Accurate Simulation of Coupling between Protein Secondary Structure and Liquid-Liquid Phase Separation DOI Creative Commons
Yumeng Zhang, Shanlong Li, Xiping Gong

et al.

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

Published: Aug. 23, 2023

Abstract Intrinsically disordered proteins (IDPs) frequently mediate liquid-liquid phase separation (LLPS) that underlies the formation of membraneless organelles. Together with theory and experiment, efficient coarse-grained (CG) simulations have been instrumental in understanding sequence- specific IDPs. However, widely-used Cα-only models are severely limited capturing peptide nature IDPs, including backbone-mediated interactions effects secondary structures, LLPS. Here, we describe a hybrid resolution (HyRes) protein model for accurate description backbone transient structures With an atomistic side chains, HyRes accurately predicts residue helical propensity chain dimension monomeric Using GY-23 as system, show is enough direct simulation spontaneous separation, at same time to resolve single mutations. also successfully predict increased beta-sheet condensate, consistent available experimental data. We further utilize study TPD-43, where several disease-related mutants conserved region (CR) shown affect residual helicities modulate LLPS propensity. The recapitulate effect these on helicity TDP-43 CR. Analyses reveal balance between sidechain-mediated interactions, but not itself, actually determines believe represents important advance molecular will help elucidate coupling IDP separation.

Language: Английский

Sol–Gel Transition in Heteroassociative RNA-Protein Solutions: A Quantitative Comparison of Coarse-Grained Simulations and the Semenov–Rubinstein Theory DOI Creative Commons
Xinxiang Chen,

Jude Ann Vishnu,

Pol Besenius

et al.

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

Published: March 5, 2025

Protein RNA-binding domains selectively interact with specific RNA sites, a key interaction that determines the emergent cooperative behaviors in RNA-protein mixtures. Through molecular dynamics simulations, we investigate impact of binding interactions on phase transitions an exemplary system and compare it predictions Semenov–Rubinstein theory associative polymers. Our findings reveal sol–gel (percolation) transition without separation, characterized by double-reentrant behavior as or protein concentration increases. We highlight crucial role bridge formations driving these transitions, particularly when sites are saturated. The quantitatively predicts numbers at equilibrium semidilute regime, but significantly overestimates size range where percolation is observed. This can partly be traced back to fact mean-field assumption not valid dilute regime neglects existence cycles connectivity graph percolating cluster transition. study enriches understanding behaviors, providing valuable insights for interpretation experimental observations.

Language: Английский

Citations

0
Segregative phase separation in aqueous systems of whey protein and carboxymethylcellulose under isoionic conditions DOI Creative Commons
Sofía Baldor,

Malena N. Enatarriaga-Scull,

Agustín Gabriel Genna-Coronel

et al.

Agrociencia Uruguay, Journal Year: 2025, Volume and Issue: 29(NE1), P. e1602 - e1602

Published: April 24, 2025

Whey, a byproduct of cheese production, contains valuable proteins such as whey protein (WP), which are key in the food industry due to their functional properties, especially ability form gels. When combined with polysaccharides like carboxymethylcellulose (CMC), WP can undergo phase separation, affecting properties viscosity and texture products. This separation be segregative, when macromolecules incompatible, or associative, oppositely charged attract each other networks. study focuses on CMC mixtures under isoionic conditions, evaluating effect molecular weight rheological mixtures. The tests included measurements electrokinetic potential, microscopic analysis, rheology individual solutions low- high-viscosity CMC. It was found that tend segregated phases more easily. flow gelation also depended concentration type CMC, higher concentrations resulting stronger results provide insights for controlling structure functionality systems.

Language: Английский

Citations

0
Current perspectives in drug targeting intrinsically disordered proteins and biomolecular condensates DOI Creative Commons
Caolitao Qin, Yunlong Wang, Jianming Zheng

et al.

BMC Biology, Journal Year: 2025, Volume and Issue: 23(1)

Published: May 5, 2025

Intrinsically disordered proteins (IDPs) and biomolecular condensates are critical for cellular processes physiological functions. Abnormal can cause diseases such as cancer neurodegenerative disorders. IDPs, including intrinsically regions (IDRs), were previously considered undruggable due to their lack of stable binding pockets. However, recent evidence indicates that targeting them influence processes. This review explores current strategies target IDPs condensates, potential improvements, the challenges opportunities in this evolving field.

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
Multiphase separation in postsynaptic density regulated by membrane geometry via interaction valency and volume DOI Open Access
Risa Yamada, Giovanni B. Brandani, Shoji Takada

et al.

