Separation of Sticker-Spacer Energetics Governs the Coalescence of Metastable Condensates DOI Creative Commons
Aniruddha Chattaraj,

Eugene I. Shakhnovich

Published: Nov. 29, 2024

Biological condensates often emerge as a multi-droplet state and never coalesce into one large droplet within the experimental timespan. Previous work revealed that sticker-spacer architecture of biopolymers may dynamically stabilize state. Here, we simulate condensate coalescence using metadynamics approach reveal two distinct physical mechanisms underlying fusion droplets. Condensates made polymers readily undergo kinetic arrest when stickers exhibit slow exchange while fast exchanging at similar levels saturation allow merger to equilibrium states. On other hand, composed homopolymers fuse until they reach threshold density. Increase in entropy upon inter-condensate mixing chains drives chains. We map range from sticker dynamics density mediated terms energetic separation spacers. Our predictions appear be qualitative agreement with recent experiments probing dynamic nature protein-RNA condensates.

Language: Английский

Sequence-dependent material properties of biomolecular condensates and their relation to dilute phase conformations DOI Creative Commons
Dinesh Sundaravadivelu Devarajan, Jiahui Wang, Beata Szała-Mendyk

et al.

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

Citations

47
Active learning of the thermodynamics-dynamics trade-off in protein condensates DOI Creative Commons
Yaxin An, Michael Webb, William M. Jacobs

et al.

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

Citations

22
Prediction of phase separation propensities of disordered proteins from sequence DOI Creative Commons
Sören von Bülow, Giulio Tesei, Kresten Lindorff‐Larsen

et al.

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

Published: June 3, 2024

Abstract Phase separation is thought to be one possible mechanism governing the selective cellular enrichment of biomolecular constituents for processes such as transcriptional activation, mRNA regulation, and immune signaling. mediated by multivalent interactions biological macromolecules including intrinsically disordered proteins regions (IDRs). Despite considerable advances in experiments, theory simulations, prediction thermodynamics IDR phase behaviour remains challenging. We combined coarse-grained molecular dynamics simulations active learning develop a fast accurate machine model predict free energy saturation concentration directly from sequence. validate using both experimental computational data. apply our all 27,663 IDRs chain length up 800 residues human proteome find that 1,420 these (5%) are predicted undergo homotypic with transfer energies < −2 k B T . use understand relationship between single-chain compaction separation, changes charge-to hydrophobicity-mediated can break symmetry intra-and inter-molecular interactions. also analyse structural preferences at condensate interfaces substantial heterogeneity determined same sequence properties separation. Our work refines established rules relationships features propensities, models will useful interpreting designing experiments on role design specific propensities.

Language: Английский

Citations

18
Chemically Informed Coarse-Graining of Electrostatic Forces in Charge-Rich Biomolecular Condensates DOI Creative Commons
Andrés R. Tejedor,

Anne Aguirre Gonzalez,

Maria Julia Maristany

et al.

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

Citations

2
Theory and Simulation of Multiphase Coexistence in Biomolecular Mixtures DOI
William M. Jacobs

Journal of Chemical Theory and Computation, Journal Year: 2023, Volume and Issue: 19(12), P. 3429 - 3445

Published: June 5, 2023

Biomolecular condensates constitute a newly recognized form of spatial organization in living cells. Although many are believed to as result phase separation, the physicochemical properties that determine behavior heterogeneous biomolecular mixtures only beginning be explored. Theory and simulation provide invaluable tools for probing relationship between molecular determinants, such protein RNA sequences, emergence phase-separated complex environments. This review covers recent advances prediction computational design phase-separate into coexisting phases. First, we efforts understand with hundreds or thousands species using theoretical models statistical approaches. We then describe progress developing analytical theories coarse-grained predict multiphase detail required make contact biophysical experiments. conclude by summarizing challenges ahead modeling inhomogeneous

Language: Английский

Citations

25
Label-Free Techniques for Probing Biomolecular Condensates DOI
Khalid A. Ibrahim,

Akhil S. Naidu,

Helena Miljkovic

et al.

ACS Nano, Journal Year: 2024, Volume and Issue: 18(16), P. 10738 - 10757

Published: April 12, 2024

Biomolecular condensates play important roles in a wide array of fundamental biological processes, such as cellular compartmentalization, regulation, and other biochemical reactions. Since their discovery first observations, an extensive expansive library tools has been developed to investigate various aspects properties, encompassing structural compositional information, material evolution throughout the life cycle from formation eventual dissolution. This Review presents overview expanded set methods that researchers use probe properties biomolecular across diverse scales length, concentration, stiffness, time. In particular, we review recent years' exciting development label-free techniques methodologies. We broadly organize into 3 categories: (1) imaging-based techniques, transmitted-light microscopy (TLM) Brillouin (BM), (2) force spectroscopy atomic (AFM) optical tweezer (OT), (3) microfluidic platforms emerging technologies. point out tools' key opportunities, challenges, future perspectives analyze correlative potential well compatibility with techniques. Additionally, namely, differential dynamic (DDM) interferometric scattering (iSCAT), have huge for applications studying condensates. Finally, highlight how some these can be translated diagnostics therapy purposes. hope this serves useful guide new field aids advancing biophysical study

Language: Английский

Citations

11
Solutes unmask differences in clustering versus phase separation of FET proteins DOI Creative Commons
Mrityunjoy Kar, Laura T. Vogel, Gaurav Chauhan

et al.

