Electrostatics of Salt-Dependent Reentrant Phase Behaviors Highlights Diverse Roles of ATP in Biomolecular Condensates DOI Open Access
Yi‐Hsuan Lin, Tae Hun Kim, Suman Das

et al.

Published: Dec. 30, 2024

Liquid-liquid phase separation (LLPS) involving intrinsically disordered protein regions (IDRs) is a major physical mechanism for biological membraneless compartmentalization. The multifaceted electrostatic effects in these biomolecular condensates are exemplified here by experimental and theoretical investigations of the different salt- ATP-dependent LLPSs an IDR messenger RNA-regulating Caprinl its phosphorylated variant pY-Caprinl, exhibiting, e.g., reentrant behaviors some instances but not others. Experimental data rationalized modeling using analytical theory, molecular dynamics, polymer field-theoretic simulations, indicating that interchain ion bridges enhance LLPS polyelectrolytes such as high valency ATP-magnesium significant factor colocalization with condensed phases, similar trends observed other IDRs. nature features complements ATP’s involvement π-related interactions amphiphilic hydrotrope, underscoring general role modulating concentrations functional ramifications.

Language: Английский

Prediction of phase-separation propensities of disordered proteins from sequence DOI Creative Commons
Sören von Bülow, Giulio Tesei, Fatima Zaidi

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(13)

Published: March 25, 2025

Phase separation is 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 macromolecules including intrinsically disordered proteins regions (IDRs). Despite considerable advances in experiments, theory, simulations, prediction thermodynamics IDR phase behavior remains challenging. We combined coarse-grained molecular dynamics simulations active learning to develop a fast accurate machine model predict free energy saturation concentration directly from sequence. validate using computational previously measured experimental data, well new data six proteins. 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 changes charge- hydrophobicity-mediated can break symmetry intra- intermolecular interactions. also provide proof principle how be used force field refinement. Our work refines quantifies established rules connection sequence features phase-separation propensities, models will useful interpreting designing experiments on role separation, design specific propensities.

Language: Английский

Citations

2
Benchmarking residue-resolution protein coarse-grained models for simulations of biomolecular condensates DOI Creative Commons
Alejandro Feito, Ignacio Sanchez‐Burgos,

Ignacio Tejero

et al.

PLoS Computational Biology, Journal Year: 2025, Volume and Issue: 21(1), P. e1012737 - e1012737

Published: Jan. 13, 2025

Intracellular liquid–liquid phase separation (LLPS) of proteins and nucleic acids is a fundamental mechanism by which cells compartmentalize their components perform essential biological functions. Molecular simulations play crucial role in providing microscopic insights into the physicochemical processes driving this phenomenon. In study, we systematically compare six state-of-the-art sequence-dependent residue-resolution models to evaluate performance reproducing behaviour material properties condensates formed seven variants low-complexity domain (LCD) hnRNPA1 protein (A1-LCD)—a implicated pathological liquid-to-solid transition stress granules. Specifically, assess HPS, HPS-cation– π , HPS-Urry, CALVADOS2, Mpipi, Mpipi-Recharged predictions condensate saturation concentration, critical solution temperature, viscosity A1-LCD variants. Our analyses demonstrate that, among tested models, Mpipi-Recharged, CALVADOS2 provide accurate descriptions temperatures concentrations for multiple tested. Regarding prediction its variants, stands out as most reliable model. Overall, study benchmarks range coarse-grained thermodynamic stability establishes direct link between ranking intermolecular interactions these consider.

