Conformational changes of the p53-binding cleft of MDM2 revealed by molecular dynamics simulations

Two 35-ns molecular dynamics simulations of both ligated [mouse double minute protein 2 (MDM2(p53))] and unligated (MDM2(apo)) structures of human MDM2 bound to the N-terminal domain of the tumor suppressor p53 have been performed. Analysis of the dynamics revealed that the most flexible region of MDM2 was the p53-binding cleft. When MDM2 was bound to p53, a wider and more stable topology of the cleft was obtained, while unligated MDM2 showed a narrower and highly flexible cleft. It was also found that the dynamics involved in the opening/closing motions were due to the movement of different domains of the protein, which is in agreement with recent experimental data. Considering our results, a mechanism in which p53 might be recognized and attached to MDM2 is proposed, and some implications on future directions for in silico anticancer drug design efforts are discussed. In summary, the observations made here would be very useful not only for better understanding of the biological implications of the MDM2 dynamics, but also for future efforts in anticancer drug design and discovery.