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Inhibition of the p53–MDM2 interaction is a new therapeutic strategy to activate the wild-type function of p53 in tumors. Molecular dynamics (MD) simulations and calculations of binding free energies were performed to investigate the binding mechanisms of p53 and two inhibitors PMI and VZV to MDM2. The results show that van der Waals interaction is the main force to control the bindings of ligands to the hydrophobic cleft of MDM2, which basically agrees with the previous calculated and experimental studies. The results from the RMSF calculation, cross-correlation analysis and principal component (PC) analysis prove that the ligand bindings produce a significant effect on the conformation of the binding cleft of MDM2. In addition, the calculations of residue-based free energy decomposition suggest that the CH–CH, CH–π, and π–π interactions dominate the bindings of p53 and inhibitors to MDM2. This study can provide significant help for the design of potent inhibitors targeting the p53–MDM2 interaction. [ABSTRACT FROM AUTHOR]