A coarse‐grained model for disordered and multi‐domain proteins

Protein Science, Год журнала: 2024, Номер 33(11)

Опубликована: Окт. 16, 2024

Many proteins contain more than one folded domain, and such modular multi-domain help expand the functional repertoire of proteins. Because their larger size often substantial dynamics, it may be difficult to characterize conformational ensembles by simulations. Here, we present a coarse-grained model for that is both fast provides an accurate description global properties in solution. We show accuracy one-bead-per-residue depends on how interaction sites domains are represented. Specifically, find excessive domain-domain interactions if located at position C

Язык: Английский

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COCOMO2: A Coarse-Grained Model for Interacting Folded and Disordered Proteins

Journal of Chemical Theory and Computation, Год журнала: 2025, Номер unknown

Опубликована: Фев. 5, 2025

Biomolecular interactions are essential in many biological processes, including complex formation and phase separation processes. Coarse-grained computational models especially valuable for studying such processes via simulation. Here, we present COCOMO2, an updated residue-based coarse-grained model that extends its applicability from intrinsically disordered peptides to folded proteins. This is accomplished with the introduction of a surface exposure scaling factor, which adjusts interaction strengths based on solvent accessibility, enable more realistic modeling involving domains without additional costs. COCOMO2 was parametrized directly solubility data improve performance predicting concentration-dependent broader range biomolecular systems compared original version. enables new applications study condensates involve IDPs together assembly also provides expanded foundation development multiscale approaches span residue-level atomistic resolution.

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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Chemically Informed Coarse-Graining of Electrostatic Forces in Charge-Rich Biomolecular Condensates

ACS Central Science, Год журнала: 2025, Номер 11(2), С. 302 - 321

Опубликована: Фев. 11, 2025

Biomolecular condensates composed of highly charged biomolecules, such as DNA, RNA, chromatin, and nucleic-acid binding proteins, are ubiquitous in the cell nucleus. The biophysical properties these charge-rich largely regulated by electrostatic interactions. Residue-resolution coarse-grained models that describe solvent ions implicitly widely used to gain mechanistic insights into condensates, offering transferability, computational efficiency, accurate predictions for multiple systems. However, their predictive accuracy diminishes due implicit treatment ions. Here, we present Mpipi-Recharged, a residue-resolution model improves description charge effects biomolecular containing disordered multidomain and/or single-stranded RNAs. Mpipi-Recharged introduces pair-specific asymmetric Yukawa potential, informed atomistic simulations. We show this coarse-graining forces captures intricate effects, blockiness, stoichiometry variations complex coacervates, modulation salt concentration, without requiring explicit solvation. provides excellent agreement with experiments predicting phase behavior condensates. Overall, tools available investigate physicochemical mechanisms regulating enhancing scope computer simulations field.

Язык: Английский

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AFflecto: A web server to generate conformational ensembles of flexible proteins from AlphaFold models

Journal of Molecular Biology, Год журнала: 2025, Номер unknown, С. 169003 - 169003

Опубликована: Фев. 1, 2025

Язык: Английский

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Coarse-Grained Model of Disordered RNA for Simulations of Biomolecular Condensates

Journal of Chemical Theory and Computation, Год журнала: 2025, Номер unknown

Опубликована: Фев. 26, 2025

Protein–RNA condensates are involved in a range of cellular activities. Coarse-grained molecular models intrinsically disordered proteins have been developed to shed light on and predict single-chain properties phase separation. An RNA model compatible with such for would enable the study complex biomolecular mixtures involving RNA. Here, we present sequence-independent coarse-grained, two-beads-per-nucleotide disordered, flexible based hydropathy scale. We parametrize model, which term CALVADOS-RNA, using combination bottom-up top-down approaches reproduce local geometry intramolecular interactions atomistic simulations vitro experiments. The semiquantitatively captures several aspects RNA–RNA RNA–protein interactions. examined by comparing calculated experimental virial coefficients nonspecific interaction studying reentrant behavior protein–RNA mixtures. demonstrate utility simulating formation mixed consisting region MED1 chains selective partitioning regions from transcription factors into these compare results Despite simplicity our show that it key may therefore be used as baseline biophysics biology condensates.

