Multiscale simulations of folded and intrinsically disordered region-containing protein condensates

We present a multiscale simulation framework that integrates all-atom (AA) structure modeling, coarse-grained (CG) Martini 3 simulations, and AA backmapping to investigate supramolecular assembly behaviors of proteins implicated in misfolding diseases. As representative systems, we modeled the C-terminal domain of human TDP-43 (residues 274-414) and a broad region of white-tailed deer prion protein (PrP) (residues 24-233), both associated with misfolding-related pathologies and exhibiting distinct structural features. This AA-CG-AA framework enables the construction and analysis of large multiunit assemblies using two Martini 3-based CG parameter sets that differ in their treatment of nonbonded interactions, including electrostatic cutoffs and the scaling of interactions involving Na⁺ and Cl^- ions present in solution. The framework successfully captured key mesoscale features of early supramolecular condensation and revealed pronounced condition-dependent differences in both condensate morphology and chain dynamics. Parameter sets with longer cutoffs and rescaled ion interactions promoted more interconnected, network-like assemblies-particularly for PrP-whereas standard cutoffs yielded more dispersed systems with higher translational mobility. Mean-square displacement analysis and diffusivity estimates reflected clear differences in translational mobility consistent with varying degrees of local association. Further analysis of low-mean-square-displacement chains revealed the emergence of condensate-like subpopulations, especially in PrP, where percolation-like networks formed. Solvent-accessible surface area analyses confirmed that protein chains remained solvent exposed throughout, consistent with known fluid-like phase-condensation behavior. Follow-up AA analysis revealed persistent interchain dynamical coupling even in the absence of direct chain contacts, suggesting solvent-mediated interactions. Notably, analyses revealed an inverse relationship between protein translational mobility and Na⁺ and Cl^- ion contact counts, suggesting that ion association contributes to early-stage condensation. These findings demonstrate the potential of integrated CG-AA simulation strategies to probe supramolecular condensation in structurally heterogeneous protein systems and support their continued development for studying misfolding-driven assembly processes at mesoscopic scales.