Sequence-dependent material properties of biomolecular condensates and their relation to dilute phase conformations

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 1, 2024

Abstract Material properties of phase-separated biomolecular condensates, enriched with disordered proteins, dictate many cellular functions. Contrary to the progress made in understanding sequence-dependent phase separation little is known about sequence determinants condensate material properties. Using hydropathy scale and Martini models, we computationally decipher these relationships for charge-rich protein condensates. Our computations yield dynamical, rheological, interfacial condensates that are quantitatively comparable experimentally characterized Interestingly, find model natural proteins respond similarly charge segregation, despite different compositions. Molecular interactions within closely resemble those single-chain ensembles. Consequently, strongly correlate molecular contact dynamics structural We demonstrate potential harness characteristics predicting engineering functional insights from dilute

Language: Английский

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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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Chemically Informed Coarse-Graining of Electrostatic Forces in Charge-Rich Biomolecular Condensates

ACS Central Science, Journal Year: 2025, Volume and Issue: 11(2), P. 302 - 321

Published: Feb. 11, 2025

Biomolecular condensates composed of highly charged biomolecules, such as DNA, RNA, chromatin, and nucleic-acid binding proteins, are ubiquitous in the cell nucleus. The biophysical properties these charge-rich largely regulated by electrostatic interactions. Residue-resolution coarse-grained models that describe solvent ions implicitly widely used to gain mechanistic insights into condensates, offering transferability, computational efficiency, accurate predictions for multiple systems. However, their predictive accuracy diminishes due implicit treatment ions. Here, we present Mpipi-Recharged, a residue-resolution model improves description charge effects biomolecular containing disordered multidomain and/or single-stranded RNAs. Mpipi-Recharged introduces pair-specific asymmetric Yukawa potential, informed atomistic simulations. We show this coarse-graining forces captures intricate effects, blockiness, stoichiometry variations complex coacervates, modulation salt concentration, without requiring explicit solvation. provides excellent agreement with experiments predicting phase behavior condensates. Overall, tools available investigate physicochemical mechanisms regulating enhancing scope computer simulations field.

Language: Английский

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Location and Concentration of Aromatic‐Rich Segments Dictates the Percolating Inter‐Molecular Network and Viscoelastic Properties of Ageing Condensates

Advanced Science, Journal Year: 2023, Volume and Issue: 10(25)

Published: June 29, 2023

Maturation of functional liquid-like biomolecular condensates into solid-like aggregates has been linked to the onset several neurodegenerative disorders. Low-complexity aromatic-rich kinked segments (LARKS) contained in numerous RNA-binding proteins can promote aggregation by forming inter-protein β-sheet fibrils that accumulate over time and ultimately drive liquid-to-solid transition condensates. Here, atomistic molecular dynamics simulations are combined with sequence-dependent coarse-grained models various resolutions investigate role LARKS abundance position within amino acid sequence maturation Remarkably, tail-located display much higher viscosity than those which placed toward center. Yet, at very long timescales, a single LARKS-independently its location-can still relax form high viscous liquid However, phase-separated containing two or more become kinetically trapped due formation percolated networks gel-like behavior. Furthermore, as work case example, they demonstrate how shifting location LARKS-containing low-complexity domain FUS protein center effectively precludes accumulation FUS-RNA condensates, maintaining behavior without ageing.

Language: Английский

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Surfactants or scaffolds? RNAs of varying lengths control the thermodynamic stability of condensates differently

Biophysical Journal, Journal Year: 2023, Volume and Issue: 122(14), P. 2973 - 2987

Published: March 7, 2023

Language: Английский

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Capturing chemical reactions inside biomolecular condensates with reactive Martini simulations

Communications Chemistry, Journal Year: 2024, Volume and Issue: 7(1)

Published: July 3, 2024

Biomolecular condensates are phase separated systems that play an important role in the spatio-temporal organisation of cells. Their distinct physico-chemical nature offers a unique environment for chemical reactions to occur. The compartmentalisation is also believed be central development early life. To demonstrate how molecular dynamics may used capture condensates, here we perform reactive simulations using coarse-grained Martini forcefield. We focus on formation rings benzene-1,3-dithiol inside synthetic peptide-based condensate, and find ring size distribution shifts larger macrocycles compared when reaction takes place aqueous environment. Moreover, rates noticeably increased peptides simultaneously undergo separation, hinting act as chaperones recruiting molecules hubs.

