Interplay between charge distribution and DNA in shaping HP1 paralog phase separation and localization DOI Open Access
Tien M. Phan,

Young C. Kim,

Galia T. Debelouchina

et al.

Published: Feb. 8, 2024

The heterochromatin protein 1 (HP1) family is a crucial component of with diverse functions in gene regulation, cell cycle control, and differentiation. In humans, there are three paralogs, HP1α, HP1β, HP1γ, which exhibit remarkable similarities their domain architecture sequence properties. Nevertheless, these paralogs display distinct behaviors liquid-liquid phase separation (LLPS), process linked to formation. Here, we employ coarse-grained simulation framework uncover the features responsible for observed differences LLPS. We highlight significance net charge patterning along governing paralog LLPS propensities. also show that both highly conserved folded less-conserved disordered domains contribute differences. Furthermore, explore potential co-localization different HP1 multicomponent assemblies impact DNA on this process. Importantly, our study reveals can significantly reshape stability minimal condensate formed by due competitive interactions HP1α HP1β HP1γ versus DNA. conclusion, work highlights physicochemical nature govern phase-separation provides molecular understanding role chromatin organization.

Language: Английский

Single-stranded nucleic acid binding and coacervation by linker histone H1 DOI
Rachel Leicher, Adewola Osunsade, Gabriella N. L. Chua

et al.

Nature Structural & Molecular Biology, Journal Year: 2022, Volume and Issue: 29(5), P. 463 - 471

Published: April 28, 2022

Language: Английский

Citations

56
Interplay between charge distribution and DNA in shaping HP1 paralog phase separation and localization DOI Creative Commons
Tien M. Phan,

Young C. Kim,

Galia T. Debelouchina

et al.

eLife, Journal Year: 2024, Volume and Issue: 12

Published: April 9, 2024

The heterochromatin protein 1 (HP1) family is a crucial component of with diverse functions in gene regulation, cell cycle control, and differentiation. In humans, there are three paralogs, HP1α, HP1β, HP1γ, which exhibit remarkable similarities their domain architecture sequence properties. Nevertheless, these paralogs display distinct behaviors liquid-liquid phase separation (LLPS), process linked to formation. Here, we employ coarse-grained simulation framework uncover the features responsible for observed differences LLPS. We highlight significance net charge patterning along governing paralog LLPS propensities. also show that both highly conserved folded less-conserved disordered domains contribute differences. Furthermore, explore potential co-localization different HP1 multicomponent assemblies impact DNA on this process. Importantly, our study reveals can significantly reshape stability minimal condensate formed by due competitive interactions HP1α HP1β HP1γ versus DNA. conclusion, work highlights physicochemical nature govern phase-separation provides molecular understanding role chromatin organization.

Language: Английский

Citations

9
Molecular interactions underlying the phase separation of HP1α: role of phosphorylation, ligand and nucleic acid binding DOI Creative Commons

Cheenou Her,

Tien M. Phan,

Nina Jovic

et al.

Nucleic Acids Research, Journal Year: 2022, Volume and Issue: 50(22), P. 12702 - 12722

Published: Dec. 9, 2022

Abstract Heterochromatin protein 1α (HP1α) is a crucial element of chromatin organization. It has been proposed that HP1α functions through liquid-liquid phase separation (LLPS), which allows it to compact into transcriptionally repressed heterochromatin regions. In vitro, can undergo upon phosphorylation its N-terminus extension (NTE) and/or interactions with DNA and chromatin. Here, we combine computational experimental approaches elucidate the molecular drive these processes. phosphorylation-driven LLPS, exchange intradimer hinge-NTE interdimer contacts, also leads structural change from compacted an extended dimer conformation. This process be enhanced by presence positively charged peptide ligands disrupted addition negatively or neutral peptides. DNA-driven both perturb separation. Our findings demonstrate importance electrostatic in LLPS where binding partners modulate overall charge droplets screen enhance hinge region specific non-specific effects. study illuminates complex framework fine-tune properties contribute regulation function.

Language: Английский

Citations

37
Location and Concentration of Aromatic‐Rich Segments Dictates the Percolating Inter‐Molecular Network and Viscoelastic Properties of Ageing Condensates DOI Creative Commons
S. Blazquez, Ignacio Sanchez‐Burgos, Jorge Ramı́rez

et al.

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

Citations

20
ATP Acts as a Hydrotrope to Regulate the Phase Separation of NBDY Clusters DOI Creative Commons
Fei Liu, Jin Wang

JACS Au, Journal Year: 2023, Volume and Issue: 3(9), P. 2578 - 2585

Published: Sept. 4, 2023

Nonannotated P-body dissociating polypeptide (NBDY) is a recently discovered human microprotein that has been found to be novel component of the mRNA decapping complex. Previous studies have shown phosphorylation NBDY promotes liquid phase remixing in vitro. Typically, during process phosphorylation, phosphate group added protein through adenosine triphosphate (ATP) hydrolysis. It ATP acts as biological hydrotrope, affecting separation proteins solution. In this study, we utilized simulation methods investigate dynamic properties clusters at various concentrations. Our findings demonstrate can regulate clusters. Specifically, identified critical point concentration ratio between and exhibits dual effect on NBDY. We observed nonsaturated facilitate formation separation, while oversaturated diffusion NBDY, ATP-NBDY interaction impedes Additionally, ATPs bind surface by aggregating into clusters, which further hinders work provides general insight role condensates.

