Mechanisms of p53 core tetramer stability mediated by multi-interface interactions: A molecular dynamics study.

p53 is a tumor suppressor protein for impeding cancer development and maintaining genetic integrity. The formation of the p53 core tetramer is regulated by multiple cooperative interaction interfaces. To investigate the internal mechanisms of tetramer stability, we performed all-atom molecular dynamics simulations. Our findings indicate that the symmetric interface maintains highly conserved interactions, while the dimer-dimer interface displays notable flexibility. Additionally, we identified a novel salt bridge at the dimer-dimer interface that significantly contributes to the interaction energy. Moreover, the affinity of p53 for DNA is more than twice that of protein-protein interactions, driven primarily by five key residues that form multiple hydrogen bonds. Through independent simulations of the two dimeric models, we provide a theoretical explanation for why only the symmetric dimeric structure has been observed experimentally. The study identifies key regions and residues that contribute to stability at the inter-molecular interaction interfaces within the p53 tetramer, and highlight the important roles of each contact surface in the formation and stability of the tetramer.