5 years ago

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

Bridging Microscopic and Macroscopic Mechanisms of p53-MDM2 Binding with Kinetic Network Models
Sudipto Mukherjee, Vincent A. Voelz, Guangfeng Zhou, George A. Pantelopulos


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 intermediates, each with a nonnative arrangement of hydrophobic residues in the MDM2 binding cleft, control the overall on-rate. Using microscopic rate information from the MSM, we parameterize a simple four-state kinetic model to 1) determine that induced-fit pathways dominate the binding flux over a large range of concentrations, and 2) predict how modulation of residual p53 helicity affects binding, in good agreement with experiment. These results suggest new ways in which microscopic models of peptide binding, coupled with simple few-state binding flux models, can be used to understand biological function in physiological contexts.

Publisher URL: http://www.cell.com/biophysj/fulltext/S0006-3495(17)30806-8

DOI: 10.1016/j.bpj.2017.07.009

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