Language: Английский

Citations

18
The scales, mechanisms, and dynamics of the genome architecture DOI Creative Commons
Ludvig Lizana, Yuri B. Schwartz

Science Advances, Journal Year: 2024, Volume and Issue: 10(15)

Published: April 10, 2024

Even when split into several chromosomes, DNA molecules that make up our genome are too long to fit the cell nuclei unless massively folded. Such folding must accommodate need for timely access selected parts of by transcription factors, RNA polymerases, and replication machinery. Here, we review current understanding inside interphase nuclei. We consider resulting architecture at three scales with a particular focus on intermediate (meso) scale summarize insights gained from recent experimental observations diverse computational models.

Language: Английский

Citations

6
Kinetic trapping organizes actin filaments within liquid-like protein droplets DOI Creative Commons
Aravind Chandrasekaran, Kristin Graham, Jeanne C. Stachowiak

et al.

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

Published: April 11, 2024

Abstract Several actin-binding proteins (ABPs) phase separate to form condensates capable of curating the actin network shapes. Here, we use computational modeling understand principles organization within VASP condensate droplets. Our simulations reveal that different shapes, namely shells, rings, and mixture states are highly dependent on kinetics VASP-actin interactions, suggesting they arise from kinetic trapping. Specifically, show reducing residence time filaments reduces degree bundling, thereby promoting assembly shells rather than rings. We validate model predictions experimentally using a VASP-mutant with decreased bundling capability. Finally, investigate ring opening deformed droplets found sphere-to-ellipsoid transition is favored under wide range filament lengths while ellipsoid-to-rod only permitted when have specific lengths. findings highlight key mechanisms phase-separated ABPs.

Language: Английский

Citations

6
Transferable Implicit Solvation via Contrastive Learning of Graph Neural Networks DOI Creative Commons
Justin Airas, Xinqiang Ding, Bin Zhang

et al.

ACS Central Science, Journal Year: 2023, Volume and Issue: 9(12), P. 2286 - 2297

Published: Nov. 16, 2023

Implicit solvent models are essential for molecular dynamics simulations of biomolecules, striking a balance between computational efficiency and biological realism. Efforts underway to develop accurate transferable implicit coarse-grained (CG) force fields in general, guided by bottom-up approach that matches the CG energy function with potential mean (PMF) defined finer system. However, practical challenges arise due lack analytical expressions PMF algorithmic limitations parameterizing fields. To address these challenges, machine learning-based is proposed, utilizing graph neural networks (GNNs) represent solvation free contrasting parameter optimization. We demonstrate effectiveness deriving GNN model using 600,000 atomistic configurations six proteins obtained from explicit simulations. The provides estimations much more accurately than state-of-the-art models, reproducing configurational distributions also reasonable transferability outside training data. Our study offers valuable insights systematically improvable perspective.

Language: Английский

Citations

14
Interplay between charge distribution and DNA in shaping HP1 paralog phase separation and localization DOI Creative Commons
Tien M. Phan,

Young C. Kim,

Galia T. Debelouchina

et al.

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Oct. 5, 2023

The heterochromatin protein 1 (HP1) family is a crucial component of with diverse functions in gene regulation, cell cycle control, and differentiation. In humans, there are three paralogs, HP1α, HP1β, HP1γ, which exhibit remarkable similarities their domain architecture sequence properties. Nevertheless, these paralogs display distinct behaviors liquid-liquid phase separation (LLPS), process linked to formation. Here, we employ coarse-grained simulation framework uncover the features responsible for observed differences LLPS. We highlight significance net charge patterning along governing paralog LLPS propensities. also show that both highly conserved folded less-conserved disordered domains contribute differences. Furthermore, explore potential co-localization different HP1 multicomponent assemblies impact DNA on this process. Importantly, our study reveals can significantly reshape stability minimal condensate formed by due competitive interactions HP1α HP1β HP1γ versus DNA. conclusion, work highlights physicochemical nature govern phase-separation provides molecular understanding role chromatin organization.

Language: Английский

Citations

12
Coarse-Grained Models to Study Protein–DNA Interactions and Liquid–Liquid Phase Separation DOI Creative Commons
Utkarsh Kapoor,

Young C. Kim,

Jeetain Mittal

et al.

Journal of Chemical Theory and Computation, Journal Year: 2023, Volume and Issue: 20(4), P. 1717 - 1731

Published: Nov. 21, 2023

Recent advances in coarse-grained (CG) computational models for DNA have enabled molecular-level insights into the behavior of complex multiscale systems. However, most existing CG are not compatible with protein models, limiting their applications emerging topics such as protein–nucleic acid assemblies. Here, we present a new computationally efficient model. We first use experimental data to establish model's ability predict various aspects behavior, including melting thermodynamics and relevant local structural properties major minor grooves. then employ an all-atom hydropathy scale define nonbonded interactions between sites, make our model (HPS-Urry), which is extensively used study phase separation, show that reasonably reproduces binding affinity prototypical protein–DNA system. To further demonstrate capabilities this model, simulate full nucleosome without histone tails, on microsecond time scale, generating conformational ensembles provide molecular role tails influencing liquid–liquid separation (LLPS) HP1α proteins. find interact favorably DNA, ensemble antagonizing contacts thus affecting promote LLPS HP1α. These findings shed light framework fine-tunes transition heterochromatin proteins contributes regulation function. Overall, presented here suitable facilitate micrometer-scale studies sub-nm resolution many biological engineering can be investigate complexes, nucleosomes, or enabling mechanistic understanding how information may propagated at genome level.

Language: Английский

Citations

12