Masters Thesis

Conformational dynamics of the bound and unbound states of human alkyladenine glycosylase

An intricate base excision repair (BER) mechanism maintains the integrity of human DNA against exposure to environmental pollutants and carcinogens, and natural error in DNA replication. Human alkyladenine glycosylase (hAAG) initiates BER for alkylated and deaminated adenine bases. The overall catalytic mechanism for hAAG is known, but the method of formation of the protein-DNA complex is not known. Two hypotheses for BER proteins compare a sliding vs. clamping mechanism to search for lesions. In this work, conformational differences between bound and unbound enryme were studied via molecular dynamics (MD) simulations. Analysis was based on MD trajectory data and included calculations of hydrogen bond interactions, P-factor, and RMS fluctuations. We propose hAAG searches the DNA duplex via sliding mechanism. The insights obtained in this work point to the development of future cancer therapeutics.

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