Fundamental Aspects of Phase-Separated Biomolecular Condensates

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

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

ACS Central Science, Journal Year: 2025, Volume and Issue: 11(2), P. 302 - 321

Published: Feb. 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.

Language: Английский

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The Cation−π Interaction in Chemistry and Biology

Chemical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 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.

Language: Английский

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Predicting Heteropolymer Interactions: Demixing and Hypermixing of Disordered Protein Sequences

Physical Review X, Journal Year: 2024, Volume and Issue: 14(3)

Published: July 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

Language: Английский

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

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 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.

Language: Английский

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

The Journal of Chemical Physics, Journal Year: 2024, Volume and Issue: 160(6)

Published: Feb. 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

Language: Английский

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

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 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.

Language: 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, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 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.

Language: Английский

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

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 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.

Language: Английский

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Energy landscapes for clusters of hexapeptides

The Journal of Chemical Physics, Journal Year: 2024, Volume and Issue: 161(5)

Published: Aug. 2, 2024

We present the results for energy landscapes of hexapeptides obtained using interfaces to Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS) program. have used basin-hopping global optimization and discrete path sampling explore hexapeptide monomers, dimers, oligomers containing 10, 100, 200 monomers modeled a residue-level coarse-grained potential, Mpipi, implemented in LAMMPS. find that dimers peptides amino acid residues are better at promoting phase separation, such as tyrosine arginine, melting peaks higher temperature their heat capacity compared phenylalanine lysine, respectively. This observation correlates with previous work on same uncapped atomistic potential. For oligomers, we compare variation monomer conformations radial distance observe trends selected angles calculated each monomer. The LAMMPS GMIN OPTIM programs landscape exploration offer new opportunities investigate larger systems provide access potentials within

Language: Английский

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