Investigating Conformational Dynamics and Allostery in the p53 DNA-Binding Domain Using Molecular Simulations

The p53 tumor suppressor is a multifaceted context-dependent protein, which is involved in multiple cellular pathways, with the ability to either keep the cells alive or to kill them through mechanisms such as apoptosis. To complicate this picture, cancer cells that express mutant p53 becomes addicted to the mutant activity, so that the mutant variant features a myriad of gain-of-function activities, opening different venues for therapy. This makes essential to think outside the box and apply new approaches to the study of p53 structure–(mis)function relationship to find new critical components of its pathway or to understand how known parts are interconnected, compete, or cooperate. In this context, I will here illustrate how to integrate different computational methods to the identification of possible allosteric effects transmitted from the DNA binding interface of p53 to regions for cofactor recruitment. The protocol can be extended to any other cases of study. Indeed, it does not necessarily apply only to the study of DNA-induced effects, but more broadly to the investigation of long-range effects induced by a biological partner that binds to a biomolecule of interest. © 2021, Springer Science+Business Media, LLC, part of Springer Nature.