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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Martini3-IDP: improved Martini 3 force field for disordered proteins

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

Published: March 24, 2025

Coarse-grained (CG) molecular dynamics (MD) is widely used for the efficient simulation of intrinsically disordered proteins (IDPs). The Martini model, one most popular CG force fields in biomolecular simulation, was reported to yield too compact IDP conformations, limiting its applications. Addressing this, we optimized bonded parameters based on fitting reference simulations a diverse set IDPs at atomistic resolution, resulting Martini3-based protein model coined Martini3-IDP. This leads expanded greatly improving reproduction experimentally measured radii gyration. Moreover, contrary ad-hoc fixes scaling protein-protein or protein-water interactions, Martini3-IDP keeps overall interaction balance underlying 3. To validate that, perform comprehensive testing including full-length multidomain proteins, IDP-lipid membrane binding and IDP-small molecule binding, confirming ability successfully capture complex interplay between components. Finally, recently emerging concept condensate, through liquid-liquid phase separation, also reproduced by number both homotypic heterotypic systems. With improved expand simulate processes involving environments, spatio-temporal scales inaccessible with all-atom models. Here, authors introduce Martini3-IDP, refined that addresses prior over-compact structures. Validated across systems, it captures interactions condensates.

Language: Английский

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Determining the Role of Electrostatics in the Making and Breaking of the Caprin1–ATP Nanocondensate

The Journal of Physical Chemistry B, Journal Year: 2025, Volume and Issue: unknown

Published: May 2, 2025

We employ a multiscale computational approach to investigate the condensation process of C-terminal low-complexity region Caprin1 protein as function increasing ATP concentration for three states: initial mixed state, nanocondensate formation, and dissolution droplet it reenters state. show that upon condensation, assembles via pi-pi interactions, resulting in formation large cluster stacked molecules stabilized by sodium counterions. The surface assembly interacts with arginine-rich regions protein, particularly its N-terminus, promote complete phase-separated on length scale tens nanometers. In order understand stability, we analyzed near-surface electrostatic potential (NS-ESP) estimated zeta Caprin1-ATP assemblies. predict positive NS-ESP at low concentrations defines early excellent agreement obtained from NMR experiments using paramagnetic resonance enhancement. By contrast, moderate levels is highly negative compared estimates outside dense charge further explain remarkable stability this assembly. As rise further, strong forces needed are replaced weaker interactions drive re-entry into state exhibits much lower potential.

Language: Английский

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A complex network of interdomain interactions underlies the conformational ensemble of monomeric TDP‐43 and modulates its phase behavior

Protein Science, Journal Year: 2023, Volume and Issue: 33(2)

Published: Dec. 31, 2023

TAR DNA-binding protein 43 (TDP-43) is a multidomain involved in the regulation of RNA metabolism, and its aggregates have been observed neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) frontotemporal dementia (FTD). Numerous studies indicate TDP-43 can undergo liquid-liquid phase separation (LLPS) vitro component biological condensates. Homo-oligomerization via folded N-terminal domain (aa:1-77) conserved helical region (aa:319-341) disordered, C-terminal found to be an important driver separation. However, comprehensive molecular view separation, particularly regarding nature heterodomain interactions, lacking due challenges associated with stability purification. Here, we utilize all-atom coarse-grained (CG) dynamics (MD) simulations uncover network interdomain interactions implicated All-atom uncovered presence transient, involving flexible linkers, RNA-recognition motif (RRM) domains charged segment disordered (CTD). CG these inter-domain which affect conformational landscape dilute are also prevalent condensed phase. Finally, sequence surface charge distribution analysis coupled (at high salt) confirmed that transient contacts predominantly electrostatic nature. Overall, our findings from multiscale lead greater appreciation complex interaction underlying structural TDP-43.

Language: Английский

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Capturing chemical reactions inside biomolecular condensates with reactive Martini simulations

Communications Chemistry, Journal Year: 2024, Volume and Issue: 7(1)

Published: July 3, 2024

Biomolecular condensates are phase separated systems that play an important role in the spatio-temporal organisation of cells. Their distinct physico-chemical nature offers a unique environment for chemical reactions to occur. The compartmentalisation is also believed be central development early life. To demonstrate how molecular dynamics may used capture condensates, here we perform reactive simulations using coarse-grained Martini forcefield. We focus on formation rings benzene-1,3-dithiol inside synthetic peptide-based condensate, and find ring size distribution shifts larger macrocycles compared when reaction takes place aqueous environment. Moreover, rates noticeably increased peptides simultaneously undergo separation, hinting act as chaperones recruiting molecules hubs.

