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bioRxiv · 10.64898/2026.09.30.755554

SOP-Multi-π: A Two-Site Coarse-Grained Model with Rescaled Aromatic Interactions to Bridge Single-Chain Ensembles and Condensate Phase Behavior of IDPs and Multidomain Proteins

Prajapati, S.·Mathur, N.·Chakraborty, D.·Srivastava, A.
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Abstract

We present SOP-Multi-{pi}, 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 behavior in biomolecular condensates. The original SOP-IDP and SOP-Multi models work well for chains in good solvents that predominantly adopt expanded conformations. However, they fail to reproduce the single-chain properties and phase-separation behavior of 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 {pi}-{pi} and cation-{pi} interactions at the coarse-grained (CG) resolution. These interactions are weak but important for biomolecular recognition and for driving and stabilizing biomolecular condensates. Dimensionless rescaling prefactors ({lambda}) were applied exclusively to the aromatic {pi}-{pi} (Phe, Tyr, Trp) and cation-{pi} (Arg/Lys with Phe, Tyr, Trp) pairs. They were optimized iteratively against experimental radii of gyration of the hnRNPA1 low-complexity domain (A1-LCD) and its 16 aromatic and charge mutants. This restored a physically meaningful Tyr > Phe interaction hierarchy, and the Pearson correlation for Rg improved from r = 0.07 (SOP-IDP) to r = 0.83 (RMSD = 0.08 nm). The same parameters, without further tuning, gave r = 0.93 for 34 additional IDPs (24-198 residues) and reproduced Flory scaling ( {nu} ~ 0.588). We back-mapped microsecond-scale CG ensembles to all-atom representations and computed SAXS and Kratky profiles for direct comparison with experiments on IDPs and on the multidomain proteins hnRNPA1, TDP-43, G3BP1, and FUS. In direct-coexistence slab simulations, the model captures the phase behavior of A1-LCD condensates and their variants, with critical temperatures that correlate strongly with experiment (r = 0.88) but are somewhat underestimated in absolute terms. The model is implemented in LAMMPS, and a detailed user manual is provided for setting up single-chain and multi-chain condensate simulations of full-length multidomain proteins.

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Prajapati, S., Mathur, N., Chakraborty, D., Srivastava, A.. 2026-10-01. SOP-Multi-π: A Two-Site Coarse-Grained Model with Rescaled Aromatic Interactions to Bridge Single-Chain Ensembles and Condensate Phase Behavior of IDPs and Multidomain Proteins. https://doi.org/10.64898/2026.09.30.755554

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