Full-atomistic Molecular Dynamics Analysis of p53 Active Tetramer

Abstract

p53 is a tumor suppressor protein that plays a crucial role in inhibiting cancer development and maintaining the genetic integrity. Within the cell nucleus, four p53 molecules form a stable tetrameric active structure through highly cooperative interactions, bind to DNA via its DNA-binding domain, and transcriptionally activate or inhibit their target genes. However, in most human tumor cells, there are numerous p53 mutations. The majority of these mutations are formed in the p53 DNA-binding domain, importantly, the p53 DNA-binding domain is critical for p53 to form the tetrameric active structures and to regulate the transcription of its downstream target genes.<br/>This study exploited the all-atom molecular dynamics simulations to investigate the mechanisms of interactions within the wild-type p53 tetramers. This study indicates that the symmetric dimers on either side of the DNA are stable ones, keep stable structures both before and after DNA bindings. The binding of two monomers on the same side of the DNA depends on proteinprotein interactions provided by two contact surfaces. DNA scaffold stabilizes the tetrameric active structure. Such interactions play a crucial role in helping the tetramer formation. This study clarifies the internal interactions and key residues within the p53 tetramer during dynamic processes, as well as the critical sites at various interaction interfaces. The findings of this study may provide a significant foundation for us to further understand the p53's anticancer mechanisms, to explore the effective cancer treatment strategies, and in near future, to develop the effective anti-cancer drugs.