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

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

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