Abstract
A comparative molecular dynamics (MD) simulation study was performed on the p53 oncoprotein to investigate the effect of the Arg273His (R273H) mutation on the p53→DNA Binding Domain (DBD). The two p53 dimer structures of the wild-type and mutant Arg273His (R273H) were simulated with the same thermodynamic and environmental parameters. The obtained results demonstrate that the induced Arg273His mutation has a considerable effect on the p53→DNA close contact interaction and changes the picture of hydrogen formation. The Arg273His mutation, in some cases, destroys the existing native hydrogen bond, but, in other cases, forms a strong p53→DNA hydrogen bond, which is not proper for the native protein. The MD simulation results illustrate some molecular mechanism of the conformational changes of the Arg273His key amino acid residue in the p53→DNA binding domain, which might be important for the understanding of the physiological functioning of the p53 protein and the origin of cancer.
Highlights
The p53 tumor suppressor protein is involved in preventing cancer and plays a central role in conserving genomic stability by preventing a genome mutation [1,2,3,4,5]. p53 (the 53 kilodalton protein) is activated either to induce a cell cycle arrest allowing the repair and survival of the cell, or apoptosis to discard the damaged cell
The molecular dynamics (MD) simulation results illustrate some molecular mechanism of the conformational changes of the Arg273His key amino acid residue in the p53 DNA binding domain, which might be important for the understanding of the physiological functioning of the p53 protein and the origin of cancer
Our MD simulation results on the structure of the p53 oncoprotein with Arg273His (R273H) mutation suggest that the induced mutation disturbs essentially the stability of the p53 core domain
Summary
The p53 tumor suppressor protein is involved in preventing cancer and plays a central role in conserving genomic stability by preventing a genome mutation [1,2,3,4,5]. p53 (the 53 kilodalton (kDa) protein) is activated either to induce a cell cycle arrest allowing the repair and survival of the cell, or apoptosis to discard the damaged cell. Single amino acid substitutions (mutations) in the p53 structure deactivate the p53 protein, which results in cancer [1,2,3,4,5,6,7,8]. Most of the mutations (95% of all known tumor mutations) occur in the DNA-binding domain (DBD) of the p53 protein. An oncogenic form of p53 is predominantly a full-length p53 protein with a single amino acid substitution in the DBD. Most of these mutations destroy the ability of the protein to bind to its target DNA sequences, and prevent the transcriptional activation of these genes. Tumors with inactive p53 mutants are aggressive and often resistant to ionizing radiation and chemotherapy
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