Fundamental Aspects of Phase-Separated Biomolecular Condensates

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(13), P. 8550 - 8595

Published: June 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.

Language: Английский

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

Science Advances, Journal Year: 2024, Volume and Issue: 10(1)

Published: Jan. 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.

Language: Английский

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

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 168953 - 168953

Published: Jan. 1, 2025

Language: 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, Journal Year: 2024, Volume and Issue: 15(32), P. 8248 - 8256

Published: Aug. 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.

Language: Английский

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Predicting Heteropolymer Interactions: Demixing and Hypermixing of Disordered Protein Sequences

Physical Review X, Journal Year: 2024, Volume and Issue: 14(3)

Published: July 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

Language: Английский

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

Journal of Chemical Theory and Computation, Journal Year: 2024, Volume and Issue: 20(15), P. 6881 - 6889

Published: July 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

Language: Английский

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

ACS Nano, Journal Year: 2024, Volume and Issue: 18(26), P. 16530 - 16544

Published: June 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.

Language: Английский

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

ACS Omega, Journal Year: 2024, Volume and Issue: 9(21), P. 22677 - 22690

Published: May 13, 2024

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

Language: Английский

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

Physical Review Research, Journal Year: 2024, Volume and Issue: 6(3)

Published: July 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

Language: Английский

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Accelerated Simulations Reveal Physicochemical Factors Governing Stability and Composition of RNA Clusters

Journal of Chemical Theory and Computation, Journal Year: 2024, Volume and Issue: 20(22), P. 10209 - 10222

Published: Nov. 6, 2024

Under certain conditions, RNA repeat sequences phase separate, yielding protein-free biomolecular condensates. Importantly, have also been implicated in neurological disorders, such as Huntington's disease. Thus, mapping to their behavior, functions, and dysfunctions is an active area of research. However, despite several advances, it remains challenging characterize the behavior at a submolecular resolution. Here, we implemented residue-resolution coarse-grained model LAMMPS─that incorporates both sequence structure─to study clustering propensities systems. achieve multifold speedup simulation time compared previous work. Leveraging this efficiency, propensity all 20 nonredundant trinucleotide sequences. Our results align with findings from experiments, emphasizing that canonical base-pairing G–U wobble pairs play dominant roles regulating cluster formation Strikingly, find strong entropic contributions stability composition clusters, which demonstrated for single-component systems well binary mixtures repeats. Additionally, investigate behaviors (odd) repeats quadranucleotide (even) counterparts. We observe odd exhibit stronger tendencies, attributed presence consecutive base are disrupted even Altogether, our work extends set computational tools probing resolution uncovers physicochemical principles govern resulting clusters.

Language: Английский

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