets. Such multicomponent phase separation has been studied but an analysis interactions lacking. We propose such theory study corresponding diagrams numerically. find between three are similar to whereas composition-dependent can oppose separation. This surprising result only be revealed from equilibrium diagrams, implying oft-used stability homogeneous states inadequate these systems. thus show could play role forming droplets their manipulation offer novel approaches controlling Published by American Physical Society 2024

Язык: Английский

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