Leveraging a large language model to predict protein phase transition: A physical, multiscale, and interpretable approach

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(33)

Published: Aug. 7, 2024

Protein phase transitions (PPTs) from the soluble state to a dense liquid (forming droplets via liquid–liquid separation) or solid aggregates (such as amyloids) play key roles in pathological processes associated with age-related diseases such Alzheimer’s disease. Several computational frameworks are capable of separately predicting formation amyloid based on protein sequences, yet none have tackled prediction both within unified framework. Recently, large language models (LLMs) exhibited great success structure prediction; however, they not been used for PPTs. Here, we fine-tune LLM PPTs and demonstrate its usage evaluating how sequence variants affect PPTs, an operation useful design. In addition, show superior performance compared suitable classical benchmarks. Due “black-box” nature LLM, also employ random forest model along biophysical features facilitate interpretation. Finally, focusing disease-related proteins, that greater aggregation is reduced gene expression disease, suggesting natural defense mechanism.

Language: Английский

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Single-point mutations in disordered proteins: Linking sequence, ensemble, and function

Current Opinion in Structural Biology, Journal Year: 2025, Volume and Issue: 91, P. 102987 - 102987

Published: Feb. 5, 2025

Mutations in genomic DNA often result single-point missense mutations proteins. For folded proteins, the functional effect of these can be understood by their impact on structure. However, intrinsically disordered protein regions (IDRs) remain poorly understood. In IDRs, function depend structural ensemble- collection accessible, interchanging conformations that is encoded amino acid sequence. We argue that, analogously to IDRs alter ensemble, and consequently biological function. To make this argument, we first provide experimental evidence from literature showcasing how affect ensemble dimensions. Then, use data patients show disease-linked occurring can, many cases, significantly IDR ensembles. hope analysis prompts further study disease-linked, IDRs.

Language: Английский

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Chemical Synthesis Reveals Pathogenic Role of N-Glycosylation in Microtubule-Associated Protein Tau

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of tau protein aggregates. In this study, we investigated effects N-glycosylation on tau, focusing its impact aggregation and phase behavior. We chemically prepared homogeneous glycoproteins with high-mannose glycans or single N-acetylglucosamine at confirmed glycosylation sites in K18 2N4R tau. Our findings reveal that significantly alters biophysical properties potentially cellular functions Small promote liquid–liquid separation (LLPS), while larger reduce these effects. High mannose N410 enhance phosphorylation GSK3β, suggesting pathological role AD. Functional assays demonstrate does not microtubule polymerization dynamics but modulates kinetics morphology. This research underscores importance pathology opens new avenues for therapeutic interventions targeting glycan processing.

Language: Английский

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Intrinsically Disordered Proteins Can Behave as Different Polymers across Their Conformational Ensemble

The Journal of Physical Chemistry B, Journal Year: 2025, Volume and Issue: 129(9), P. 2359 - 2369

Published: Feb. 21, 2025

Intrinsically disordered proteins (IDPs) are macromolecules, which in contrast to well-folded explore a large number of conformationally heterogeneous states. In this work, we investigate the conformational space protein β-casein using Hamiltonian replica exchange atomistic molecular dynamics (MD) simulations explicit water. The energy landscape contains global minimum along with two shallow funnels. Employing static polymeric scaling laws separately for individual funnels, find that they cannot be described by same exponent. Around minimum, conformations globular, whereas vicinity local minima, recover coil-like scaling. To elucidate implications structural diversity on equilibrium dynamics, initiated standard MD NVT ensemble representative from each funnel. Global and internal motions different classes trajectories show globule signatures. Thus, IDPs can behave as entirely polymers regions space.

Language: Английский

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Conformational signatures induced by ubiquitin modification in the amyloid-forming tau repeat domain

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(15)

Published: April 8, 2025

Posttranslational modifications can critically affect conformational changes of amyloid-forming proteins. Ubiquitination the microtubule-associated tau protein, an intrinsically disordered biomolecule, has been proposed to influence formation filamentous deposits in neurodegenerative conditions. Given reported link between aggregation propensity and intrinsic structural preferences (e.g., transient extended motifs or tertiary contacts) proteins, we sought explore landscape ubiquitinated tau. Exploiting selective conjugation reactions, produced single- double-monoubiquitinated protein samples. Next, examined species from different standpoints using NMR spectroscopy, small-angle X-ray scattering experiments, native ion mobility–mass spectrometry (IM–MS). Moreover, obtained atomistic representations ensembles via scaled MD calculations, consistent with experimental data. Modifying repeat domain ubiquitin had a limited effect on secondary structure propensities local mobility distal regions. Instead, ubiquitination enhanced compaction ensemble, modulated by site number modifications. Native IM–MS patterns pinpointed similarities differences distinct proteoforms. It emerges that exerts position-specific distribution molecules. This study reveals unique features forms points their potential impact phase separation propensities, offering clues for better understanding disease-related alterations.

