Direct prediction of intrinsically disordered protein conformational properties from sequence

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

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SOURSOP: A Python Package for the Analysis of Simulations of Intrinsically Disordered Proteins

Journal of Chemical Theory and Computation, Год журнала: 2023, Номер 19(16), С. 5609 - 5620

Опубликована: Июль 18, 2023

Conformational heterogeneity is a defining hallmark of intrinsically disordered proteins and protein regions (IDRs). The functions IDRs the emergent cellular phenotypes they control are associated with sequence-specific conformational ensembles. Simulations ensembles that based on atomistic coarse-grained models routinely used to uncover interactions may contribute IDR functions. These simulations performed either independently or in conjunction data from experiments. Functionally relevant features can span range length scales. Extracting these requires analysis routines quantify properties. Here, we describe new suite simulation unfolded (SOURSOP), an object-oriented open-source toolkit designed for simulated IDRs. SOURSOP implements several motivated by principles polymer physics, offering unique collection simple-to-use characterize As extendable framework, supports development implementation be easily packaged shared.

Язык: Английский

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Labile assembly of a tardigrade protein induces biostasis

Protein Science, Год журнала: 2024, Номер 33(4)

Опубликована: Март 19, 2024

Tardigrades are microscopic animals that survive desiccation by inducing biostasis. To drying tardigrades rely on intrinsically disordered CAHS proteins, which also function to prevent perturbations induced in vitro and heterologous systems. proteins have been shown form gels both vivo, has speculated be linked their protective capacity. However, the sequence features mechanisms underlying gel formation necessity of gelation for protection not demonstrated. Here we report a mechanism fibrillization D similar intermediate filament assembly. We show vitro, restricts molecular motion, immobilizing protecting labile material from harmful effects drying. In observe forms fibrillar networks during osmotic stress. Fibrillar networking improves survival osmotically shocked cells. two emergent properties associated with fibrillization; (i) prevention cell volume change (ii) reduction metabolic activity shock. find there is no significant correlation between maintenance survival, while reduced metabolism survival. Importantly, D's network reversible rates return control levels after fibers resolved. This work provides insights into how induce biostasis through self-assembly gels.

Язык: Английский

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Deep generative modeling of temperature-dependent structural ensembles of proteins

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 13, 2025

Deep learning has revolutionized protein structure prediction, but capturing conformational ensembles and structural variability remains an open challenge. While molecular dynamics (MD) is the foundation method for simulating biomolecular dynamics, it computationally expensive. Recently, deep models trained on MD have made progress in generating at reduced cost. However, they remain limited modeling atomistic details and, crucially, incorporating effect of environmental factors. Here, we present aSAM (atomistic autoencoder model), a latent diffusion model to generate heavy atom ensembles. Unlike most methods, atoms space, greatly facilitating accurate sampling side chain backbone torsion angle distributions. Additionally, extended into first reported transferable generator conditioned temperature, named aSAMt. Trained large mdCATH dataset, aSAMt captures temperature-dependent ensemble properties demonstrates generalization beyond training temperatures. By comparing long simulations fast folding proteins, find that high-temperature enhances ability generators explore energy landscapes. Finally, also show our MD-based can already capture experimentally observed thermal behavior proteins. Our work step towards generalizable generation complement physics- based approaches.

Язык: Английский

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Excluded Volume and Weak Interactions in Crowded Solutions Modulate Conformations and RNA Binding of an Intrinsically Disordered Tail

The Journal of Physical Chemistry B, Год журнала: 2023, Номер 127(26), С. 5837 - 5849

Опубликована: Июнь 22, 2023

The cellular milieu is a solution crowded with significant concentration of different components (proteins, nucleic acids, metabolites,

Язык: Английский

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Multiphosphorylation-Dependent Recognition of Anti-pS2 Antibodies against RNA Polymerase II C-Terminal Domain Revealed by Chemical Synthesis

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(17), С. 12074 - 12086

Опубликована: Апрель 19, 2024

Phosphorylation is a major constituent of the CTD code, which describes set post-translational modifications on 52 repeats YSPTSPS consensus heptad that orchestrates binding regulatory proteins to C-terminal domain (CTD) RNA polymerase II. Phospho-specific antibodies are used detect phosphorylation patterns. However, their recognition repertoire underexplored due limitations in synthesis long multiphosphorylated peptides. Herein, we describe development strategy provides access peptides high purity without HPLC purification for immobilization onto microtiter plates. Native chemical ligation was assemble 12 various phosphoforms. The >60 peptides, 48–90 amino acids length and containing up 6 phosphosites, enabled detailed rapid analysis characteristics different anti-pSer2 antibodies. three tested showed positional selectivity with marked differences affinity pSer2-containing Furthermore, phosphopeptides allowed systematic multivalent chelate-type interactions. absence multivalency-induced enhancements probably flexibility scaffold. effect clustered proved be more complex. Recognition pSer2 by anti-pSer2-antibodies can prevented and, perhaps surprisingly, enhanced "bystander" vicinity. results have relevance functional cell biological experiments.

