Dependencies between effective parameters in coarse-grained models for phase separation of DNA-based fluids DOI
Soumen De Karmakar, Thomas Speck

The Journal of Chemical Physics, Journal Year: 2024, Volume and Issue: 161(23)

Published: Dec. 18, 2024

DNA is now firmly established as a versatile and robust platform for achieving synthetic nanostructures. While the folding of single molecules into complex structures routinely achieved through engineering basepair sequences, very little known about emergence structure on larger scales in fluids. The fact that polymeric fluids can undergo phase separation dense fluid dilute gas opens avenues to design hierachical multifarious assemblies. Here, we investigate which extent behavior single-stranded be captured by minimal model semiflexible charged homopolymers while neglecting specific hybridization interactions. We first characterize single-polymer then perform direct coexistence simulations test against experimental data. low-resolution models show great promise bridge gap relevant length time scales, obtaining consistent transferable parameters challenging. In particular, conclude counterions not only determine effective range electrostatic interactions but also contribute attractions.

Language: Английский

Fundamental Aspects of Phase-Separated Biomolecular Condensates DOI
Huan‐Xiang Zhou,

Divya Kota,

Sanbo Qin

et al.

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

Citations

23
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
Coarse-Grained Model of Disordered RNA for Simulations of Biomolecular Condensates DOI
Ikki Yasuda, Sören von Bülow, Giulio Tesei

et al.

Journal of Chemical Theory and Computation, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 26, 2025

Protein–RNA condensates are involved in a range of cellular activities. Coarse-grained molecular models intrinsically disordered proteins have been developed to shed light on and predict single-chain properties phase separation. An RNA model compatible with such for would enable the study complex biomolecular mixtures involving RNA. Here, we present sequence-independent coarse-grained, two-beads-per-nucleotide disordered, flexible based hydropathy scale. We parametrize model, which term CALVADOS-RNA, using combination bottom-up top-down approaches reproduce local geometry intramolecular interactions atomistic simulations vitro experiments. The semiquantitatively captures several aspects RNA–RNA RNA–protein interactions. examined by comparing calculated experimental virial coefficients nonspecific interaction studying reentrant behavior protein–RNA mixtures. demonstrate utility simulating formation mixed consisting region MED1 chains selective partitioning regions from transcription factors into these compare results Despite simplicity our show that it key may therefore be used as baseline biophysics biology condensates.

Language: Английский

Citations

1
Coarse-Grained Modeling of Liquid–Liquid Phase Separation in Cells: Challenges and Opportunities DOI

Shaokang Shi,

Zhao Li, Zhong‐Yuan Lu

et al.

The Journal of Physical Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(28), P. 7280 - 7287

Published: July 9, 2024

Liquid-liquid phase separation (LLPS) within cells gives rise to membraneless organelles, which play pivotal roles in numerous cellular functions. A comprehensive understanding of the functional aspects intrinsically disordered protein (IDP) condensates necessitates elucidating their inherent structures and establishing correlations with biological Coarse-grained (CG) molecular dynamics (MD) simulations present a promising avenue for gaining insights into LLPS mechanisms biomacromolecules. Essential this endeavor is development tailored CG force fields MD simulations, incorporating full spectrum biomolecules involved formation accounting real-time biochemical reactions coupled LLPS. Moreover, developing accurate theoretical frameworks links between condensate structure its function are imperative thorough comprehension systems.

Language: Английский

Citations

5
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
Connected Chromatin Amplifies Acetylation-Modulated Nucleosome Interactions DOI
Ranran Li, Xingcheng Lin

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

Published: March 3, 2025

Histone acetylation is a key regulatory post-translational modification closely associated with gene transcription. In particular, H4K16 (H4K16ac) crucial activation marker that induces an open chromatin configuration. While previous studies have explored the effects of H4K16ac on nucleosome interactions, how this local affects higher-order organization remains unclear. To bridge chemical modifications these histone tail lysine residues to global structure, we utilized residue-resolution coarse-grained model and enhanced sampling techniques simulate charge-neutralization stability, internucleosome structure. Our simulations reveal stabilizes single due reduced entropic contribution tails during DNA unwrapping. addition, modestly weakens interactions by diminishing contacts between tails, DNA, acidic patches. These weakened are amplified when nucleosomes connected linker where increases in entry-exit angles lead significant destacking decompaction, exposing transcriptional activity. findings suggest geometric constraint imposed plays critical role driving structural reorganization upon modifications.

Language: Английский

Citations

0
Protein Language Model Identifies Disordered, Conserved Motifs Driving Phase Separation DOI Open Access
Yumeng Zhang,

Jared Zheng,

Bin Zhang

et al.

