SOP-Multi-π: A coarse-grained model for multidomain IDPs proteins with rescaled aromatic interactions for accurate simulations of Biomolecular Condensates

Abstract: We present an enhanced version of the two-bead-per-amino-acid resolution Self-Organized Polymer (SOP) model designed to investigate the conformational dynamics of Intrinsically Disordered Proteins (IDPs) and their phase behaviour in biomolecular condensates The original SOP-IDP and SOP-Multi models work well for chains in good solvents that pre-dominantly adopt expanded conformations However, they fail to reproduce the single-chain properties and phase-separation behavior of specific IDPs such as hnRNPA1 and its variants, which have a distinct pattern of aromatic residues We therefore reparameterized the SOP-IDP force field to explicitly capture π − π and cation-π interactions at the coarse-grained resolution, which are weak yet important for biomolecular recognition and for driving and stabilizing biomolecular condensates In our rescaled model, we systematically reparameterized the non-bonded terms governing aromatic interactions using an iterative optimization procedure to accurately capture both π −π and cation-π interactions We used hnRNPA1-LCD and its 16 aromatic-mutant systems to rescale and benchmark the force field parameters. We then back-map the microsecond-scale coarse-grained (CG) ensembles of conformations to all-atom representation and compute SAXS profiles for direct comparison with experimental SAXS profiles of IDPs and multidomain proteins. We validated the force field against 34 different IDPs of varying lengths The SOP-Multi-π model effectively captures both the single-chain properties of multidomain proteins and the phase behavior of A1-LCD condensates and their variants, with predicted critical temperatures that closely align with experimental values. Keywords: Coarse-graining (CG), Self-Organized Polymer (SOP), Intrinsically Disordered Proteins (IDPs), heterogeneous nuclear RiboNucleoProtein A1 (hnRNPA1), Biomolecular Condensate, Valence Patterning, Aromatic interactions