65 QM-MM simulations on p53-DNA complex: comparison of DNA-binding property between cancer and their rescue mutants

Abstract

p53 is a transcription factor involved in expression of a number of downstream genes in response to genotoxic stress. In normal cells, it is present in the latent or inactive state, and the in case of cancer cells it is activated by various post translation modifications. It is found to be mutated in 50% of the cancers. These mutations occur at a high frequency in the DNA binding region of p53. All seven hot spot cancer mutations R175H, Y220C, G245S, R248Q, R249S, R273C, and R282 W have been studied here using quantum and molecular mechanics hybrid simulations. The experimentally proven rescue mutations of the above mentioned cancer mutants have also been included in the present work. Each of the p53 mutants has been simulated for 30 ns each. A comparative study of these cancer mutations along with wild-type and their rescue mutations have been studied. The key residues which contribute to the binding of the p53 to the DNA by forming crucial hydrogen bonds have been studied in detail. Free energy changes, principal component analysis, hydrogen bonding, and various other structural parameters have been calculated to quantify the loss and gain in DNA binding property and local structural alterations of all the p53 mutants.