Prediction of phase-separation propensities of disordered proteins from sequence DOI Creative Commons
Sören von Bülow, Giulio Tesei, Fatima Zaidi

и другие.

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

Accurate model of liquid–liquid phase behavior of intrinsically disordered proteins from optimization of single-chain properties DOI
Giulio Tesei, Thea K. Schulze, Ramón Crehuet

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2021, Номер 118(44)

Опубликована: Окт. 29, 2021

Significance Cells may compartmentalize proteins via a demixing process known as liquid–liquid phase separation (LLPS), which is often driven by intrinsically disordered (IDPs) and regions. Protein condensates arising from LLPS develop into insoluble protein aggregates, in neurodegenerative diseases cancer. Understanding the of formation, dissolution, aging requires models that accurately capture underpinning interactions at residue level. In this work, we leverage data biophysical experiments on IDPs dilute solution to sequence-dependent model predicts conformational behavior diverse unrelated sequences with good accuracy. Using model, gain insight coupling between chain compaction propensity.

Язык: Английский

Процитировано

287
Physics-driven coarse-grained model for biomolecular phase separation with near-quantitative accuracy DOI
Jerelle A. Joseph,

Aleks Reinhardt,

Anne Aguirre

и другие.

Nature Computational Science, Год журнала: 2021, Номер 1(11), С. 732 - 743

Опубликована: Ноя. 22, 2021

Язык: Английский

Процитировано

257
The molecular basis for cellular function of intrinsically disordered protein regions DOI
Alex S. Holehouse, Birthe B. Kragelund

Nature Reviews Molecular Cell Biology, Год журнала: 2023, Номер 25(3), С. 187 - 211

Опубликована: Ноя. 13, 2023

Язык: Английский

Процитировано

235
Condensates formed by prion-like low-complexity domains have small-world network structures and interfaces defined by expanded conformations DOI Creative Commons
Mina Farag, Samuel R. Cohen, Wade M. Borcherds

и другие.

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Дек. 13, 2022

Abstract Biomolecular condensates form via coupled associative and segregative phase transitions of multivalent macromolecules. Phase separation to percolation is one example such transitions. Here, we characterize molecular mesoscale structural descriptions formed by intrinsically disordered prion-like low complexity domains (PLCDs). These systems conform sticker-and-spacers architectures. Stickers are cohesive motifs that drive interactions through reversible crosslinking spacers affect the cooperativity overall macromolecular solubility. Our computations reproduce experimentally measured sequence-specific behaviors PLCDs. Within simulated condensates, networks inter-sticker crosslinks organize PLCDs into small-world topologies. The dimensions vary with spatial location, being most expanded at preferring be oriented perpendicular interface. results demonstrate even simple type macromolecule feature inhomogeneous organizations molecules interfacial features likely prime them for biochemical activity.

Язык: Английский

Процитировано

146
Conformational ensembles of the human intrinsically disordered proteome DOI
Giulio Tesei, Anna Ida Trolle, Nicolas Jonsson

и другие.

Nature, Год журнала: 2024, Номер 626(8000), С. 897 - 904

Опубликована: Янв. 31, 2024

Язык: Английский

Процитировано

133
Conformational Dynamics of Intrinsically Disordered Proteins Regulate Biomolecular Condensate Chemistry DOI Creative Commons
Anton Abyzov, Martin Blackledge, Markus Zweckstetter

и другие.

Chemical Reviews, Год журнала: 2022, Номер 122(6), С. 6719 - 6748

Опубликована: Фев. 18, 2022

Motions in biomolecules are critical for biochemical reactions. In cells, many reactions executed inside of biomolecular condensates formed by ultradynamic intrinsically disordered proteins. A deep understanding the conformational dynamics proteins is therefore utmost importance but complicated diverse obstacles. Here we review emerging data on motions liquidlike condensates. We discuss how liquid-liquid phase separation modulates internal across a wide range time and length scales. further highlight intermolecular interactions that not only drive appear as key determinants changes aging human diseases. The provides framework future studies to reveal regulation condensate chemistry.

Язык: Английский

Процитировано

132
Improving Martini 3 for Disordered and Multidomain Proteins DOI
F. Emil Thomasen, Francesco Pesce, Mette Ahrensback Roesgaard

и другие.