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

Published: May 23, 2024

Abstract Phase separation and percolation contribute to phase transitions of multivalent macromolecules. Contributions are evident through the viscoelasticity condensates formation heterogeneous distributions nano- mesoscale pre-percolation clusters in sub-saturated solutions. Here, we show that formed solutions FET (FUS-EWSR1-TAF15) proteins affected differently by glutamate versus chloride. These differences on nanoscale, gleaned using a suite methods deployed across wide range protein concentrations, prevalent can be unmasked even though driving forces for remain unchanged Strikingly, anion-mediated interactions drive clustering saturate micron-scale. Beyond this length scale system separates into coexisting phases. Overall, find sequence-encoded interactions, mediated solution components, make synergistic distinct contributions solutions, separation.

Language: Английский

Citations

11
Metastable condensates suppress conversion to amyloid fibrils DOI Creative Commons
Tapojyoti Das, Fatima Zaidi, Mina Farag

et al.

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

Published: March 3, 2024

Stress granules form via co-condensation of RNA binding proteins with prion-like low complexity domains (PLCDs) and molecules released by stress-induced polysomal runoff. Homotypic interactions among PLCDs can drive amyloid fibril formation this is enhanced ALS-associated mutations. We find that homotypic condensation versus are separable for A1-LCD, the PLCD hnRNPA1. These lead to condensates metastable fibrils globally stable. Metastable suppress formation, mutations enhance weakening condensate metastability. Mutations designed A1-LCD metastability restore wild-type behaviors stress in cells even when present. This suggests be suppressed enhancing through condensate-driving interactions.

Language: Английский

Citations

10
Molecular Drivers of Aging in Biomolecular Condensates: Desolvation, Rigidification, and Sticker Lifetimes DOI Creative Commons
Subhadip Biswas, Davit A. Potoyan

PRX Life, Journal Year: 2024, Volume and Issue: 2(2)

Published: June 6, 2024

Biomolecular condensates are dynamic intracellular entities defined by their sequence- and composition-encoded material properties. During aging, these properties can change dramatically, potentially leading to pathological solidlike states, the mechanisms of which remain poorly understood. Recent experiments reveal that aging involves a complex interplay solvent depletion, strengthening sticker links, formation rigid structural segments such as beta fibrils. In this study, we use various coarse-grained models investigate how expulsion, biopolymer chain rigidity, lifetimes contacts influence viscoelastic dynamics condensates. We find rigidity backbone is essential for replicating predominant elastic behavior observed in experiments. contrast, using fully flexible chains-an assumption common simulations intrinsically disordered proteins-fail exhibit dominant regime. also demonstrate altering content within affects crossover between storage loss moduli. This suggests desolvation plays significant role condensate promoting transition from viscous an state. Furthermore, lifetime pairs profoundly influences mature state condensates; short-lived stickers lead Maxwell fluid behavior, while longer-lived, irreversibly cross-linked result properties, consistent with Kelvin-Voigt model. Finally, incorporating rigidification, desolvation, pair into nonequilibrium simulation, show molecular mechanism forming solid shells around surfaces recent experimental report.

Language: Английский

Citations

9
Sequence-Dependent Material Properties of Biomolecular Condensates and their Relation to Dilute Phase Conformations DOI Creative Commons
Dinesh Sundaravadivelu Devarajan, Jiahui Wang, Beata Szała-Mendyk

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: May 12, 2023

Material properties of phase-separated biomolecular assemblies, enriched with disordered proteins, dictate their ability to participate in many cellular functions. Despite the significant effort dedicated understanding how sequence protein drives its phase separation form condensates, little is known about determinants condensate material properties. Here, we computationally decipher these relationships for charged proteins using model sequences comprised glutamic acid and lysine residues as well naturally occurring LAF1's RGG domain DDX4's N-terminal domain. We do so by delineating arrangement oppositely within influences dynamical, rheological, interfacial condensed through equilibrium non-equilibrium molecular simulations hydropathy scale Martini models. Our computations yield that are quantitatively comparable experimentally characterized systems. Interestingly, find both natural respond similarly segregation charges, despite very different compositions. Condensates highly charge-segregated exhibit slower dynamics than uniformly charge-patterned sequences, because comparatively long-lived contacts between residues. Surprisingly, interactions similar those a single-chain all sequences. Consequently, strongly correlated dense contact structural findings demonstrate potential harness characteristics predicting engineering functional insights from dilute

Language: Английский

Citations

10