Unraveling the Allosteric Mechanism of Four Cancer-related Mutations in the Disruption of p53-DNA Interaction.

Abstract

The p53 protein plays active roles in the physiological regulation of cell cycle as well as in cancer developments. In more than half of human cancers, the protein is inactivated by mutations located primarily in its DNA-binding domain (DBD), and some mutations located in the β-sandwich region of DBD are reported to decrease p53-DNA binding affinities. To understand the long-range correlation between p53 β-sandwich and DNA, and the allosteric mechanism of β-sandwich mutations in the disruption of p53-DNA interactions, we first identify three regions with a strong correlation with DNA based on microsecond molecular dynamics (MD) simulations of wild-type p53-DNA complex and then perform multiple MD simulations on four cancer-related mutants L145Q, P151S, Y220C, and G266R, which are located in these three regions. Our simulations show that these mutations allosterically destabilize the structural stability of the DNA-binding groove in p53 and disrupt the p53-DNA interactions. Network analyses reveal optimal correlation paths through which the mutation-induced allosteric signal passes to DNA, and the disturbance effect of these mutations on the global connectivity and dynamical correlation of the p53-DNA complex. This work paves the way for the in-depth understanding of the mutation-induced loss in p53's DNA-recognition ability and the pathological mechanism of cancer development.