Molecular Drivers of RNA Phase Separation

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 22, 2025

RNA molecules are essential in orchestrating the assembly of biomolecular condensates and membraneless compartments cells. Many form via association with proteins containing specific binding motifs. However, recent reports indicate that low-complexity sequences can self-assemble into condensate phases without protein assistance. Divalent cations significantly influence thermodynamics dynamics condensates, which exhibit base-specific lower-critical solution temperatures (LCST). The precise molecular origins these remain elusive. In this study, we employ atomistic simulations to elucidate driving forces governing temperature-dependent phase behavior RNA, providing new insights LCST. Using tetranucleotides their chemically modified analogs, map condensates' equilibrium thermodynamic profiles structural ensembles across various ionic conditions. Our findings reveal magnesium ions promote LCST by inducing local order-disorder transitions within structures. Consistent experimental observations, demonstrate thermal stability follows Poly(G) > Poly(A) Poly(C) Poly(U) order shaped interplay base-stacking hydrogen bonding interactions. Furthermore, our show conditions post-translational modifications fine-tune self-assembly modulate physical properties. for organizing play critical roles cellular processes. While many through interactions between proteins, studies have shown certain This ability is influenced sequence composition presence like magnesium. detailed carried out systematic study how temperature affect condensation. We discovered a key role condense at lower promoting changes RNA. also revealed varies depending on sequence, guanine-rich being most stable. Additionally, demonstrated chemical properties condensates. provides forms highlights potential strategies control behavior, could implications understanding organization developing therapies.

Язык: Английский

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Atomistic insights into the reentrant phase-transitions in polyuracil and polylysine mixtures

The Journal of Chemical Physics, Год журнала: 2024, Номер 161(1)

Опубликована: Июль 1, 2024

The phase separation of protein and RNA mixtures underpins the assembly regulation numerous membraneless organelles in cells. ubiquity protein-RNA condensates cellular regulatory processes is part due to their sensitivity concentration, which affects physical properties stability. Recent experiments with poly-cationic peptide-RNA have revealed closed-loop diagrams featuring lower upper critical solution temperatures. These indicate reentrant transitions shaped by biomolecular interactions entropic forces such as solvent ion reorganization. We employed atomistic simulations study various RNA-polylysine stoichiometries temperatures elucidate microscopic driving behind mixtures. Our findings reveal an intricate interplay between hydration, condensation, specific hydrogen bonding, resulting distinct stoichiometry-dependent equilibria governing stabilities structures condensate phase. show that are accompanied desolvation around phosphate groups RNA, increased contacts lysine side chains. In RNA-rich systems at temperatures, molecules can form extensive pi-stacking bond network, leading percolation. protein-rich systems, no percolation-induced observed. Furthermore, we assessed performance three prominent water force fields-Optimal Point Charge (OPC), TIP4P-2005, TIP4P-D-in capturing transitions. OPC provided a superior balance interactions, enabling effective capture accurate characterization changes This offers insights into nature using simple model peptide nucleotide believe our results broadly applicable larger classes exhibiting

Язык: Английский

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Decoding Biomolecular Condensate Dynamics: An Energy Landscape Approach

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

Опубликована: Сен. 26, 2024

A significant fraction of eukaryotic proteins contain low-complexity sequence elements with unknown functions. Many these sequences are prone to form biomolecular condensates unique material and dynamic properties. Mutations in regions often result abnormal phase transitions into pathological solid-like states. Therefore, understanding how the patterns encode properties is crucial for uncovering cellular functions evolutionary forces behind emergence proteins. In this work, we employ an alphabet-free energy landscape framework stickers spacers dissect low complexity condensates. We find a broad diagram determined by distinct features, showing that periodic repeat motifs promote elastic-dominated while random viscous-dominated certain degree sticker periodicity necessary maintain fluidity condensates, preventing them from forming glassy or Finally, show captures viscoelastic trends seen recent experiments on prion domains makes predictions systematic variation protein condensate viscoelasticity via altering strength motifs.

Язык: Английский

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Nucleoprotein Phase-Separation Affinities Revealed via Atomistic Simulations of Short Peptide and RNA Fragments

The Journal of Physical Chemistry Letters, Год журнала: 2024, Номер 15(43), С. 10811 - 10817

Опубликована: Окт. 21, 2024

Liquid–liquid phase separation of proteins and nucleic acids into condensate phases is a versatile mechanism for ensuring the compartmentalization cellular biochemistry. RNA molecules play critical roles in these condensates, particularly transcriptional regulation stress responses, exhibiting wide range thermodynamic dynamic behaviors. However, deciphering molecular grammar that governs stability dynamics protein–RNA condensates remains challenging due to multicomponent heterogeneous nature condensates. In this study, we employ atomistic simulations 20 distinct mixtures containing minimal peptide fragments which allows us dissect phase-separating affinities all amino presence RNA. Our findings elucidate chemically specific interactions, hydration profiles, ionic effects synergistically promote or suppress separation. We map ternary diagram identifying four groups residues promote, maintain, suppress, disrupt clusters.

Язык: Английский

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