Language: Английский

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Controlling Drug Partitioning in Individual Protein Condensates through Laser-Induced Microscale Phase Transitions

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(28), P. 19555 - 19565

Published: July 4, 2024

Gelation of protein condensates formed by liquid–liquid phase separation occurs in a wide range biological contexts, from the assembly biomaterials to formation fibrillar aggregates, and is therefore interest for biomedical applications. Soluble-to-gel (sol–gel) transitions are controlled through macroscopic processes such as changes temperature or buffer composition, resulting bulk conversion liquid droplets into microgels within minutes hours. Using microscopy mass spectrometry, we show that an engineered mini-spidroin (NT2repCTYF) undergo spontaneous sol–gel transition loss exchange proteins between soluble condensed phase. This feature enables us specifically trap silk-domain-tagged target spidroin microgels. Surprisingly, laser pulses trigger near-instant gelation. By loading with fluorescent dyes drugs, can control wavelength at which gelation triggered. Fluorescence reveals laser-induced significantly further increases partitioning molecules condensates. In summary, our findings demonstrate direct individual condensates, opening new avenues functional structural characterization.

Language: Английский

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Accuracy limit of non-polarizable four-point water models: TIP4P/2005 vs OPC. Should water models reproduce the experimental dielectric constant?

The Journal of Chemical Physics, Journal Year: 2024, Volume and Issue: 161(4)

Published: July 24, 2024

The last generation of four center non-polarizable models water can be divided into two groups: those reproducing the dielectric constant water, as OPC, and significantly underestimating its value, TIP4P/2005. To evaluate global performance OPC TIP4P/2005, we shall follow test proposed by Vega Abascal in 2011 evaluating about 40 properties to fairly address this comparison. liquid–vapor liquid–solid equilibria are computed, well heat capacities, isothermal compressibilities, surface tensions, densities different ice polymorphs, density maximum, equations state at high pressures, transport properties. General aspects phase diagram considered comparing ratios temperatures (namely, temperature maximum density, melting hexagonal ice, critical temperature). final scores 7.2 for TIP4P/2005 6.3 OPC. results work strongly suggest that have reached limit what achieved with attempt reproduce experimental deteriorates force field. reason is depends on surfaces (potential energy dipole moment surfaces), whereas absence an electric field, all determined simply from just one (the potential surface). consequences choice model modeling electrolytes also discussed.

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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Chemically-informed coarse-graining of electrostatic forces in charge-rich biomolecular condensates

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 27, 2024

Biomolecular condensates composed of highly charged biomolecules like DNA, RNA, chromatin, and nucleic-acid binding proteins are ubiquitous in the cell nucleus. The biophysical properties these charge-rich largely regulated by electrostatic interactions. Residue-resolution coarse-grained models that describe solvent ions implicitly widely used to gain mechanistic insights into condensates, offering transferability, computational efficiency, accurate predictions for many systems. However, their predictive accuracy diminishes due implicit treatment ions. Here, we present Mpipi-Recharged model, a residue-resolution model improves description charge effects biomolecular containing disordered proteins, multi-domain and/or RNAs. maintains efficiency its predecessor—the Mpipi model—by still treating implicitly, but incorporating pair-specific asymmetric potential informed atomistic simulations explicit We show such coarse-graining forces is needed recapitulate stronger mean-field impact associative interactions between opposite-charge pairs over repulsion among equally revealed our simulations. shows excellent agreement with experimental phase behavior systems, capturing subtle challenging without solvation, as blockiness, stoichiometry changes, salt concentration variation. By improved extends tools available investigate physicochemical mechanisms regulating condensates.

Language: Английский

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