10.1021/acs.jcim.8b00238.s001 Ryan W. Kung Ryan W. Kung Purshotam Sharma Purshotam Sharma Stacey D. Wetmore Stacey D. Wetmore Effect of Size and Shape of Nitrogen-Containing Aromatics on Conformational Preferences of DNA Containing Damaged Guanine American Chemical Society 2018 AMBER DNA Containing Damaged Guanine dG adducted DNA MD 3LYP model DNA lesions DFT C 8 NCA moiety shape 2018-06-20 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Effect_of_Size_and_Shape_of_Nitrogen-Containing_Aromatics_on_Conformational_Preferences_of_DNA_Containing_Damaged_Guanine/6771299 The present work investigates the effects of the size and shape of the nitrogen-containing aromatic (NCA) skeleton on the structure of DNA damaged through adduct formation at C<sup>8</sup> of 2′-deoxyguanosine (dG), a common DNA lesion associated with chemical carcinogenesis. Specifically, density functional theory (DFT) calculations (B3LYP-D3) and molecular dynamics (MD) simulations (AMBER) are performed on seven model adducts with systematic expansion of the NCA moiety. DFT calculations reveal that the NCA moiety shape affects the structure at the nucleobase–carcinogen linkage. Approximately 4.5 μs of MD simulations on damaged oligonucleotides adopting three established conformational themes (namely, B, W, and S) illustrate that the structure and lesion-site stabilization strongly depend on the NCA moiety shape and size, which provides insight into the repair propensity of C<sup>8</sup>-dG adducted DNA. Our results add bulky moiety shape to the growing list of previously established effects on the conformational and repair outcomes of damaged DNA (i.e., size, ionization state, substitution, linker type, and DNA sequence). Furthermore, this work illustrates the utility of a systematic set of model DNA lesions for understanding the structure–activity relationship for DNA damaged by carcinogens of different sizes and shapes, which should be used in future studies of the cellular processing of damaged DNA.