Fundamental Aspects of Phase-Separated Biomolecular Condensates

Chemical Reviews, Год журнала: 2024, Номер 124(13), С. 8550 - 8595

Опубликована: Июнь 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.

Язык: Английский

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Chemically Informed Coarse-Graining of Electrostatic Forces in Charge-Rich Biomolecular Condensates

ACS Central Science, Год журнала: 2025, Номер 11(2), С. 302 - 321

Опубликована: Фев. 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.

Язык: Английский

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The Cation−π Interaction in Chemistry and Biology

Chemical Reviews, Год журнала: 2025, Номер unknown

Опубликована: Фев. 20, 2025

The cation-π interaction is an important noncovalent binding force that impacts all areas of chemistry and biology. Extensive computational gas phase experimental studies have established the potential strength essential nature interaction. Previous reviews emphasized model systems a variety biological examples. This work includes discussion those but emphasizes other are perhaps less well appreciated. These include novel ability alkali metals in water; application to organic synthesis chemical biology; cooperative behaviors multiple interactions, including adhesive proteins from mussels similar organisms formation modulation biomolecular condensates (phase separation); interactions involved recognizing DNA/RNA.

Язык: Английский

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Predicting Heteropolymer Interactions: Demixing and Hypermixing of Disordered Protein Sequences

Physical Review X, Год журнала: 2024, Номер 14(3)

Опубликована: Июль 18, 2024

Cells contain multiple condensates which spontaneously form due to the heterotypic interactions between their components. Although proteins and disordered region sequences that are responsible for condensate formation have been extensively studied, rule of components allow demixing, i.e., coexistence condensates, is yet be elucidated. Here, we construct an effective theory interaction heteropolymers by fitting it molecular dynamics simulation results obtained more than 200 sampled from regions human proteins. We find sum amino acid pair across two predicts Boyle temperature qualitatively well, can quantitatively improved dimer approximation, where incorporate effect neighboring acids in sequences. The theory, combined with finding a metric captures strength distinct sequences, allowed selection up three demix each other multicomponent simulations, as well generation artificial given sequence. points generic sequence design strategy or hypermix thanks low-dimensional nature space identify. As consequence geometric arguments interactions, number strongly constrained, irrespective choice coarse-grained model. Altogether, theoretical basis methods estimate heteropolymers, utilized predicting phase separation properties rules assignment localization functions Published American Physical Society 2024

Язык: Английский

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Chemically-informed coarse-graining of electrostatic forces in charge-rich biomolecular condensates

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 27, 2024

Biomolecular condensates composed of highly charged biomolecules like 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 many systems. However, their predictive accuracy diminishes due implicit treatment ions. Here, we present Mpipi-Recharged model, a residue-resolution model improves description charge effects biomolecular containing disordered proteins, multi-domain and/or RNAs. maintains efficiency its predecessor—the Mpipi model—by still treating implicitly, but incorporating pair-specific asymmetric potential informed atomistic simulations explicit We show such coarse-graining forces is needed recapitulate stronger mean-field impact associative interactions between opposite-charge pairs over repulsion among equally revealed our simulations. shows excellent agreement with experimental phase behavior systems, capturing subtle challenging without solvation, as blockiness, stoichiometry changes, salt concentration variation. By improved extends tools available investigate physicochemical mechanisms regulating condensates.

Язык: Английский

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Unveiling the multicomponent phase separation through molecular dynamics simulation and graph theory

The Journal of Chemical Physics, Год журнала: 2024, Номер 160(6)

