Too close for comfort: Self‐crowding transforms protein structure and stability beyond volume exclusion

-sheets and turns in both proteins, indicating structural changes that are stable but distinct from amyloid aggregation. Small-angle X-ray scattering shows that LYS exhibits net attractive interprotein interactions, whereas BSA displays dominant repulsions that destabilize its dimeric state. At low concentrations, BSA acts as a self-hydrotrope, stabilizing monomers through weak attractions, while at higher concentrations self-crowding promotes dimer dissociation through protein interface destabilization and solution reorganization. Together, these findings demonstrate that protein self-crowding drives reversible restructuring of protein conformation and interactions, challenging classical volume-exclusion models of macromolecular crowding.