Language: Английский

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Water-directed pinning is key to tau prion formation

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(18)

Published: April 28, 2025

Tau forms fibrillar aggregates that are pathological hallmarks of a family neurodegenerative diseases known as tauopathies. The synthetic replication disease-specific fibril structures is critical gap for developing diagnostic and therapeutic tools. This study debuts strategy identifying minimal folding motif in fibrils characteristic tauopathies generating seeding-competent from the isolated tau peptides. 19-residue jR2R3 peptide (295 to 313) which spans R2/R3 splice junction tau, includes P301L mutation, one such prion-competent fibrils. fragment contains hydrophobic VQIVYK hexapeptide part core all an intramolecular counterstrand stabilizes strand–loop–strand (SLS) observed 4R tauopathy shows exhibits duality effects: it lowers barrier adopt aggregation-prone conformations enhances local structuring water around mutation site facilitate site-directed pinning dewetting sites 300-301 achieve in-register stacking cross β-sheets. We solved 3 Å cryo-EM structure jR2R3-P301L each protofilament layer two copies, adopts SLS fold found other wraps stabilize it, reminiscent three- fourfold These competent template full-length prion-like manner.

Language: Английский

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Making tau amyloid models in vitro: a crucial and underestimated challenge

FEBS Letters, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

The protein Tau accumulates in the brain as insoluble deposits a number of neurodegenerative diseases called tauopathies. In vitro work studying properties reconstituted tau assemblies has played major role understanding fundamental mechanisms underlying Yet, our view, extent to which models represent found is not sufficiently addressed. Here, we provide an overview procedures used form amyloids and discuss their similarities differences with deposits. We emphasize that, date, further needed establish how accurate recombinant protein, let alone disease‐specific that discriminate

Language: Английский

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Weighted families of contact maps to characterize conformational ensembles of (highly-)flexible proteins

Bioinformatics, Journal Year: 2024, Volume and Issue: 40(11)

Published: Oct. 21, 2024

Abstract Motivation Characterizing the structure of flexible proteins, particularly within realm intrinsic disorder, presents a formidable challenge due to their high conformational variability. Currently, structural representation relies on (possibly large) ensembles derived from combination experimental and computational methods. The detailed analysis these is difficult task, for which existing tools have limited effectiveness. Results This study proposes an innovative extension concept contact maps ensemble framework, incorporating probabilistic nature disordered proteins. Within this characterized through weighted family maps. To achieve this, conformations are first described using refined definition that appropriately accounts geometry inter-residue interactions sequence context. Representative features naturally emerge subsequent clustering resulting contact-based descriptors. Importantly, transiently populated readily identified large ensembles. performance method illustrated by several use cases compared with other approaches, highlighting its superiority in capturing relevant highly Availability implementation An open-source provided together easy-to-use Jupyter notebook, available at https://gitlab.laas.fr/moma/WARIO.

Language: Английский

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Single point mutations in disordered proteins: linking sequence, ensemble, and function

Published: Dec. 13, 2024

Mutations in genomic DNA often result single-point missense mutations proteins. For most folded proteins, the functional effect of these can be understood by their impact on structure. However, intrinsically disordered protein regions (IDRs) remain poorly understood. In IDRs, function depend structural ensemble - collection accessible, interchanging conformations that is encoded amino acid sequence. We argue that, analogously to single point IDRs alter ensemble, and consequently biological function. To make this argument, we first provide experimental evidence from literature showcasing how affect dimensions. Then, use data patients show disease-linked occurring can, many cases, IDR ensembles. hope analysis prompts further study disease-linked, IDRs.

Language: Английский

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Ensemble-based design of tau to inhibit aggregation while preserving biological activity

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 16, 2024

The microtubule-associated protein tau is implicated in neurodegenerative diseases characterized by amyloid formation. Mutations associated with frontotemporal dementia increase aggregation propensity and disrupt its endogenous microtubule-binding activity. structural relationship between biological activity remains unclear. We employed a multi-disciplinary approach, including computational modeling, NMR, cross-linking mass spectrometry, cell models to design sequences that stabilize ensemble. Our findings reveal substitutions near the conserved 'PGGG' beta-turn motif can modulate local conformation, more stably engaging interactions

Language: Английский

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