Predictive all-atom simulations of disordered proteins and biomolecular condensates through osmometry-guided force-field optimization
Year: 2026
Type: preprint
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.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7204491390