Predictive all-atom simulations of disordered proteins and biomolecular condensates through osmometry-guided force-field optimization
Abstract
All-atom simulations with explicit solvent can provide a detailed and accurate description of dynamics and mechanisms in biomolecular systems, including intrinsically disordered proteins (IDPs) and their condensates. However, interactions involving charged residues and ions remain a persistent source of systematic error. Here we introduce an osmometry-guided optimization strategy that directly targets residue-residue, residue-ion and ion-ion interactions. Osmotic pressure provides key experimental information on molecular interactions and can be calculated directly and rapidly from simulations, enabling iterative force-field optimization. The resulting parameters improve agreement with single-molecule FRET data for IDPs, NMR relaxation data for an IDP-folded-domain complex, and chain dynamics and dimensions in biomolecular condensates of charged IDPs. For such condensates, simulations with our osmometry-optimized force field provide the missing link for predicting condensate dynamics across length and time scales. The strategy is broadly extensible to other interaction classes, including those governing protein-nucleic-acid assemblies.
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BibTeX
@misc{ivanovic2026predictive,
title = {{Predictive all-atom simulations of disordered proteins and biomolecular condensates through osmometry-guided force-field optimization}},
author = {M. T. Ivanovic and V. von Roten and B. Schuler and R. B. Best},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.25.747127},
url = {https://www.biorxiv.org/content/10.64898/2026.08.25.747127v2},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Predictive all-atom simulations of disordered proteins and biomolecular condensates through osmometry-guided force-field optimization
AU - M. T. Ivanovic
AU - V. von Roten
AU - B. Schuler
AU - R. B. Best
PY - 2026
DA - 2026/08/25
PB - bioRxiv
DO - 10.64898/2026.08.25.747127
UR - https://www.biorxiv.org/content/10.64898/2026.08.25.747127v2
AB - All-atom simulations with explicit solvent can provide a detailed and accurate description of dynamics and mechanisms in biomolecular systems, including intrinsically disordered proteins (IDPs) and their condensates. However, interactions involving charged residues and ions remain a persistent source of systematic error. Here we introduce an osmometry-guided optimization strategy that directly targets residue-residue, residue-ion and ion-ion interactions. Osmotic pressure provides key experimental information on molecular interactions and can be calculated directly and rapidly from simulations, enabling iterative force-field optimization. The resulting parameters improve agreement with single-molecule FRET data for IDPs, NMR relaxation data for an IDP-folded-domain complex, and chain dynamics and dimensions in biomolecular condensates of charged IDPs. For such condensates, simulations with our osmometry-optimized force field provide the missing link for predicting condensate dynamics across length and time scales. The strategy is broadly extensible to other interaction classes, including those governing protein-nucleic-acid assemblies.
ER -