Bridging Microscopic and Macroscopic Mechanisms of p53-MDM2 Binding with Kinetic Network Models.

ABSTRACT: Under normal cellular conditions, the tumor suppressor protein p53 is kept at low levels in part due to ubiquitination by MDM2, a process initiated by binding of MDM2 to the intrinsically disordered transactivation domain (TAD) of p53. Many experimental and simulation studies suggest that disordered domains such as p53 TAD bind their targets nonspecifically before folding to a tightly associated conformation, but the microscopic details are unclear. Toward a detailed prediction of binding mechanisms, pathways, and rates, we have performed large-scale unbiased all-atom simulations of p53-MDM2 binding. Markov state models (MSMs) constructed from the trajectory data predict p53 TAD binding pathways and on-rates in good agreement with experiment. The MSM reveals that two key bound intermediate

SUBMITTER: Zhou G 

PROVIDER: S-EPMC5567610 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature