Abstract
Oxidative/nitrosative stresses, common characters of inflamed/cancer tissues, produce reactive oxygen/nitrogen species that alter guanine, such as 8-hydroxy-2'-deoxyguanosine (8-hydroxy-dG)-a lesion highly involved in carcinogenesis. Although its biological relevance is established, structural impact of such lesions remains partially clarified. Here, reactive molecular dynamics (RMD) simulations have been used for examining spatial distribution of the hydroxylated guanines dictates canonical B-DNA's 3D structure towards canonical B-DNA structure. Through the Dickerson-Drew dodecamer, a standard, five schemes of hydroxylation have been modeled, such as global (MtOH), site-visited (MdOH, MlOH), and orientation-dependent terminal schemes (Ml2r14OH, Ml2r24OH). Five helical deformation descriptors-center-of-base-pair distance (COBP), propeller twist angle (PTA), global/local twist angle (GTA/LTA), and end-to-end DNA length-were obtained from equilibrium trajectory for encoding local/global disturbances structure quantitatively. The results display a clear-cut priority of deformation: fully hydroxylated duplexes display isotropic elongation and wide unwinding, while vertically assembled terminal lesions retain almost native helical structure, oppositely cross-axis lesions, which impose collaborative end-fraying with wide alterations. The results illustrate that more than lesion occurrence, positional symmetry decisively dictates the stability of DNA, giving mechanistic information relevant for mutagenesis, genome instability, and pathogenetic processes under oxidative stress.