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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GENESIS CGDYN: large-scale coarse-grained MD simulation with dynamic load balancing for heterogeneous biomolecular systems

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Апрель 20, 2024

Abstract Residue-level coarse-grained (CG) molecular dynamics (MD) simulation is widely used to investigate slow biological processes that involve multiple proteins, nucleic acids, and their complexes. Biomolecules in a large system are distributed non-uniformly, limiting computational efficiency with conventional methods. Here, we develop hierarchical domain decomposition scheme dynamic load balancing for heterogeneous biomolecular systems keep even after drastic changes particle distribution. These schemes applied the of intrinsically disordered protein (IDP) droplets. During fusion two droplets, find droplet shape correlate mixing IDP chains. Additionally, simulate achieving sizes comparable those observed microscopy. In our MD simulations, directly observe Ostwald ripening, phenomenon where small droplets dissolve molecules redeposit into larger methods have been implemented CGDYN GENESIS software, offering tool investigating mesoscopic using residue-level CG models.

Язык: Английский

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

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

Опубликована: Фев. 7, 2024

Abstract 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 α atoms. also centre mass residue, obtain good agreement between simulations experiments across wide range then optimize our previously described CALVADOS using this centre-of-mass representation, validate resulting independent data. Finally, use revised simulate phase separation disordered proteins, examine stability differ dilute dense phases. Our results provide starting point understanding regions these affect propensity self-associate undergo separation.

Язык: Английский

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Aromatic and arginine content drives multiphasic condensation of protein-RNA mixtures

Biophysical Journal, Год журнала: 2023, Номер unknown

Опубликована: Июль 1, 2023

Multiphasic architectures are found ubiquitously in biomolecular condensates and thought to have important implications for the organization of multiple chemical reactions within same compartment. Many these multiphasic contain RNA addition proteins. Here, we investigate importance different interactions comprising two proteins using computer simulations with a residue-resolution coarse-grained model RNA. We find that multilayered containing both phases, protein-RNA dominate, aromatic residues arginine forming key stabilizing interactions. The total content must be appreciably distinct phases form, show this difference increases as system is driven toward greater multiphasicity. Using trends observed interaction energies system, demonstrate can also construct preferentially concentrated one phase. “rules” identified thus enable design synthetic facilitate further study their function.

Язык: Английский

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DNAJA2 and Hero11 mediate similar conformational extension and aggregation suppression of TDP-43

RNA, Год журнала: 2024, Номер 30(11), С. 1422 - 1436

Опубликована: Авг. 8, 2024

Many RNA-binding proteins (RBPs) contain low-complexity domains (LCDs) with prion-like compositions. These long intrinsically disordered regions regulate their solubility, contributing to physiological roles in RNA processing and organization. However, this also makes these RBPs prone pathological misfolding aggregation that are characteristic of neurodegenerative diseases. For example, TAR DNA-binding protein 43 (TDP-43) forms aggregates associated amyotrophic lateral sclerosis (ALS) frontotemporal lobar degeneration (FTLD). While molecular chaperones well-known suppressors aberrant events, we recently reported highly disordered, hydrophilic, charged heat-resistant obscure (Hero) may have similar effects. Specifically, Hero can maintain the activity other from denaturing conditions vitro, while overexpression suppress cellular toxicity aggregation-prone proteins. it is unclear how protective effects achieved. Here, used single-molecule FRET monitor conformations LCD TDP-43. observed high conformational heterogeneity wild-type LCD, ALS-associated mutation A315T promoted collapsed conformations. In contrast, an Hsp40 chaperone, DNAJA2, a protein, Hero11, stabilized extended states consistent ability Our results link on conformation macro bulk aggregation, where like integrity client prevent its aggregation.

Язык: Английский

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The Regulation of TDP-43 Structure and Phase Transitions: A Review

The Protein Journal, Год журнала: 2025, Номер unknown

Опубликована: Фев. 22, 2025

Язык: Английский

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No structure, no problem: Protein stabilization by Hero proteins and other chaperone-like IDPs

Biochimica et Biophysica Acta (BBA) - General Subjects, Год журнала: 2025, Номер unknown, С. 130786 - 130786

Опубликована: Март 1, 2025

Язык: Английский

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Scaling molecular dynamics for large-scale simulation of biological systems on AMD CPU/GPU supercomputers: Lessons from LUMI

Опубликована: Фев. 19, 2025

Язык: Английский

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IPAMD: A Plugin-Based Software for Biomolecular Condensate Simulations

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

Опубликована: Май 27, 2025

The study of intrinsically disordered proteins (IDPs) and their role in biomolecular condensate formation has become a critical area research, offering insights into fundamental biological processes therapeutic development. Here, we present IPAMD (Intrinsically Protein Aggregation Molecular Dynamics), plugin-based software designed to simulate the dynamics condensates IDPs. provides modular, efficient, customizable simulation platform specifically for studies. It incorporates advanced force fields, such as HPS-based Mpipi models, employs optimization techniques large-scale simulations. features user-friendly interface supports batch processing, making it accessible researchers with varying computational expertise. Benchmarking case studies demonstrate ability accurately analyze structures properties.

Язык: Английский

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Bioinformatic analysis of the regulatory potential of tagging SNPs provides evidence of the involvement of genes encoding the heat-resistant obscure (Hero) proteins in the pathogenesis of cardiovascular diseases

Berichte aus der medizinischen Informatik und Bioinformatik/Journal of integrative bioinformatics, Год журнала: 2025, Номер unknown

Опубликована: Июнь 2, 2025

Although multiple aspects of molecular pathology underlying cardiovascular diseases (CVDs) have been revealed, the complete picture has yet to be elucidated. In this respect, annotation novel links between genes and atherosclerosis is great importance for medicine. Aligning with our previous research, we aimed analyze predisposition contribution encoding Hero-proteins, polypeptides chaperone activity. Following bioinformatic sources were utilized annotate data regarding Hero-proteins their genes: SNPinfo Web Server, The Cardiovascular Disease Knowledge Portal, GTEx HaploReg, rSNPBase, RegulomeDB, atSNP, Gene Ontology, QTLbase, Blood eQTL browser. Almost all analyzed characterized by a very high regulatory potential tag SNPs (except BEX3). Multiple substantial impacts on histone modifications, effects CVD-related genes, binding transcription factors involved in biological processes pathogenetically significant CVDs discovered. Here provide silico evidence involvement C9orf16 (BBLN), C11orf58, SERBP1, SERF2, C19orf53 risk (high blood pressure, dyslipidemia, obesity, arrhythmias, etc.), thus revealing as putative actors pathobiology heart vessels.

Язык: Английский

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