Опубликована: Фев. 13, 2024

Biomolecular condensates formed by multicomponent phase separation play crucial roles in diverse cellular processes. Accurate assessment of individual-molecule contributions to condensate formation and precise characterization their spatial organization within are for understanding the underlying mechanism separation. Using molecular dynamics simulations graph theoretical analysis, we demonstrated quantitatively significant cation-π π–π interactions mediated aromatic residues arginine polypeptide systems. Our findings reveal temperature chain length-dependent alterations network parameters, such as number layers, changes aggregation connectivity. Notably, observe a transition between assortativity disassortativity network. Moreover, polypeptides W, Y, F, R consistently promote formation, while other charged two polar (Q N) depend on length. Furthermore, polyadenosine polyguanosine can establish stable connections with polypeptides, resulting reduced involvement K, E, D, Q, N Overall, this study provides distinctive, precise, quantitative approach characterize

Язык: Английский

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Selective phase separation of transcription factors is driven by orthogonal molecular grammar

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 31, 2025

Protein production is critically dependent on gene transcription rates, which are regulated by RNA polymerase and a large collection of different factors (TFs). How these selectively address genes only partially known. Recent discoveries show that the differential condensation separate TF families through phase separation may contribute to selectivity. Here we this conducting studies six TFs from three with residue-scale coarse-grained molecular dynamics simulations. Our exploration ternary diagrams reveals four dominant sticker motifs two orthogonal driving forces dictate resultant condensate morphology, pointing sequence-dependent grammar as generic mechanism drives selective transcriptional in expression. Transcription factor (TF) rates. Exploration morphology.

Язык: Английский

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The Effect of Dipeptide Repeat Proteins on FUS/TDP43-RNA Condensation in C9orf72 ALS/FTD

The Journal of Physical Chemistry B, Год журнала: 2024, Номер unknown

Опубликована: Сен. 23, 2024

Condensation of RNA binding proteins (RBPs) with is essential for cellular function. The most common familial cause the diseases ALS and FTD C9orf72 repeat expansion disorders that produce dipeptide (DPRs). We explore hypothesis DPRs disrupt native condensation behavior RBPs through molecular interactions resulting in toxicity. FUS TDP43 are two known to be affected ALS/FTD. use our previously developed 1-bead-per-amino acid a newly 3-bead-per-nucleotide dynamics model ternary phase diagrams FUS/TDP43-RNA-DPR systems. show toxic arginine containing (R-DPRs) can RBP condensates cation-π strongly sequester electrostatic interactions. droplet morphologies already modified at small additions R-DPRs leading non-native FUS/TDP43-encapsulated marbled RNA/DPR core.

Язык: Английский

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Studies of Protein Phase Separation Using Leishmania Kinetoplastid Membrane Protein-11

The Journal of Physical Chemistry B, Год журнала: 2024, Номер unknown

Опубликована: Окт. 23, 2024

Despite the significant understanding of phase separation in proteins with intrinsically disordered regions, a considerable percentage without such regions also undergo separation, presenting an intriguing area for ongoing research across all kingdoms life. Using combination spectroscopic and microscopic techniques, we report here first time that low temperature pH can trigger liquid–liquid (LLPS) parasitic protein, kinetoplastid membrane protein-11 (KMP-11). Electrostatic hydrophobic forces are found to be essential formation stability phase-separated protein assemblies. We show further increase ionic strength beyond threshold decreases interchain electrostatic interactions acting between alternate charged blocks, altering propensity separation. More interestingly, addition cholesterol inhibits LLPS by engaging recognition amino acid consensus (CRAC)-like domains present protein. This was confirmed using CRAC-deleted mutant perturbed binding, which did not LLPS.

Язык: Английский

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Emerging biophysical principles of macromolecular phase separation

