Investigation of the impact of R273H and R273C mutations on the DNA binding domain of P53 protein through molecular dynamic simulation

Abstract

The P53 protein, a cancer-associated transcriptional factor and tumor suppressor, houses a Zn2+ ion in its DNA-binding domain (DBD), essential for sequence-specific DNA binding. However, common mutations at position 273, specifically from Arginine to Histidine and Cysteine, lead to a loss of function as a tumor suppressor, also called DNA contact mutations. The mutant (MT) P53 structure cannot stabilize DNA due to inadequate interaction. To investigate the conformational changes, we performed a comparative molecular dynamic simulation (MDS) to study the effect of the P53-Wildtype (P53-WT) and the DNA contact mutations (R273H and R273C) on the DBD. Our research indicated that the DNA binding bases lose Hydrogen bonds (H bonds) when mutated to P53-R273H and P53-R273C during the simulation. We employed tools, such as PDIviz to highlight the contacts with DNA bases and backbone, major and minor grooves, and various pharmacophore forms of atoms. The contact maps for R273H and R273C were generated using the COZOID tool, which displayed changes in the frequency of the amino acids and DNA bases interaction in the DNA binding domain. These residues have diminished interactions, and the zinc-binding domain shows significant movements by Zn2+ ion binding to the phosphate group of the DNA, moving away from its binding sites. In conclusion, our research suggests that R273H and R273C each have unique stability and self-assembly properties. This understanding might assist researchers in better comprehending the function of the p53 protein and its importance in cancer. Communicated by Ramaswamy H. Sarma