Computational investigations of alkylation damage to the DNA nucleobase thymine

Abstract

DNA alkylation damage is caused by numerous sources in the environment. Alkylation damage can stall standard DNA polymerases and replication instead occurs through a process called translesion synthesis (TLS). This thesis uses a combination of density functional theory calculations and molecular dynamics simulations to rationalize the mutagenic patterns of O-alkylthymine adducts and elucidate the role of human TLS polymerase η in their replication. Specifically, this thesis unveils the effect of alkyl chain position by considering O2-methylthymine and O4-methylthymine. Furthermore, the impact of alkyl chain size is revealed by studying the O4-[4-(3-pyridyl)-4-oxobut-1-yl]-thymine lesion, which is derived from tobacco smoke. Finally, insight into the impact of alkyl chain shape is obtained by considering the synthetic O2-n-butylthymine and O2-iso-butylthymine adducts. Overall, this thesis addresses some of the unanswered questions surrounding the replication of thymine alkylation damage and provides a better understanding of human polymerase η that has been implicated in disease.