Biophysical Journal, Год журнала: 2024, Номер 123(11), С. E1 - E3

Опубликована: Май 17, 2024

Over the last decade, scientists have established that cells contain not only membrane-enclosed organelles but also a plethora of membraneless termed "biomolecular condensates." These structures represent pervasive and fundamental components cellular architecture are crucial for control functions through spatiotemporal organization, compartmentalization, localization. Composed complex interplay proteins nucleic acids, condensates product multitude weak, noncovalent, transient, multivalent interactions, culminating in emergence highly dynamic, mesoscopic, viscoelastic both reversible selectively permeable. This special issue Biophysical Journal focusing on biological addresses some fascinating aspects these by using diverse array emerging experimental, theoretical, computational approaches. Pappu co-workers quantitatively examined forces driving macromolecular phase separation (1Chauhan G. Bremer A. R.V. et al.Crowder titrations enable quantification separation.Biophys. J. 2023; : ▪▪▪https://doi.org/10.1016/j.bpj.2023.09.006Abstract Full Text PDF Scopus (1) Google Scholar). By integrating theoretical analysis, simulations, vitro experiments, team determined crowding agents, provided they true depletants, can be used to effectively measure intrinsic responsible separation. relate saturation concentrations absence crowders second virial coefficients, which assess strength solvent-driven intermolecular interactions. study establishes methodical framework facilitates comparative analysis intrinsic, macromolecule-specific drive Showcasing power NMR spectroscopy illuminate atomic-level details biomolecular condensates, Fawzi studied structure interactions Candida albicans transcription factor Egf1 condensed (2Wang S.-H. Zheng T. N.L. Structure prion-like domains Efg1 2024; ▪▪▪https://doi.org/10.1016/j.bpj.2024.01.030Abstract work, featured New Notable article Iwahara, highlighted importance transient helices promoting protein self-association context health disease (3Iwahara Transient with functional roles.Biophys. ▪▪▪https://doi.org/10.1016/j.bpj.2024.01.038Abstract Stachowiak, Parekh, focused between lipid droplets intrinsically disordered showed droplet surfaces nucleate (4Kamatar Bravo J.P.K. Parekh S.H. al.Lipid as substrates ▪▪▪https://doi.org/10.1016/j.bpj.2024.03.015Abstract (0) They hypothesized interface might play role regulation organization cell. Havenith recently developed terahertz method quantify elusive contributions water (5König B. Pezzotti S. M. al.Real-time solvation free energy changes upon liquid-liquid α-elastin.Biophys. ▪▪▪https://doi.org/10.1016/j.bpj.2023.07.023Abstract (7) Although there large entropic enthalpic due hydrophobic hydrophilic hydration networks, compensate each other, producing small differences easily manipulated tip balance favor or against Shi, Stone, presented new hydrodynamic model micropipette aspiration experimental data (6Roggeveen J.V. Wang H. Stone H.A. al.A calibration-free measuring properties condensates.Biophys. ▪▪▪https://doi.org/10.1016/j.bpj.2023.09.018Abstract improved allows determination viscosity surface tension just one experiment manner, presenting simple powerful approach investigate material other fluids. Collepardo-Guevara, Reinhardt, investigated factors multiphasic condensation biomolecules (7Chew P.Y. Joseph J.A. Reinhardt al.Aromatic arginine content drives protein-RNA mixtures.Biophys. ▪▪▪https://doi.org/10.1016/j.bpj.2023.06.024Abstract The authors conducted residue/nucleotide-resolution simulations RNA explore how amino acid sequence composition influences nature condensates. research discovered aromatic residues is critical multiple-phase physicochemical could pave way designing Coupe Fakhri addressed effect ATP condensate DEAD-box helicase, key regulator range (8Coupe N. ATP-induced cross-linking condensate.Biophys. ▪▪▪https://doi.org/10.1016/j.bpj.2023.07.013Abstract demonstrated physical effects mutant form helicase modulated ATP, alters emergent properties. Ameta fluorescence correlation dynamics short oligonucleotides within charged