title: Molecular modeling of the intrastrand guanine-guanine DNA adducts produced by cisplatin and oxaliplatin.
abstract: Intrastrand DNA adducts formed by cisplatin and oxaliplatin were modeled with molecular mechanics minimization and restrained molecular dynamics simulations in a comparative study. A reasonable set of force field parameters for the Pt atom were refined by using the available cisplatinated DNA crystal structure as a guide. This crystal structure was also used as the starting structure for the simulations. Analysis of the resulting structures indicated that the covalent effects of oxaliplatin coordination on DNA structure were very similar to those of cisplatin. The most prominent difference between the two structures resulted from the presence of the 1,2-diaminocyclohexane ring in the oxaliplatin adduct. The modeling indicated that this ring protrudes directly outward into, and fills much of, the narrowed major groove of the bound DNA, forming a markedly altered and less polar major groove in the area of the adduct. The differences in the structure of the adducts produced by cisplatin and oxaliplatin are consistent with the observation that they are differentially recognized by the DNA mismatch repair system.
authors.affiliation: Department of Medicine and Cancer Center, University of California, San Diego, La Jolla, California, USA.
authors.forename: E D
authors.initials: ED
authors.lastname: Scheeff
authors.forename: J M
authors.initials: JM
authors.lastname: Briggs
authors.forename: S B
authors.initials: SB
authors.lastname: Howell
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D018736:DNA Adducts; D006147:Guanine / Q000737:chemistry*; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D000077150:Oxaliplatin
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D006147:Guanine; D004247:DNA; D002945:Cisplatin