Total Mutagenesis and the Effects on the MDM2‐p53 Interaction

The aim of this study is to assess the impacts of mutation on the p53‐MDMD2 interaction. While the available literature explores alanine‐scanning mutagenesis of the six necessary amino acids of the p53 binding subdomain in order to obtain precise ΔG values for the wild‐type amino acids in the p53‐MDM2 binding domain, the effects of non‐alanine point mutations have not been explored. Many mutations of MDM2 that could affect the binding to p53 have largely gone unstudied, but several SNPs in MDM2 have been directly linked to tumor formation. The aim of this study is to assess the impacts of mutation on the p53‐MDMD2 interaction utilizing both MUMBO and MM‐PBSA. MUMBO was used in order to perform total mutagenesis of the p53‐MDM2 domain in order to determine key mutations that may influence MDM2 binding activity. Data achieved from exhaustive point‐by‐point mutagenesis suggests great variation in the mutant structures. Mutants of interest will then be further explored utilizing the MM‐PBSA approach, and structural models will be constructed. Many mutations not shown through alanine‐scanning mutagenesis may greatly impact the p53‐MDM2 interaction.