Journal of Biological Chemistry, Год журнала: 2024, Номер unknown, С. 107831 - 107831
Опубликована: Сен. 1, 2024
Язык: Английский
Journal of Chemical Theory and Computation, Год журнала: 2025, Номер unknown
Опубликована: Фев. 5, 2025
Biomolecular interactions are essential in many biological processes, including complex formation and phase separation processes. Coarse-grained computational models especially valuable for studying such processes via simulation. Here, we present COCOMO2, an updated residue-based coarse-grained model that extends its applicability from intrinsically disordered peptides to folded proteins. This is accomplished with the introduction of a surface exposure scaling factor, which adjusts interaction strengths based on solvent accessibility, enable more realistic modeling involving domains without additional costs. COCOMO2 was parametrized directly solubility data improve performance predicting concentration-dependent broader range biomolecular systems compared original version. enables new applications study condensates involve IDPs together assembly also provides expanded foundation development multiscale approaches span residue-level atomistic resolution.
Язык: Английский
Процитировано
4
Journal of Cellular Biochemistry, Год журнала: 2024, Номер 125(3)
Опубликована: Фев. 13, 2024
Abstract When the SARS‐CoV‐2 virus infects humans, it leads to a condition called COVID‐19 that has wide spectrum of clinical manifestations, from no symptoms acute respiratory distress syndrome. The initiates damage by attaching ACE‐2 protein on surface endothelial cells line blood vessels and using these as hosts for replication. Reactive oxygen species levels are increased during viral replication, which oxidative stress. About three‐fifths (~60%) people who get infected with eradicate their body after 28 days recover normal activity. However, large fraction (~40%) suffer various (anosmia and/or ageusia, fatigue, cough, myalgia, cognitive impairment, insomnia, dyspnea, tachycardia) beyond 12 weeks diagnosed syndrome long COVID. Long‐term studies in group contracted have been contrasted noninfected matched people. A subset can be distinguished set cytokine markers persistent, low‐grade inflammation often self‐report two or more bothersome symptoms. No medication alleviate efficiently. Coronavirus nucleocapsid proteins investigated extensively potential drug targets due key roles among is ability bind respective genomic RNAs incorporation into emerging virions. This review highlights basic its undergo liquid–liquid phase separation. We hypothesize this separation may contribute hypothesis unlocks new investigation angles could potentially open novel avenues better understanding COVID treating condition.
Язык: Английский
Процитировано
9
Molecular Biology of the Cell, Год журнала: 2024, Номер 35(7)
Опубликована: Май 29, 2024
Fluorescent protein (FP) tags are extensively used to visualize and characterize the properties of biomolecular condensates despite a lack investigation into effects these on phase separation. Here, we characterized dynamic µNS, viral hypothesized undergo separation main component mammalian orthoreovirus factories. Our interest in sequence determinants nucleation process µNS led us compare size density formed by FP::µNS untagged protein. We found an FP-dependent increase droplet density, which suggests that FP can promote condensation. To further assess effect formation, fused mutants show could variably induce otherwise noncondensing proteins. By comparing fluorescent constructs with identified mNeonGreen as least artifactual tag minimally perturbed These results some more suitable for visualizing characterizing minimal experimental artifacts.
Язык: Английский
Процитировано
8
Small, Год журнала: 2023, Номер 20(15)
Опубликована: Дек. 1, 2023
Compartments are a fundamental feature of life, based variously on lipid membranes, protein shells, or biopolymer phase separation. Here, this combines self-assembling bacterial microcompartment (BMC) shell proteins and liquid-liquid separation (LLPS) to develop new forms compartmentalization. It is found that BMC assemble at the interfaces between either 1) dextran-rich droplets PEG-rich continuous poly(ethyleneglycol)(PEG)/dextran aqueous two-phase system, 2) polypeptide-rich coacervate dilute polylysine/polyaspartate complex system. Interfacial assemblies in system sensitive ratio cationic anionic polypeptides, consistent with electrostatically-driven assembly. In both systems, interfacial assembly competes aggregation, concentration polycation availability impacting coating. These two LLPS systems then combined form three-phase wherein contained within droplets. localization hexameric tunable by changing polyelectrolyte charge ratio. The tens-of-micron scale protein-coated introduced here can accommodate bioactive cargo such as enzymes RNA represent synthetic cell strategy for organizing biomimetic functionality.
Язык: Английский
Процитировано
7
Physical Review Letters, Год журнала: 2024, Номер 132(20)
Опубликована: Май 14, 2024
In many biopolymer solutions, attractive interactions that stabilize finite-sized clusters at low concentrations also promote phase separation high concentrations. Here we study a model system exhibits the opposite behavior, whereby self-assembly of DNA oligonucleotides into finite-sized, stoichiometric tends to inhibit separation. We first use microfluidics-based experiments map novel transition in which condense as temperature increases divalent cations. then show theoretical competition between and quantitatively predicts changes experimental diagrams arising from sequence perturbations. Our results point general mechanism by shapes boundaries complex solutions.