Language: Английский

Citations

1
Electrostatics of salt-dependent reentrant phase behaviors highlights diverse roles of ATP in biomolecular condensates DOI Creative Commons
Yi‐Hsuan Lin, Tae Hun Kim, Suman Das

et al.

eLife, Journal Year: 2025, Volume and Issue: 13

Published: March 3, 2025

Liquid-liquid phase separation (LLPS) involving intrinsically disordered protein regions (IDRs) is a major physical mechanism for biological membraneless compartmentalization. The multifaceted electrostatic effects in these biomolecular condensates are exemplified here by experimental and theoretical investigations of the different salt- ATP-dependent LLPSs an IDR messenger RNA-regulating Caprin1 its phosphorylated variant pY-Caprin1, exhibiting, example, reentrant behaviors some instances but not others. Experimental data rationalized modeling using analytical theory, molecular dynamics, polymer field-theoretic simulations, indicating that interchain ion bridges enhance LLPS polyelectrolytes such as high valency ATP-magnesium significant factor colocalization with condensed phases, similar trends observed other IDRs. nature features complements ATP’s involvement π-related interactions amphiphilic hydrotrope, underscoring general role modulating concentrations functional ramifications.

Language: Английский

Citations

1
Intrinsic stiffness and Θ-solvent regime in intrinsically disordered proteins: Implications for liquid-liquid phase separation DOI Creative Commons
Lipika Baidya, Kurt Kremer, Govardhan Reddy

et al.

PNAS Nexus, Journal Year: 2025, Volume and Issue: 4(2)

Published: Feb. 1, 2025

Liquid-liquid phase separation (LLPS) exhibited by intrinsically disordered proteins (IDPs) depends on the solvation state around Θ-regime, which separates good from poor solvent. Experimentally, Θ-solvent regime of finite length (N) IDPs, as probed small angle X-ray scattering (SAXS) and single molecular fluorescence resonance energy transfer (smFRET), is in disagreement. Using computer simulations a coarse-grained IDP model, we address effect chain Θ-regime IDPs with polar side chains (polyglutamine) hydrophobic (polyleucine) subject to varying concentrations cosolvents [C] , urea (denaturant) or trimethylamine N-oxide (protective osmolyte) water. Due their intrinsic stiffness, these are always expanded short-length scales, independent solvent quality. As result, for short sequences ( ≈10 25 residues), propensity exhibit LLPS cannot be inferred single-chain properties. Further, finite-size cosolvent concentration attain [CΘ] ) extracted structure factor emulating SAXS pair distances mimicking smFRET differs. They converge same only at large N, indicating that size corrections vary different We show radius gyration Rg satisfies scaling relation Rg2=Nf(cN) can exploited accurately extract c=([C]/[CΘ]-1) ). demonstrate importance aspects originating stiffness thermal blob analyzing properties identify regime.

Language: Английский

Citations

0
Structural and Functional Relevance of Charge-Based Transient Interactions inside Intrinsically Disordered Proteins DOI Creative Commons
Samuel Wohl,

Yishai Gilron,

Wenwei Zheng

et al.

ACS Physical Chemistry Au, Journal Year: 2025, Volume and Issue: unknown

Published: April 15, 2025

Language: Английский

Citations

0
Quantitative Equivalence and Performance Comparison of Particle and Field-Theoretic Simulations DOI Creative Commons
Joshua Lequieu

Macromolecules, Journal Year: 2024, Volume and Issue: 57(22), P. 10870 - 10884

Published: Nov. 12, 2024

Particle and field-theoretic simulations are both commonly used methods to study the equilibrium properties of polymeric materials. Yet despite formal equivalence two methods, no comprehensive comparisons particle exist in literature. In this work, we seek fill gap by performing a systematic quantitative comparison simulations. our comparison, consider four representative systems: homopolymer melt/solution, diblock copolymer melt, polyampholyte solution, polyelectrolyte gel. For each these systems, first demonstrate that equivalent yield exactly same results for pressure chemical potential. We next quantify performance method across range different conditions including variations chain length, system density, interaction strength, size, polymer volume fraction. The outcome calculations is look into systems when either or preferred. find equal faster than nearly all examined. many situations, several orders magnitude simulations, especially if chains long, density high, long-range Coulombic interactions present. also considerably at calculating potential bypass challenges associated with particle-based Widom insertion techniques. Taken together, provide evidence can reach sample while simultaneously producing results.

Language: Английский

Citations

3
Toward Predictive Coarse-Grained Simulations of Biomolecular Condensates DOI
Shuming Liu, Cong Wang, Bin Zhang

et al.

