# Structural Effects and Competition Mechanisms Targeting the Interactions between p53 and Mdm2 for Cancer Therapy

## TL;DR

This study uses molecular dynamics simulations to analyze the structural interactions between p53 and Mdm2/MdmX, aiming to inform the design of inhibitors for cancer therapy by revealing key binding mechanisms.

## Contribution

It provides detailed atomistic insights into p53-Mdm2/MdmX interactions and identifies critical structural features influencing inhibitor binding and disruption processes.

## Key findings

- Specific alpha helices in Mdm2/MdmX are crucial for inhibitor binding.
- The Trp23 hydrogen bond in p53 governs competitive binding dynamics.
- Results aid in designing targeted cancer therapeutics.

## Abstract

About half of human cancers show normal TP53 gene and aberrant overexpression of Mdm2 and/or MdmX. This fact promotes a promising cancer therapeutic strategy which targeting the interactions between p53 and Mdm2/MdmX. For developing the inhibitors to disrupt the p53-Mdm2/MdmX interactions, we systematically investigate structural and interaction characteristics of p53 and inhibitors with Mdm2 and MdmX from atomistic level by exploiting stochastic molecular dynamics simulations. We find that some specific $\alpha$ helices in Mdm2 and MdmX structure play key role in their bindings with inhibitors and the hydrogen bond formed by residue Trp23 of p53 with its counterpart in Mdm2/MdmX determines dynamical competition processes of the disruption of Mdm2-p53 interaction and replacement of p53 from Mdm2-p53 complex {\it in vivo}. We hope that the results reported in this paper provide basic information for designing functional inhibitors and realizing cancer gene therapy.