BPS2026 – Interplay of counterion release and conformational plasticity in highly charged disordered proteins

The organization of the genome involves a complex interplay between densely packed, highly charged DNA and nuclear proteins. Among these, highly charged intrinsically disordered proteins (IDPs) play critical roles. Recent evidence shows that counterion release during polyelectrolyte complexation contributes to protein complexes that are thermodynamically stable yet highly dynamic and disordered. In this study, we integrate single-molecule Förster resonance energy transfer with all-atom and coarse-grained molecular dynamics (MD) simulations to investigate the thermodynamics of polyelectrolyte complexation and polyampholyte compaction. We establish and validate a framework for quantifying counterion condensation and release by integrating residue-level coarse-grained simulations with nonlinear Poisson-Boltzmann calculations. Benchmarking against all-atom MD simulations with explicit solvent and ions confirms the accuracy of the approach. Our results demonstrate that counterion release during complexation varies with salt concentration and can be experimentally inferred from equilibrium dissociation constants. Furthermore, local charge segregation governs counterion release in both polyelectrolytes and polyampholytes, shaping their conformational ensembles and intrachain interactions. By extending the computational analysis to the disordered human proteome, this work advances our understanding of polyelectrolyte and polyampholyte assemblies that are central to genome organization and nuclear function.