Charged peptides enriched in aromatic residues decelerate condensate ageing driven by cross-β-sheet formation DOI Creative Commons
Ignacio Sanchez‐Burgos, Andrés R. Tejedor,

A. Ruiz Castro

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 20, 2024

Biomolecular condensates, formed through liquid-liquid phase separation, play wide-ranging roles in cellular compartmentalization and biological processes. However, their transition from a functional liquid-like into solid-like state - usually termed as condensate ageing represents hallmark associated with the onset of multiple neurodegenerative diseases. In this study, we design computational pipeline to explore potential candidates, form small peptides, regulate kinetics biomolecular condensates. By combining equilibrium non-equilibrium simulations sequence-dependent residue-resolution force field, investigate impact peptide insertion different composition, patterning, net charge diagram archetypal proteins driving ageing: TDP-43 FUS. We reveal that peptides composed by specific balance aromatic charged residues can substantially decelerate up two orders magnitude. The mechanism is controlled density reduction induced self-repulsive electrostatic interactions specifically target protein regions prone cross-beta-sheet fibrils. Our work proposes an efficient framework rapidly scan molecule develop novel pathways for controlling transitions relevant disease prevention.

Language: Английский

A coarse‐grained model for disordered and multi‐domain proteins DOI Creative Commons
Fan Cao, Sören von Bülow, Giulio Tesei

et al.

Protein Science, Journal Year: 2024, Volume and Issue: 33(11)

Published: Oct. 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

Language: Английский

Citations

17
COCOMO2: A Coarse-Grained Model for Interacting Folded and Disordered Proteins DOI Creative Commons
Alexander Jussupow,

Divya Bartley,

Lisa J. Lapidus

et al.

Journal of Chemical Theory and Computation, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 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.

Language: Английский

Citations

3
Chemically Informed Coarse-Graining of Electrostatic Forces in Charge-Rich Biomolecular Condensates DOI Creative Commons
Andrés R. Tejedor,

Anne Aguirre Gonzalez,

Maria Julia Maristany

et al.

ACS Central Science, Journal Year: 2025, Volume and Issue: 11(2), P. 302 - 321

Published: Feb. 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.

Language: Английский

Citations

2
Prediction of phase-separation propensities of disordered proteins from sequence DOI Creative Commons
Sören von Bülow, Giulio Tesei, Fatima Zaidi

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(13)

Published: March 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.

Language: Английский

Citations

2
Coarse-Grained Model of Disordered RNA for Simulations of Biomolecular Condensates DOI
Ikki Yasuda, Sören von Bülow, Giulio Tesei

et al.

Journal of Chemical Theory and Computation, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 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.

Language: Английский

Citations

1
AFflecto: A web server to generate conformational ensembles of flexible proteins from AlphaFold models DOI Creative Commons
Mátyás Pajkos,

Ilinka Clerc,

Christophe Zanon

et al.

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169003 - 169003

Published: Feb. 1, 2025

Language: Английский

Citations

0
Deciphering driving forces of biomolecular phase separation from simulations DOI Creative Commons
Lars V. Schäfer, Lukas S. Stelzl

Current Opinion in Structural Biology, Journal Year: 2025, Volume and Issue: 92, P. 103026 - 103026

Published: March 8, 2025

The formation and modulation of biomolecular condensates as well their structural dynamic properties are determined by an intricate interplay different driving forces, which down at the microscopic scale involve molecular interactions biological macromolecules surrounding solvent ions. Molecular simulations increasingly used to provide detailed insights into various processes thermodynamic forces play, thereby yielding mechanistic understanding aiding interpretation experiments level individual amino acid residues or even atoms. Here we summarize recent advances in field biocondensate with a focus on coarse-grained all-atom dynamics (MD) simulations. We highlight possible future challenges concerning computationally efficient physically accurate large complex systems.

Language: Английский

Citations

0
Machine learning methods to study sequence–ensemble–function relationships in disordered proteins DOI Creative Commons
Sören von Bülow, Giulio Tesei, Kresten Lindorff‐Larsen

et al.

Current Opinion in Structural Biology, Journal Year: 2025, Volume and Issue: 92, P. 103028 - 103028

Published: March 12, 2025

Language: Английский

Citations

0
Toward Predictive Coarse-Grained Simulations of Biomolecular Condensates DOI
Shuming Liu, Cong Wang, Bin Zhang

et al.

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 2, 2025

Phase separation is a fundamental process that enables cellular organization by forming biomolecular condensates. These assemblies regulate diverse functions creating distinct environments, influencing reaction kinetics, and facilitating processes such as genome organization, signal transduction, RNA metabolism. Recent studies highlight the complexity of condensate properties, shaped intrinsic molecular features external factors temperature pH. Molecular simulations serve an effective approach to establishing comprehensive framework for analyzing these influences, offering high-resolution insights into stability, dynamics, material properties. This review evaluates recent advancements in simulations, with particular focus on coarse-grained 1-bead-per-amino-acid (1BPA) protein models, emphasizes OpenABC, tool designed simplify streamline simulations. OpenABC supports implementation various force fields, enabling their performance evaluation. Our benchmarking identifies inconsistencies phase behavior predictions across even though models accurately capture single-chain statistics. finding underscores need enhanced field accuracy, achievable through enriched training data sets, many-body potentials, advanced optimization techniques. Such refinements could significantly improve predictive capacity bridging details emergent behaviors.

Language: Английский

Citations

0
Random mutagenesis and semi-rational design enhance the tolerance of Metabacillus litoralis C44 α-L-rhamnosidase DOI
Ziqiang Wang, Chunhui Li, Jian Liu

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 142971 - 142971

Published: April 1, 2025

Language: Английский

Citations

0