The present study employs density-functional electronic structure methods to investigate the effect of chemical modification at the C5 position of cytosine. A series of experimentally motivated chemical modifications are considered, including alkyl, halogen, aromatic, fused ring, and strong σ and π withdrawing functional groups. The effect of these modifications on cytosine geometry, electronic structure, proton affinities, gas phase basicities, cytosine-guanine base pair hydrogen bond network and corresponding nucleophilicity at guanine are examined. Ultimately, these results play a part in dissecting the effect of endogenous cytosine methylation on the reactivity of neighboring guanine toward carcinogens and DNA alkylating agents.
Bibliographical noteFunding Information:
D. Y. is grateful for financial support provided by the National Institutes of Health (Grant GM62248) and the University of Minnesota Biomedical Informatics and Computational Biology program, and NT is grateful for financial support provided by National Cancer Institute (CA-100670). AM is grateful for support through a Department of Energy NDSEG fellowship, and RG thanks the National Institutes of Health for support through the Chemistry–Biology Interface Training Grant (T32-GM08700). Computational resources were provided by the Minnesota Supercomputing Institute.