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.