Язык: Английский

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Molecular insights into the interaction between a disordered protein and a folded RNA

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(49)

Опубликована: Ноя. 26, 2024

Intrinsically disordered protein regions (IDRs) are well established as contributors to intermolecular interactions and the formation of biomolecular condensates. In particular, RNA-binding proteins (RBPs) often harbor IDRs in addition folded domains that contribute RBP function. To understand dynamic an IDR–RNA complex, we characterized features a small (68 residues), positively charged IDR-containing protein, Small ERDK-Rich Factor (SERF). At high concentrations, SERF RNA undergo charge-driven associative phase separation form protein- RNA-rich dense phase. A key advantage this model system is threshold for demixing sufficiently could use solution-state biophysical methods interrogate stoichiometric complexes with one-phase regime. Herein, describe our comprehensive characterization alone complex fragment HIV-1 Trans-Activation Response (TAR) complementary molecular simulations. We find binding event not accompanied by acquisition structure either molecule; however, see evidence modest global compaction ensemble when bound RNA. This behavior likely reflects attenuated charge repulsion within via polyanionic provides rationale higher-order assembly context envision SERF–RNA will lower barrier accessing details support likewise deepen understanding role contacts liquid–liquid separation.

Язык: Английский

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Protein folding stability estimation with an explicit consideration of unfolded states

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 13, 2025

Abstract Thermal folding stability is a critical requirement for the vast majority of proteins. Computational methods suggested to date absolute (Δ G ) prediction – including those driven from protein structure AIs show clear limitations on reproducing quantitative experimental values. Here we present IEFFEUM, deep neural network that jointly estimates Δ and equilibrium ensemble folded unfolded states represented by their residue-pair distance probability distributions. This joint learning considerably enhances accuracy against scenario where was learned alone. To improve model, further extend dataset compared previous related works, which includes Mega-scale small proteins disordered training, as well wild-type natural with sizes up 900 residues thorough validation. We IEFFEUM robust various types sizes, can be applied more general mutational effects such sequence insertions or deletions.

Язык: Английский

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Disentangling Folding from Energetic Traps in Simulations of Disordered Proteins

Journal of Chemical Information and Modeling, Год журнала: 2025, Номер 65(6), С. 2897 - 2910

Опубликована: Март 5, 2025

Protein conformational heterogeneity plays an essential role in a myriad of different biological processes. Extensive is especially characteristic intrinsically disordered proteins and protein regions (collectively IDRs), which lack well-defined three-dimensional structure instead rapidly exchange between diverse ensemble configurations. An emerging paradigm recognizes that the biases encoded IDR ensembles can play central their function, necessitating understanding these sequence-ensemble relations. All-atom simulations have provided critical insight into our modern solution behavior IDRs. However, effectively exploring accessible space associated with large, heterogeneous challenging. In particular, identifying poorly sampled or energetically trapped often relies on qualitative assessment based visual inspection and/or analysis data. These approaches, while convenient, run risk masking simulations. this work, we present algorithm for quantifying per-residue local Our work builds prior compares similarity backbone dihedral angle distributions generated from molecular limiting polymer model across independent all-atom regime, serves as statistical reference extensive real chain. Quantitative comparisons probability vectors reveal extent sampling simulation, enabling us to distinguish situations are well-sampled, sampled, folded. To demonstrate effectiveness approach, apply several toy, synthetic, systems. Accurately assessing IDRs will help better quantify new enhanced methods, ensure force field equivalent, provide confidence conclusions drawn robust.

Язык: Английский

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Noncovalent Lasso Entanglements are Common in Experimentally Derived Intrinsically Disordered Protein Ensembles and Strongly Influenced by Protein Length and Charge

The Journal of Physical Chemistry B, Год журнала: 2025, Номер unknown

Опубликована: Май 3, 2025

Noncovalent lasso entanglements are conformations in which a protein backbone segment forms loop closed by noncovalent interactions and that is threaded one or more times either the N- C-terminal of both. While these common globular proteins, their presence intrinsically disordered proteins regions (IDPs/IDRs) remains largely unexplored. Here, we examine whether IDPs/IDRs monomeric form populate how sequence length charge composition influence entanglement prevalence. Using experimentally derived IDP/IDR ensembles from Protein Ensemble Database, find 48% (199 416) its entries contain subpopulations with entangled conformations, 25% having conformational 50% entangled. This includes IDPs such as nuclear pore complex Nup153, nonstructural V Hendra virus, Eukaryotic initiation factor 4F subunit p150. molecular simulations, (i) most prevalent weak polyampholytes polyelectrolytes, strong but rare polyelectrolytes; (ii) populations increase IDP length; (iii) probability positively correlates chain compaction; (iv) human proteome exhibit conformations. A GO enrichment analysis reveals function subcellular localization. Thus, findings indicate widespread structural feature have potential to be biologically relevant.

Язык: Английский

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