Expanding the molecular language of protein liquid–liquid phase separation

Nature Chemistry, Год журнала: 2024, Номер 16(7), С. 1113 - 1124

Опубликована: Март 29, 2024

Язык: Английский

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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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Prediction of phase-separation propensities of disordered proteins from sequence

Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(13)

Опубликована: Март 25, 2025

Phase separation is one possible mechanism governing the selective cellular enrichment of biomolecular constituents for processes such as transcriptional activation, mRNA regulation, and immune signaling. mediated by multivalent interactions macromolecules including intrinsically disordered proteins regions (IDRs). Despite considerable advances in experiments, theory, simulations, prediction thermodynamics IDR phase behavior remains challenging. We combined coarse-grained molecular dynamics simulations active learning to develop a fast accurate machine model predict free energy saturation concentration directly from sequence. validate using computational previously measured experimental data, well new data six proteins. apply our all 27,663 IDRs chain length up 800 residues human proteome find that 1,420 these (5%) are predicted undergo homotypic with transfer energies < −2 k B T . use understand relationship between single-chain compaction changes charge- hydrophobicity-mediated can break symmetry intra- intermolecular interactions. also provide proof principle how be used force field refinement. Our work refines quantifies established rules connection sequence features phase-separation propensities, models will useful interpreting designing experiments on role separation, design specific propensities.

Язык: Английский

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Prediction of phase separation propensities of disordered proteins from sequence

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

Опубликована: Июнь 3, 2024

Abstract Phase separation is thought to be one possible mechanism governing the selective cellular enrichment of biomolecular constituents for processes such as transcriptional activation, mRNA regulation, and immune signaling. mediated by multivalent interactions biological macromolecules including intrinsically disordered proteins regions (IDRs). Despite considerable advances in experiments, theory simulations, prediction thermodynamics IDR phase behaviour remains challenging. We combined coarse-grained molecular dynamics simulations active learning develop a fast accurate machine model predict free energy saturation concentration directly from sequence. validate using both experimental computational data. apply our all 27,663 IDRs chain length up 800 residues human proteome find that 1,420 these (5%) are predicted undergo homotypic with transfer energies < −2 k B T . use understand relationship between single-chain compaction separation, changes charge-to hydrophobicity-mediated can break symmetry intra-and inter-molecular interactions. also analyse structural preferences at condensate interfaces substantial heterogeneity determined same sequence properties separation. Our work refines established rules relationships features propensities, models will useful interpreting designing experiments on role design specific propensities.

Язык: Английский

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Machine learning methods to study sequence–ensemble–function relationships in disordered proteins

Current Opinion in Structural Biology, Год журнала: 2025, Номер 92, С. 103028 - 103028

Опубликована: Март 12, 2025

Язык: Английский

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Multiobjective Optimization for Targeted Self-Assembly among Competing Polymorphs

Physical Review X, Год журнала: 2025, Номер 15(1)

Опубликована: Март 31, 2025

Most approaches for designing self-assembled materials focus on the thermodynamic stability of a target structure or crystal polymorph. Yet in practice, outcome self-assembly process is often controlled by kinetic pathways. Here we present an efficient machine-learning-guided design algorithm to identify globally optimal interaction potentials that maximize both yield and accessibility We show exist along Pareto front, indicating possibility trade-off between objectives. Although extent this depends polymorph assembly conditions, generically find arises from competition among alternative polymorphs: The most kinetically potentials, which favor short timescales, tend stabilize competing at longer times. Our work establishes general-purpose approach multiobjective optimization, reveals fundamental trade-offs crystallization speed defect formation presence polymorphs, suggests guiding principles algorithms optimize accessibility. Published American Physical Society 2025

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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Asymmetry in Polymer–Solvent Interactions Yields Complex Thermoresponsive Behavior

ACS Macro Letters, Год журнала: 2024, Номер 13(7), С. 818 - 825

Опубликована: Июнь 14, 2024

We introduce a lattice framework that incorporates elements of Flory–Huggins solution theory and the q-state Potts model to study phase behavior polymer solutions single-chain conformational characteristics. Without empirically introducing temperature-dependent interaction parameters, standard describes systems are either homogeneous across temperatures or exhibit upper critical temperatures. The proposed Flory–Huggins–Potts extends these capabilities by predicting lower temperatures, miscibility loops, hourglass-shaped spinodal curves. particularly show including orientation-dependent interactions, specifically between monomer segments solvent particles, is alone sufficient observe such behavior. Signatures emergent found in Monte Carlo simulations, which display heating- cooling-induced coil–globule transitions linked energy fluctuations. also capably range experimental systems. Importantly, contrast many prior theoretical approaches, does not employ any temperature- composition-dependent parameters. This work provides new insights regarding microscopic physics underpin complex thermoresponsive polymers.

Язык: Английский

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Deciphering driving forces of biomolecular phase separation from simulations

Current Opinion in Structural Biology, Год журнала: 2025, Номер 92, С. 103026 - 103026

Опубликована: Март 8, 2025

The formation and modulation of biomolecular condensates as well their structural dynamic properties are determined by an intricate interplay different driving forces, which down at the microscopic scale involve molecular interactions biological macromolecules surrounding solvent ions. Molecular simulations increasingly used to provide detailed insights into various processes thermodynamic forces play, thereby yielding mechanistic understanding aiding interpretation experiments level individual amino acid residues or even atoms. Here we summarize recent advances in field biocondensate with a focus on coarse-grained all-atom dynamics (MD) simulations. We highlight possible future challenges concerning computationally efficient physically accurate large complex systems.

Язык: Английский

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Scaling law-informed machine learning for predicting thermal and electrical properties of polymers: A physics-based approach

Computational Materials Science, Год журнала: 2025, Номер 253, С. 113887 - 113887

Опубликована: Апрель 10, 2025

Язык: Английский

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