Missense mutations are often observed in tumor suppressor p53 from cancerous cells. The most frequently occurring mutation is R175H, which leads to unfolding of the mutant protein at physiological conditions. Thus an important issue in restoring the function of a mutant p53 is to increase its stability. Here we assess the restoration of R175H mutant via a small copper-containing molecule. Explicit water molecular dynamics methods are used to assess the destabilizing of the mutant and stabilizing effect of the small molecule. Specifically unfolding kinetics rates were simulated at high temperature simulation condition. Based on the correlation between unfolding rates and stability for p53 mutants, our unfolding simulations shows that R175H is indeed more unstable than the wild type protein. And the binding of the molecule does restore its stability to the wild type level.

Computational analysis of small molecule rescue of p53 cancer mutant

251st National Meeting (2016)

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