Journal of Chemical Theory and Computation, Год журнала: 2022, Номер 18(4), С. 2033 - 2041

Опубликована: Апрель 4, 2022

Coarse-grained molecular dynamics simulations are a useful tool to determine conformational ensembles of proteins. Here, we show that the coarse-grained force field Martini 3 underestimates global dimensions intrinsically disordered proteins (IDPs) and multidomain when compared with small-angle X-ray scattering (SAXS) data increasing strength protein-water interactions favors more expanded conformations. We find between protein water by ca. 10% results in improved agreement SAXS for IDPs also this correction accurate description self-association folded better paramagnetic relaxation enhancement most IDPs. While revised still deviations experiments some systems, our suggest it is overall substantial improvement soluble

Язык: Английский

Процитировано

126
Disease‐linked TDP‐43 hyperphosphorylation suppresses TDP‐43 condensation and aggregation DOI Creative Commons
Lara A. Gruijs da Silva, Francesca Simonetti,

Saskia Hutten

и другие.

The EMBO Journal, Год журнала: 2022, Номер 41(8)

Опубликована: Фев. 3, 2022

Post-translational modifications (PTMs) have emerged as key modulators of protein phase separation and been linked to aggregation in neurodegenerative disorders. The major aggregating amyotrophic lateral sclerosis frontotemporal dementia, the RNA-binding TAR DNA-binding (TDP-43), is hyperphosphorylated disease on several C-terminal serine residues, a process generally believed promote TDP-43 aggregation. Here, we however find that Casein kinase 1δ-mediated hyperphosphorylation or phosphomimetic mutations reduce aggregation, instead render condensates more liquid-like dynamic. Multi-scale molecular dynamics simulations reveal reduced homotypic interactions low-complexity domains through enhanced solvation residues. Cellular experiments show substitutions do not affect nuclear import RNA regulatory functions TDP-43, but suppress accumulation membrane-less organelles its solubility neurons. We speculate may be protective cellular response counteract

Язык: Английский

Процитировано

124
Direct prediction of intrinsically disordered protein conformational properties from sequence DOI Creative Commons
Jeffrey M. Lotthammer, Garrett M. Ginell, Daniel Griffith

и другие.

Nature Methods, Год журнала: 2024, Номер 21(3), С. 465 - 476

Опубликована: Янв. 31, 2024

Abstract Intrinsically disordered regions (IDRs) are ubiquitous across all domains of life and play a range functional roles. While folded generally well described by stable three-dimensional structure, IDRs exist in collection interconverting states known as an ensemble. This structural heterogeneity means that largely absent from the Protein Data Bank, contributing to lack computational approaches predict ensemble conformational properties sequence. Here we combine rational sequence design, large-scale molecular simulations deep learning develop ALBATROSS, deep-learning model for predicting dimensions IDRs, including radius gyration, end-to-end distance, polymer-scaling exponent asphericity, directly sequences at proteome-wide scale. ALBATROSS is lightweight, easy use accessible both locally installable software package point-and-click-style interface via Google Colab notebooks. We first demonstrate applicability our predictors examining generalizability sequence–ensemble relationships IDRs. Then, leverage high-throughput nature characterize sequence-specific biophysical behavior within between proteomes.

Язык: Английский

Процитировано

103
Improved predictions of phase behaviour of intrinsically disordered proteins by tuning the interaction range DOI Creative Commons
Giulio Tesei, Kresten Lindorff‐Larsen

Open Research Europe, Год журнала: 2023, Номер 2, С. 94 - 94

Опубликована: Янв. 17, 2023

The formation and viscoelastic properties of condensates intrinsically disordered proteins (IDPs) is dictated by amino acid sequence solution conditions. Because the involvement biomolecular in cell physiology disease, advancing our understanding relationship between protein phase separation (PS) may have important implications formulation new therapeutic hypotheses. Here, we present CALVADOS 2, a coarse-grained model IDPs that accurately predicts conformational propensities to undergo PS for diverse sequences In particular, systematically study effect varying range nonionic interactions use findings improve temperature scale model. We further optimize residue-specific parameters against experimental data on 55 proteins, while also leveraging 70 hydrophobicity scales from literature avoid overfitting training data. Extensive testing shows chain compaction propensity length charge patterning, as well at different temperatures salt concentrations.

Язык: Английский

Процитировано

81