title: Structural and thermodynamic features of spiroiminodihydantoin damaged DNA duplexes.
abstract: Oxidation of guanine or 8-oxo-7,8-dihydroguanine can produce spiroiminodihydantoin (Sp) R and S stereoisomers. Both in vitro and in vivo experiments have shown that the Sp stereoisomers are highly mutagenic, causing G --> C and G --> T transversion mutations. Therefore, they are of interest as potential endogenous cancer causing lesions. However, their structural properties in DNA duplexes remain to be elucidated. We have employed computational methods to study the Sp lesions in 11-mer DNA duplexes with A, C, G, and T partners. Molecular dynamics simulations have been carried out to obtain ensembles of structures, and the trajectories were employed to analyze the structures and compute free energies. The structural and thermodynamic analyses reveal that the Sp stereoisomers energetically favor positioning in the B-DNA major groove, with minor groove conformers also low energy in some cases, depending on the partner base. The R and S stereoisomers adopt opposite orientations with respect to the 5' to 3' direction of the modified strand. Both syn and anti glycosidic bond conformations are energetically feasible, with partner base and stereochemistry determining the preference. The lesions adversely impact base stacking and Watson-Crick hydrogen bonding interactions in the duplex, and cause groove widening. The chemical nature of the partner base determines specific hydrogen bonding and stacking properties of the damaged duplexes. The structural characteristics may relate to observed mutagenic properties of the Sp stereoisomers, including possible stereoisomer-dependent differences.
authors.affiliation: Department of Chemistry, New York University, New York, New York 10003, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Jia
authors.forename: Vladimir
authors.initials: V
authors.lastname: Shafirovich
authors.forename: Robert
authors.initials: R
authors.lastname: Shapiro
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Geacintov
authors.forename: Suse
authors.initials: S
authors.lastname: Broyde
mesh_terms: D019295:Computational Biology; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D004249:DNA Damage; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006860:Hydrogen Bonding; D008956:Models, Chemical; D008958:Models, Molecular; D015233:Models, Statistical; D009154:Mutation; D010100:Oxygen / Q000737:chemistry; D012984:Software; D013141:Spiro Compounds / Q000494:pharmacology*; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: D013141:Spiro Compounds; C408822:spiroiminodihydantoin; D006151:Guanosine; D004247:DNA; D010100:Oxygen