Mutations in the p53 tumor suppressor protein, also known as the guardian of the genome, have been implicated in the progression of more than 50% of all human cancers. This progression is attributed to mostly single point mutations, but the mechanism through which the single point mutations can lead to loss of protein functionality remains an open question. Here, we investigate the effect of mutations on p53 DNA-binding domain (DBD) dynamics through the use of Markov State Modeling (MSM) and molecular dynamics (MD) simulations. MSMs are unique computational tools because they allow for access to dynamics at longer timescales than otherwise available through conventional simulations. We explore the application of wildtype and mutant differential dynamics MSMs to help shed light on the conformational effects of the mutations and uncover potential avenues for reactivation via small molecule binding.

Computational investigation of the mutant p53 DNA-binding domain through Markov state modeling

2019 Fall National Meeting

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