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Chemistry
Completed Project

Molecular Dynamics of DNA Mechanical Contributions of Various Promoter Sequences in p53 Complexes Motivated by a Novel Additive Binding Energy Model

In Sub M. Han, Vassar College ’15 and Prof. Kelly M. Thayer

The tumor suppressor protein p53 binds genomic DNA as a cell cycle regulator that ensures DNA integrity prior to replication as well as improve the molecular level understanding of how the binding event occurs. When excessive damage renders cells unsalvageable, the protein initiates apoptosis; however, disruption of this process may lead to tumor growth. Gaining a molecular understanding of the p53 DNA binding sites holds the potential to shed light on the role of DNA mechanics in the recognition process. An additive binding-energy model was developed as a means to categorize known DNA binding sequences based on their hydrogen bonding patterns and DNA bending mechanics. The model incorporates reported key discriminatory hydrogen bonding inter- actions and the mechanical DNA bending caused by the “TG step” that occurs in the 1TUP wild type p53 crystal structure. We have found that binding categorically occurs in five groups that we hypothesize also differ in binding mechanisms. Furthermore, the high frequency of poly(A) and poly(G) tract regions in the non-consensus p53 binding sites has prompted us to pay special attention to the DNA mechanics and its role in DNA-protein interactions specically in the p53 binding interface. To further investigate this hypothesis, sequences representing these features taken from known biological promoters simulated with molecular dynamics (MD) using the AMBER suite programs. The results can iteratively refine the additive binding energy model as more detailed mechanistic properties are elucidated.