Impact of K24N Mutation on p53TAD and its Interaction with MDM2

Abstract

The level of transcription factor p53 is negatively regulated by E3 ubiguitin ligase murine double minute clone 2 (MDM2). The interaction between p53 and MDM2 is essential for the survival of the cell and for organism activity. Structural studies revealed that MDM2 binds to p53 transactivation domain (p53TAD) from residues 17 to 29. The K24N mutation of p53TAD is a naturally occurring mutation that is found in human choriocarcinoma cell lines. In this study we used molecular dynamics simulation to determine how the K24N mutation affects the affinity, structure, and dynamics of p53TAD binding to MDM2. The results suggest that the K24N mutation decreases the affinity between p53TAD and MDM2 due primarily to the entropic contribution to the binding free energy. The results are consistent with experiments and show that this entropy difference is due to a change in the structure of the protein-protein complex that increases the bound flexibility of both the mutant p53TAD and MDM2.