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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SOP-MULTI: A Self-Organized Polymer-Based Coarse-Grained Model for Multidomain and Intrinsically Disordered Proteins with Conformation Ensemble Consistent with Experimental Scattering Data

Journal of Chemical Theory and Computation, Год журнала: 2024, Номер 20(22), С. 10179 - 10198

Опубликована: Ноя. 5, 2024

Multidomain proteins with long flexible linkers and full-length intrinsically disordered (IDPs) are best defined as an ensemble of conformations rather than a single structure. Determining high-resolution structures such poses various challenges by using tools from experimental structural biophysics. Integrative approaches combining available low-resolution ensemble-averaged data in silico biomolecular reconstructions now often used for the purpose. However, extensive Boltzmann weighted conformation sampling large proteins, especially ones where both folded domains exist same polypeptide chain, remains challenge. In this work, we present 2-site per amino-acid resolution SOP-MULTI force field simulating coarse-grained models multidomain proteins. combines two well-established self-organized polymer models─: (i) SOP-SC systems (ii) SOP-IDP IDPs. For SOP-MULTI, introduce cross-interaction terms between beads belonging to regions generate ensembles hnRNP A1, TDP-43, G3BP1, hGHR-ECD, TIA1, HIV-1 Gag, polyubiquitin, FUS. When back-mapped all-atom resolution, trajectories faithfully recapitulate scattering over range reciprocal space. We also show that individual preserve native contacts respect solved structures, root-mean-square fluctuations residues match those obtained molecular dynamics simulation systems. is made LAMMPS-compatible user package along setup codes generating required files any protein regions.

Язык: Английский

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BaNDyT: Bayesian Network Modeling of Molecular Dynamics Trajectories

Journal of Chemical Information and Modeling, Год журнала: 2025, Номер unknown

Опубликована: Янв. 23, 2025

Bayesian network modeling (BN modeling, or BNM) is an interpretable machine learning method for constructing probabilistic graphical models from the data. In recent years, it has been extensively applied to diverse types of biomedical data sets. Concurrently, our ability perform long-time scale molecular dynamics (MD) simulations on proteins and other materials increased exponentially. However, analysis MD simulation trajectories not data-driven but rather dependent user's prior knowledge systems, thus limiting scope utility simulations. Recently, we pioneered using BNM analyzing protein complexes. The resulting BN yield novel fully insights into functional importance amino acid residues that modulate proteins' function. this report, describe BaNDyT software package implements specifically attuned We believe first include specialized advanced features a model. here software's uses, methods associated with it, comprehensive Python interface underlying generalist code. This provides powerful versatile mechanism users control workflow. As application example, have utilized methodology study how membrane proteins, G protein-coupled receptors, selectively couple proteins. can be used any as well polymeric materials.

Язык: Английский

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Prediction of small-molecule partitioning into biomolecular condensates from simulation

Опубликована: Март 6, 2025

Predicting small-molecule partitioning into biomolecular condensates is key to developing drugs that selectively target aberrant condensates. However, the molecular mechanisms underlying remain largely unknown. Here, we first exploit atomistic dynamics simulations of model elucidate physicochemical rules governing partitioning. We find while hydrophobicity a major determinant, solubility becomes stronger regulator in more polar Additionally, exhibit selectivity toward certain compounds, suggesting condensate-specific therapeutics can be engineered. Building on these insights, develop minimal models (MAPPS) for efficient prediction biologically relevant demonstrate this approach reproduces partition co-efficients both systems and composed low complexity domain (LCD) FUS. Applying MAPPS various LCD-based shows protein sequence exert selective pressure, thereby influencing Collectively, our findings reveal driven by small-molecule–protein affinity complex interplay between compounds condensate chemical environment.

Язык: Английский

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