Язык: Английский
Процитировано
2
Biochemical Society Transactions, Год журнала: 2024, Номер unknown
Опубликована: Сен. 26, 2024
Understanding of the physicochemical properties and functions biomolecular condensates has rapidly advanced over past decade. More recently, many RNA viruses have been shown to form cytoplasmic replication factories, or viroplasms, via phase separation their components, akin numerous cellular membraneless organelles. Notably, diverse from Reoviridae family containing 10–12 segmented double-stranded genomes induce formation viroplasms in infected cells. Little is known about inner workings these inclusions how they may support stoichiometric assembly with genomes, raising questions roles coordinating viral genome packaging. Here, we discuss molecular composition determines properties, highlighting interplay between structure, remodelling, condensate self-organisation. Advancements structural probing theoretical modelling can reveal mechanisms through which ribonucleoprotein complexes selective enrichment distinct RNAs.
Язык: Английский
Процитировано
2
Опубликована: Окт. 30, 2024
Many biological functions and dysfunctions rely on two fundamental processes, molecular assembly the formation of condensed phases such as biomolecular condensates. Condensed generally form via phase separation, while assemblies are clusters molecules various sizes, shapes, functionality. We developed a theory that relies thermodynamic principles to understand interplay between separation. propose prototypical classes protein interactions characterize their different equilibrium states relaxation dynamics. obtain results consistent with recent in vitro experimental observations reconstituted proteins, including anomalous size distribution assemblies, gelation phases, change condensate volume during ageing. Our provides framework unravel mechanisms underlying physiological essential for cellular function, aberrant which associated several neurodegenerative disorders.
Язык: Английский
Процитировано
2
Physical Review X, Год журнала: 2024, Номер 14(4)
Опубликована: Дек. 10, 2024
Computational modeling of assembly is challenging for many systems, because their timescales can vastly exceed those accessible to simulations. This article describes the multiMSM, which a general framework that uses Markov state models (MSMs) enable simulating self-assembly and self-organization finite-sized structures on are orders magnitude longer than brute-force dynamics As with traditional MSM approaches, method efficiently overcomes free energy barriers other dynamical bottlenecks. In contrast previous approaches assembly, simultaneous clusters consequent depletion subunits or small oligomers. The algorithm accounts changes in transition rates as concentrations monomers intermediates evolve over course reaction. Using two model we show multiMSM accurately predicts full ensemble required reach equilibrium. Importantly, after constructing one system concentration, yields at be approximately calculated without any further sampling. capability allows additional speedup. addition, enables highly efficient calculation quantities such profiles, nucleation timescales, flux along pathways, entropy production rates. Identifying contributions individual transitions reveals sources kinetic traps. broadly applicable systems equilibrium nonequilibrium trivially parallelizable and, thus, scalable. Published by American Physical Society 2024
Язык: Английский
Процитировано
2
Cell, Год журнала: 2024, Номер unknown
Опубликована: Дек. 1, 2024
Replication and genome encapsidation of many negative-sense RNA viruses take place in virus-induced membraneless organelles termed viral factories (VFs). Although liquid properties VFs are believed to control the transition from replication nucleocapsid (NC) assembly, VF maturation interactions with cellular environment remain elusive. Here, we apply situ cryo-correlative light electron tomography follow NC assembly changes morphology their during Ebola virus infection. We show that NCs loosely packed helical assemblies early compact cylinders arrange into highly organized parallel bundles later Early associate intermediate filaments devoid other host material but become progressively accessible components. Our data suggest this process is coupled solidification, loss sphericity, dispersion promotes cytoplasmic exposure facilitate transport budding sites.
Язык: Английский
Процитировано
2
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Апрель 11, 2024
Abstract SARS-CoV-2 Nucleocapsid protein ( N ) is a viral structural that packages the 30kb genomic RNA inside virions and forms condensates within infected cells through liquid-liquid phase separation LLPS ). N, in both soluble condensed forms, has accessory roles life cycle including genome replication immunosuppression. The ability to perform these tasks depends on its reversibility. conditions stabilize destabilize role of N-N interactions are poorly understood. We have investigated formation dissolution minimalist system comprised an ssDNA oligomer just long enough support assembly. short oligo allows us focus interaction. developed sensitive FRET assay interrogate assembly reactions from perspective oligonucleotide. find alone can form oligomers but oligonucleotide enables their into three-dimensional phase. At ∼1:1 ratio maximal. modest excess or nucleic acid causes break down catastrophically. Under examined here critical concentration about 1 µM. responsiveness environment may biological consequences. A better understanding how modulates association will shed light condensate activity could inform antiviral strategies targeting LLPS.
Язык: Английский
Процитировано
1