uncharged phase-separated (9Singh Thutupalli al.Constrained DNA droplets.Biophys. ▪▪▪https://doi.org/10.1016/j.bpj.2023.12.025Abstract delineated parameters influence oligonucleotide dynamics, including length, charge, droplet's internal structure. underscores utility elucidating dictate diffusion processes Zidovska anomalous process nucleolar coarsening human (10Arsenadze Caragine C.M. al.Anomalous coalescing nucleoli cells.Biophys. ▪▪▪https://doi.org/10.1016/j.bpj.2024.01.005Abstract found irregularities volume distribution persist throughout cell cycle observed alongside decrease chromatin concentration space nucleoli, well an increased motion toward other. With additional information from suggested depletion effective attraction this atypical process. sheds light mechanics underpinning out-of-equilibrium nucleus enhances our understanding dynamic nuclear organization. Nordenskiöld multiscale modeling ion-mediated nucleosome core particles building blocks (11Sun Korolev L. al.Multiscale reveals particles.Biophys. ▪▪▪https://doi.org/10.1016/j.bpj.2023.10.030Abstract Elbaum-Garfinkle condensate-formation heterochromatin HP1α, central formation gene-silencing compartments (12Deshpande P. Prentice E. al.Epigenetic marks uniquely tune HP1α ▪▪▪https://doi.org/10.1016/j.bpj.2024.04.020Abstract Using rheology microscopy, researchers HP1α-DNA specific binding partners HP1α. work connected mechanical stability nucleus. Lavrentovich, Männik, tackled question what mechanisms regulate size nucleoid Escherichia coli (13Chang M.-H. Lavrentovich M.O. Mannik Differentiating roles polysomes homeostasis coli.Biophys. ▪▪▪https://doi.org/10.1016/j.bpj.2023.11.010Abstract nucleoid, distinct, organelle houses chromosomal DNA, defining feature bacterial species. growing body evidence suggesting principal mechanism behind formation, determining its been identified. Through experimentally derived, energy-based model, elucidated instrumental demarcating distinct phase. However, it entirety cytosolic govern under physiological conditions. suggests may preserve ensure feedback loop dictates dimensions, turn modulate rate synthesis. Brangwynne unmasked p62 Huntingtin poly-glutamine (polyQ) inclusions (14Choi C.-H. Lee D.S.W. C.P. al.Condensate interfaces accelerate aggregation.Biophys. ▪▪▪https://doi.org/10.1016/j.bpj.2023.10.009Abstract (3) authors, light-inducible biomimetic system, enhance polyQ aggregates interface-mediated sequestration, accelerating accumulation suppresses further p62. was Dogra Mukhopadhyay (15Dogra Illuminating interface: aggregation at interface.Biophys. ▪▪▪https://doi.org/10.1016/j.bpj.2023.10.027Abstract Castañeda phase-separation characteristics ubiquitin-binding shuttle UBQLN1, UBQLN2, UBQLN4 (16Dao T.P. Rajendran C.A. al.Short termini proline-rich domain major regulators UBQLN1/2/4 ▪▪▪https://doi.org/10.1016/j.bpj.2023.11.3401Abstract Despite being closely related, exhibit their quality associations various neurodegenerative diseases. revealed capacities transition vary significantly because regions proteins, particularly disease-associated region short, N-terminal region. insights suggest deep unique molecular grammar governs transitions future experiments UBQLNs undergoing Two review articles address important contemporary issues Weakly Keller described challenges coupled membranes (17Weakly H.M.J. S.L. Coupling liquid phases 3D 2D membranes: successes, challenges, tools.Biophys. ▪▪▪https://doi.org/10.1016/j.bpj.2023.12.023Abstract Barron impact cathelicidin LL-37 innate immune system autoimmune disorders (18Zielke C. Nielsen J.E. A.E. al.Between good evil: Complexation acids.Biophys. ▪▪▪https://doi.org/10.1016/j.bpj.2023.10.035Abstract In summary, original reviews capture excitement field biology. current trends certainly do encompass all biophysical We thank exciting issue. grateful anonymous reviewers, who helped valuable comments suggestions published Editor-in-Chief, Vasanthi Jayaraman, inviting us organize Darren Early, Meredith Zimmerman, journal editors staff help. Sandeep Rai Roopali Khanna lab providing cover art image.

Язык: Английский

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