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.