Language: Английский

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Coarse-Grained Modeling of Liquid–Liquid Phase Separation in Cells: Challenges and Opportunities

The Journal of Physical Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(28), P. 7280 - 7287

Published: July 9, 2024

Liquid-liquid phase separation (LLPS) within cells gives rise to membraneless organelles, which play pivotal roles in numerous cellular functions. A comprehensive understanding of the functional aspects intrinsically disordered protein (IDP) condensates necessitates elucidating their inherent structures and establishing correlations with biological Coarse-grained (CG) molecular dynamics (MD) simulations present a promising avenue for gaining insights into LLPS mechanisms biomacromolecules. Essential this endeavor is development tailored CG force fields MD simulations, incorporating full spectrum biomolecules involved formation accounting real-time biochemical reactions coupled LLPS. Moreover, developing accurate theoretical frameworks links between condensate structure its function are imperative thorough comprehension systems.

Language: Английский

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Benchmark of Coacervate Formation and Mechanism Exploration Using the Martini Force Field

Journal of Chemical Theory and Computation, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 25, 2025

Peptide-based coacervates are crucial for drug delivery due to their biocompatibility, versatility, high loading capacity, and cell penetration rates; however, stability mechanism phase behavior not fully understood. Additionally, although Martini is one of the most famous force fields capable describing coacervate formation with molecular details, a comprehensive benchmark its accuracy has been conducted. This research utilized 3.0 field machine learning algorithms explore representative peptide-based coacervates, including those composed polyaspartate (PAsp)/polyarginine (PArg), rmfp-1, sticker-and-spacer small molecules, HBpep molecules. We identified key driving forces such as Coulomb, cation–π, π–π interactions established three criteria determining in simulations. The results also indicate that while accurately captures trends, it tends underestimate Coulomb overestimate interactions. What more, our study on encapsulation derivative suggested loaded drugs were distributed surfaces clusters, awaiting experimental validation. employs simulation enhance understanding mechanisms benchmarking 3.0, thereby providing fundamental insights future investigations.

Language: Английский

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MartiniGlass: a Tool for Enabling Visualization of Coarse-Grained Martini Topologies

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: March 26, 2025

As molecular modeling gains ever more prominence in understanding cellular processes, high quality visualization of models and dynamics has never been important. Naturally, much software is written to enable the atomic level details structures. While necessary, this means that increasingly popular coarse-grained (CG) remains a challenge. Here, we present Python package, MartiniGlass, facilitates systems simulated with widely used CG Martini force field using package VMD. MartiniGlass rapidly processes topologies accounts for important topological features at resolution, such as secondary structure restraints, preparing them easy trajectories.

Language: Английский

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Atrazine Exposure Induces TDP-43 Protein Translocation: A Potential Mechanism for Prefrontal Cortical Neurodegeneration Induced by Environmental Pollutants

Toxicology, Journal Year: 2025, Volume and Issue: unknown, P. 154128 - 154128

Published: April 1, 2025

Language: Английский

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Temperature-Dependent Coarse-Grained Model for Simulations of Intrinsically Disordered Protein LCST and UCST Liquid–Liquid Phase Separations

Journal of Chemical Theory and Computation, Journal Year: 2025, Volume and Issue: unknown

Published: April 25, 2025

Many intrinsically disordered proteins (IDPs) can undergo a liquid-liquid phase separation (LLPS) in water, depending on solution conditions (temperature, pH, and ionic strength). There are two types of LLPS that controlled by temperature: those occurring above lower critical temperature (LCST) below an upper (UCST). IDP coarse-grained (CG) models particularly appropriate for investigating the physical chemical factors govern their supramolecular organization. However, development CG allowing simulations both LCST UCST behavior temperature-sensitive IDPs is still its infancy. In this context, we present here novel temperature-dependent (TD) model based MARTINI 3 force field. The was developed modifying Lennard-Jones potentials between apolar or charged solute beads water with TD rescaling factor. It parametrized to fit mean (PMF) molecules computed using all-atom (AA) simulations. We show able reproduce experimentally known low-complexity sequences estimate transition temperatures comparable experimental measurements.

Language: Английский

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