title: Phosphorylation modulated p53 binding to MDM2 by multiscale simulations

Weitong Ren (TALK)

institution: Nanjing university - city: Nanjing

abstract:

Phosphorylation modulated p53 binding to MDM2 by multiscale simulations

Weitong Ren, Erbin He, Jun Wang, Wenfei Li and Wei Wang

National Laboratory of Solid State Microstructure and Department of Physics, Nanjing University, Nanjing 210093, P. R. China

The tumor suppressor protein p53 plays a crucial role in determining the cell fate in response to various stresses. The quantity of p53 in cell can be regulated by the ubiquitin ligase MDM2 through phosphorylation. However, the molecular mechanism of the phosphorylation modulated recognition of p53 to MDM2 remains elusive. In this work, we developed a multiscale method, which combines the atomistic molecular dynamics simulations with a coarse-grained structure-based model. With such a multiscale strategy, we can simulate the coupled binding and folding of the MDM2 recognition region of p53 (p53 peptide) to MDM2 with different phosphorylation states. Firstly, our results can reproduce quantitatively the effect of phosphorylation on the binding affinity. Secondly, we showed that the phosphorylation decreases the binding affinity by reducing the helical propensity of the p53 peptide. In comparison, the difference of inter-molecule electrostatic interactions due to phosphorylation only has minor contributions to the binding affinity decreasing. Finally, we show that recognition mechanism between MDM2 and p53 changed from “conformational selection” to “binding induced folding” after the phosphorylations to Ser18 and Thr20.