Published: May 7, 2025

Intrinsically disordered regions (IDRs) play a critical role in phase separation and are essential for the formation of membraneless organelles (MLOs). Mutations within IDRs can disrupt their multivalent interaction networks, altering behavior contributing to various diseases. Therefore, examining evolutionary fitness provides valuable insights into relationship between protein sequences separation. In this study, we utilized ESM2 language model map landscape IDRs. Our findings reveal that IDRs, particularly those actively participating separation, contain conserved amino acids. This conservation is evident through mutational constraints predicted by supported direct analyses multiple sequence alignments. These conserved, acids include residues traditionally identified as “stickers” well “spacers” frequently form continuous motifs. The strong conservation, combined with suggests these motifs act functional units under selection support stable MLO formation. underscore separation’s molecular grammar made possible analysis enabled models.

Language: Английский

Citations

0
Protein Language Model Identifies Disordered, Conserved Motifs Driving Phase Separation DOI Open Access
Yumeng Zhang,

Jared Zheng,

Bin Zhang

et al.

Published: May 7, 2025

Intrinsically disordered regions (IDRs) play a critical role in phase separation and are essential for the formation of membraneless organelles (MLOs). Mutations within IDRs can disrupt their multivalent interaction networks, altering behavior contributing to various diseases. Therefore, examining evolutionary fitness provides valuable insights into relationship between protein sequences separation. In this study, we utilized ESM2 language model map landscape IDRs. Our findings reveal that IDRs, particularly those actively participating separation, contain conserved amino acids. This conservation is evident through mutational constraints predicted by supported direct analyses multiple sequence alignments. These conserved, acids include residues traditionally identified as “stickers” well “spacers” frequently form continuous motifs. The strong conservation, combined with suggests these motifs act functional units under selection support stable MLO formation. underscore separation’s molecular grammar made possible analysis enabled models.

Language: Английский

Citations

0
Uncovering the Molecular Interactions Underlying MBD2 and MBD3 Phase Separation DOI Creative Commons
Nicole Maurici, Tien M. Phan, Jessica L. Henty-Ridilla

et al.

The Journal of Physical Chemistry B, Journal Year: 2025, Volume and Issue: unknown

Published: May 11, 2025

Chromatin organization controls DNA's accessibility to regulatory factors influence gene expression. Heterochromatin, or transcriptionally silent chromatin enriched in methylated DNA and histone tails, self-assembles through multivalent interactions with its associated proteins into a condensed, but dynamic state. Liquid-liquid phase separation (LLPS) of key heterochromatin regulators, such as protein 1 (HP1), plays an essential role assembly function. Methyl-CpG-binding 2 (MeCP2), the most studied member methyl-CpG-binding domain (MBD) family proteins, has been recently shown undergo LLPS absence presence DNA. These studies provide new mechanistic framework for understanding readers formation. However, details molecular by which other MBD members mediate genome transcriptional regulation are not fully understood. Here, we focus on two MBD2 MBD3, that have distinct interdependent roles regulation. Using integrated computational experimental approach, uncover homotypic heterotypic governing MBD3 this process. We show despite sharing highest sequence identity structural homology among all members, exhibit differing residue patterns resulting mechanisms. Understanding underpinnings condensation offers insights higher-order, LLPS-mediated heterochromatin.

Language: Английский

Citations

0
Role of Shape Deformation of DNA-Binding Sites in Regulating the Efficiency and Specificity in Their Recognition by DNA-Binding Proteins DOI Creative Commons

Sangeeta Yadav,

Sujeet Kumar Mishra, Arnab Bhattacherjee

et al.

JACS Au, Journal Year: 2024, Volume and Issue: 4(7), P. 2640 - 2655

Published: June 18, 2024

Accurate transcription of genetic information is crucial, involving precise recognition the binding motifs by DNA-binding proteins. While some proteins rely on short-range hydrophobic and hydrogen bonding interactions at sites, others employ a DNA shape readout mechanism for specific recognition. In this mechanism, variations in motif resulted from either inherent flexibility or adjacent sites are sensed capitalized searching to locate them specifically. Through extensive computer simulations, we investigate both scenarios uncover underlying origin specificity mechanism. Our findings reveal that deformation creates an entropy funnel, allowing about altered shapes manifest as fluctuations minor groove widths. This signal enhances efficiency nonspecific search nearby directing their movement toward site, primarily driven gain entropy. We propose generic readout, where arises alignment between molecular frustration protein ruggedness entropic funnel governed features arrangement bases respectively.

Language: Английский

Citations

2