Abstract
Base excision repair (BER) is a conserved repair mechanism of the cell that restores the genetic material back to its original state. Defects in BER components lead to elevated mutation rates, eventually pushing the cell to a cancerous state. Thymine DNA glycosylase is an essential component of BER that corrects G·T mutagenic mismatches, while A·T pairs are not subject to base excision by TDG. How TDG achieves this specificity is not well understood. One hypothesis is that rejection of A·T pairs is due to unfavorable contacts with the complementary strand. In this study, we use molecular dynamics (MD) simulations to elucidate the substrate recognition of TDG in the presence of several different complementary bases including guanine, adenine and inosine. MD simulations are performed on DNA alone and the enzyme-DNA complex using the CHARMM36 additive and Drude polarizable force field, with utilization of the latter motivated by recent studies indicating that the Drude model captures the base flipping equilibria close to those obtained from experimental studies.
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