title: Site-specific OH attack to the sugar moiety of DNA: a comparison of experimental data and computational simulation.
abstract: Little computational or experimental information is available on site-specific hydroxyl attack probabilities to DNA. In this study, an atomistic stochastic model of OH radical reactions with DNA was developed to compute relative OH attack probabilities at individual deoxyribose hydrogen atoms. A model of the self-complementary decamer duplex d(CCAACGTTGG) was created including Na(+) counter ions and the water molecules of the first hydration layer. Additionally, a method for accounting for steric hindrance from nonreacting atoms was implemented. The model was then used to calculate OH attack probabilities at the various C-H sites of the sugar moiety. Results from this computational model show that OH radicals exhibit preferential attack at different deoxyribose hydrogens, as suggested by their corresponding percentage solvent-accessible surface areas. The percentage OH attack probabilities for the deoxyribose hydrogens [1H(5')+2H(5'), H(4'), H(3'), 1H(2')+2H(2'), H(1')] were calculated as approximately 54.6%, 20.6%, 15.0%, 8.5% and 1.3%, respectively, averaged across the sequence. These results are in good agreement with the latest experimental site-specific DNA strand break data of Balasubramanian et al. [Proc. Natl. Acad. Sci. USA 95, 9738-9742 (1998)]. The data from this stochastic model suggest that steric hindrance from nonreacting atoms significantly influences site-specific hydroxyl radical attack probabilities in DNA. A number of previous DNA damage models have been based on the assumption that C(4') is the preferred site, or perhaps the only site, for OH-mediated DNA damage. However, the results of the present study are in good agreement the experimental results of Balasubramanian et al. in which OH radicals exhibit preferential initial attack at sugar hydrogen atoms in the order 1H(5')+2H(5') > H(4') > H(3') > 1H(2')+2H(2') > H(1').
authors.affiliation: Department of Nuclear and Radiological Engineering, University of Florida, Gainesville, Florida 32611, USA.
authors.forename: Bulent
authors.initials: B
authors.lastname: Aydogan
authors.forename: David T
authors.initials: DT
authors.lastname: Marshall
authors.forename: Steven G
authors.initials: SG
authors.lastname: Swarts
authors.forename: James E
authors.initials: JE
authors.lastname: Turner
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Boone
authors.forename: Nigel G
authors.initials: NG
authors.lastname: Richards
authors.forename: Wesley E
authors.initials: WE
authors.lastname: Bolch
mesh_terms: D000465:Algorithms; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D004249:DNA Damage; D003855:Deoxyribose / Q000737:chemistry*; D006859:Hydrogen / Q000737:chemistry; D017665:Hydroxyl Radical / Q000494:pharmacology*; D008956:Models, Chemical; D009010:Monte Carlo Method; D009690:Nucleic Acid Conformation; D013269:Stochastic Processes
chemical_list: D017665:Hydroxyl Radical; D003855:Deoxyribose; D006859:Hydrogen; D004247:DNA