Computer Modeling of the Hydrogen-bonded Dimers Between O2-alkylthymine and the Canonical DNA Bases

Abstract

Alkylation of the DNA bases is induced by a variety of exogenous sources, including tobacco smoke, atmospheric halocarbons, chemotherapeutic drugs, and contaminants within certain foods, as well as endogenous sources, such as S-adenosylmethionine (SAM). If not repaired before DNA replication takes place, this damage typically stalls a standard DNA polymerase and replication instead occurs through translesion synthesis (TLS). Although TLSpolymerases have more flexible active sites and can bypass the damaged site, the TLS process is error-prone, and can lead to changes in the selective Watson-Crick (WC) pairing observed in undamaged DNA. These mutations can lead to diseases, such as cancer. The present study investigates the effects of alkylation at the O2 site of thymine (T), including the effects of increasing the alkyl chain size (see below), on the structures of dimers formed with the canonical DNA bases. Alkylation alters the WC face of T, leading to a high frequency of mutations during DNA replication.

However, previously reported experimental data indicates that the types and frequencies of mutations depend on the size and degree of branching of the alkyl chain. Using density functional theory (DFT) and molecular dynamics (MD) simulations, the structural properties of potential mispairs formed upon DNA alkylation are characterized. This work provides the first structural insight to rationalize the experimentally observed mutations, and provides the foundation for future modeling that will consider the interactions between damaged DNA and TLS polymerases.

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