Salt‐Mediated Long‐Range Electrostatic Signature of Native Binding Surface Pre‐Organizes Bound‐Like Conformations of p53 C‐Terminal Intrinsically Disordered Region

Intrinsically disordered proteins (IDPs) and regions (IDRs) often undergo a disorder-to-order transition via coupled folding and binding. The p53 C-terminal domain (CTD) IDR folds into a helical conformation upon binding S100B, yet the long-range influence of the ionic environment on this transition remains poorly understood. Using all-atom molecular dynamics simulations with a novel confinement setup, we investigated the conformational landscape of a 12-residue fragment of p53 CTD at varying distances from the S100B binding cleft. Comparing behavior in pure water and physiological salt (150 mM NaCl), we find that at 10 Å from the native binding surface, the peptide spontaneously forms stable, bound-like helical segments exclusively in the salt solution. This effect is distance-dependent, vanishing at 20 Å, and specific to the native binding surface, notably occurring without direct protein-IDR contacts. Our results demonstrate that the negatively charged S100B surface organizes solvated ions into a structured, long-range electrostatic microenvironment that thermodynamically stabilizes bound-like helical conformations prior to direct contact. This reveals a synergistic effect between native surface topology and physiological salt that biases the IDR's conformational ensemble to facilitate binding, identifying the ions in the solution as active participants in molecular recognition.