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 2, 2025

Phase separation is a fundamental process that enables cellular organization by forming biomolecular condensates. These assemblies regulate diverse functions creating distinct environments, influencing reaction kinetics, and facilitating processes such as genome organization, signal transduction, RNA metabolism. Recent studies highlight the complexity of condensate properties, shaped intrinsic molecular features external factors temperature pH. Molecular simulations serve an effective approach to establishing comprehensive framework for analyzing these influences, offering high-resolution insights into stability, dynamics, material properties. This review evaluates recent advancements in simulations, with particular focus on coarse-grained 1-bead-per-amino-acid (1BPA) protein models, emphasizes OpenABC, tool designed simplify streamline simulations. OpenABC supports implementation various force fields, enabling their performance evaluation. Our benchmarking identifies inconsistencies phase behavior predictions across even though models accurately capture single-chain statistics. finding underscores need enhanced field accuracy, achievable through enriched training data sets, many-body potentials, advanced optimization techniques. Such refinements could significantly improve predictive capacity bridging details emergent behaviors.

Language: Английский

Citations

0
Sequence-dependent biomolecular phase separation driven by short-range interaction: From material properties to coarsening dynamics DOI

Junqi Li,

Zengshuai Yan,

Yu‐qiang Ma

et al.

Physical review. E, Journal Year: 2025, Volume and Issue: 111(5)

Published: May 8, 2025

Language: Английский

Citations

0
Capturing single-molecule properties does not ensure accurate prediction of biomolecular phase diagrams DOI Creative Commons
Alejandro Feito, Ignacio Sanchez‐Burgos, Antonio Rey

et al.

Molecular Physics, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 16, 2024

Intracellular liquid-liquid phase separation of proteins and nucleic acids represents a fundamental mechanism by which cells organise their components into biomolecular condensates that perform multiple biological tasks. Computer simulations provide powerful tools to investigate separation, offering microscopic insights the physicochemical principles regulate these systems. In this study, we behaviour low-complexity domain (LCD) hnRNPA1 several mutants via Molecular Dynamics simulations. We systematically compare performance five state-of-the-art residue-resolution coarse-grained protein models: HPS, HPS-cation-π, CALVADOS2, Mpipi, Mpipi-Recharged. Our evaluation focuses on how well models reproduce critical solution temperatures estimated from experimental coexistence densities single-protein radii gyration for LCD-hnRNPA1 set mutants. While most yield similar intramolecular contact maps reasonable estimates radius compared in vitro measurements, only Mpipi-Recharged, CALVADOS2 accurately predict diagrams align with data. This suggests force field parameterisations optimised solely properties may not always capture solutions. Additionally, our findings reveal some can lead significant discrepancies predicting roles individual intermolecular interactions, even relatively simple intrinsically disordered like hnRNPA1. work highlights importance balancing both single-molecule collective condensate formation material properties.

Language: Английский

Citations

3
Electrostatics of Salt-Dependent Reentrant Phase Behaviors Highlights Diverse Roles of ATP in Biomolecular Condensates DOI Creative Commons
Yi‐Hsuan Lin, Tae Hun Kim, Suman Das

et al.

eLife, Journal Year: 2024, Volume and Issue: 13

Published: Sept. 5, 2024

Liquid-liquid phase separation (LLPS) involving intrinsically disordered protein regions (IDRs) is a major physical mechanism for biological membraneless compartmentalization. The multifaceted electrostatic effects in these biomolecular condensates are exemplified here by experimental and theoretical investigations of the different salt- ATP-dependent LLPSs an IDR messenger RNA-regulating Caprin1 its phosphorylated variant pY-Caprin1, exhibiting, example, reentrant behaviors some instances but not others. Experimental data rationalized modeling using analytical theory, molecular dynamics, polymer field-theoretic simulations, indicating that interchain ion bridges enhance LLPS polyelectrolytes such as high valency ATP-magnesium significant factor colocalization with condensed phases, similar trends observed other IDRs. nature features complements ATP’s involvement π-related interactions amphiphilic hydrotrope, underscoring general role modulating concentrations functional ramifications.

Language: Английский

Citations

1