Probing Difference in Binding Modes of Inhibitors to MDMX by Molecular Dynamics Simulations and Different Free Energy Methods

The p53-MDMX interaction has attracted extensive attention of anti-cancer drug development in recent years. This current work adopted molecular dynamics (MD) simulations and cross-correlation analysis to investigate conformation changes of MDMX caused by inhibitor bindings. The obtained information indicates that the binding cleft of MDMX undergoes a large conformational change and the dynamic behavior of residues obviously change by the presence of different structural inhibitors. Two different methods of binding free energy predictions were employed to carry out a comparable insight into binding mechanisms of four inhibitors PMI, pDI, WK23 and WW8 to MDMX. The data show that the main factor controlling the inhibitor bindings to MDMX arises from van der Waals interactions. The binding free energies were further divided into contribution of each residue and the derived information gives a conclusion that the hydrophobic interactions, such as CH-CH, CH-π and π-π interactions, are responsible for the inhibitor associations with MDMX.