Published: May 12, 2025

Abstract Biomolecular condensates are found at various cellular locations, nucleus, cytoplasm, and membrane. These often contain multiple components can separate into phases with morphologies such as core-shell droplets, implicating functional roles. Demixing of their arrangements determined by competitive interactions locations. Recent studies reported a puzzling multiphase morphology four postsynaptic density: AMPA-receptor, NMDA-receptor, PSD-95, CaMKII. The becomes apparently reversed we move from the solubilized constructs to In this study, using system model, study behavior in solution (3D) domain formation on beneath membrane (2D) elucidate molecular mechanisms behind puzzle. Our mesoscopic simulations reproduce that CaMKII activation induces separation 3D vitro experiment AMPA-receptor/PSD-95 core NMDA-receptor/CaMKII shell. Then, obtain high valency large volume appears be major factor reversal. Interestingly, find that, while has dominant non-specific interaction system, specific multivalent overcome for membrane, reversing morphology. On layered structures receptors CaMKIIs reduce effects receptors, making dominant. is distinct condensate modulated arrangement.

Language: Английский

Citations

0
Multiphase separation in postsynaptic density regulated by membrane geometry via interaction valency and volume DOI Open Access
Risa Yamada, Giovanni B. Brandani, Shoji Takada

et al.

Published: May 12, 2025

Abstract Biomolecular condensates are found at various cellular locations, nucleus, cytoplasm, and membrane. These often contain multiple components can separate into phases with morphologies such as core-shell droplets, implicating functional roles. Demixing of their arrangements determined by competitive interactions locations. Recent studies reported a puzzling multiphase morphology four postsynaptic density: AMPA-receptor, NMDA-receptor, PSD-95, CaMKII. The becomes apparently reversed we move from the solubilized constructs to In this study, using system model, study behavior in solution (3D) domain formation on beneath membrane (2D) elucidate molecular mechanisms behind puzzle. Our mesoscopic simulations reproduce that CaMKII activation induces separation 3D vitro experiment AMPA-receptor/PSD-95 core NMDA-receptor/CaMKII shell. Then, obtain high valency large volume appears be major factor reversal. Interestingly, find that, while has dominant non-specific interaction system, specific multivalent overcome for membrane, reversing morphology. On layered structures receptors CaMKIIs reduce effects receptors, making dominant. is distinct condensate modulated arrangement.

Language: Английский

Citations

0
FIREBALL: A tool to fit protein phase diagrams based on mean-field theories for polymer solutions DOI Creative Commons
Mina Farag, Alex S. Holehouse, Xiangze Zeng

et al.

Biophysical Journal, Journal Year: 2023, Volume and Issue: 122(12), P. 2396 - 2403

Published: May 8, 2023

Language: Английский

Citations

9
Backbone interactions and secondary structures in phase separation of disordered proteins DOI
Shanlong Li, Yumeng Zhang, Jianhan Chen

et al.

Biochemical Society Transactions, Journal Year: 2024, Volume and Issue: 52(1), P. 319 - 329

Published: Feb. 13, 2024

Intrinsically disordered proteins (IDPs) are one of the major drivers behind formation and characteristics biomolecular condensates. Due to their inherent flexibility, backbones IDPs significantly exposed, rendering them highly influential susceptible phase separation. In densely packed condensates, exposed have a heightened capacity interact with neighboring protein chains, which might lead strong coupling between secondary structures separation further modulate subsequent transitions such as aging fibrillization. this mini-review, we provide an overview backbone-mediated interactions within condensates underscore importance in We focus on recent advances experimental techniques molecular dynamics simulation methods for probing exploring roles backbone involving IDPs.

Language: Английский

Citations

2
Biomolecular phase separation through theoretical and computational microscope DOI Creative Commons
Rajeev Kumar, Da‐Hyun Koo, Yu‐Gon Eom

et al.

Bulletin of the Korean Chemical Society, Journal Year: 2024, Volume and Issue: 45(5), P. 420 - 434

Published: April 2, 2024

Abstract Biomolecular phase separation is a vital mechanism for orchestrating biomolecules within living cells. This crucial role has spurred an intense pursuit to comprehend the molecular underpinnings governing and regulating these processes. Computational methodologies offer unique perspective, augmenting experimental techniques by providing detailed information that cannot be obtained otherwise. In this review, we briefly overview theoretical computational approaches investigate biomolecular separation. As short primer, explain factors driving affecting of biomolecules, then delve into analytical simulation methods used study We how like Flory–Huggins theory, random approximation, graph‐based have been behaviors various proteins. also discuss principles applications all‐atom simulations, coarse‐grained field‐theoretical approaches. Additionally, explore recent advances in machine learning approach predict biomolecules.

Language: Английский

Citations

2