Molecular modeling of the intrastrand guanine-guanine DNA adducts producedby cisplatin and oxaliplatin

Intrastrand DNA adducts formed by cisplatin and oxaliplatin were modeled wi th molecular mechanics minimization and restrained molecular dynamics simul ations in a comparative study. A reasonable set of force field parameters f or the Pt atom were refined by using the available cisplatinated DNA crysta l structure as a guide. This crystal structure was also used as the startin g structure for the simulations. Analysis of the resulting structures indic ated that the covalent effects of oxaliplatin coordination on DNA structure were very similar to those of cisplatin. The most prominent difference bet ween the two structures resulted from the presence of the 1,2-diaminocycloh exane ring in the oxaliplatin adduct. The modeling indicated that this ring protrudes directly outward into, and fills much of, the narrowed major gro ove of the bound DNA; forming a markedly altered and less polar major groov e in the area of the adduct. The differences in the structure of the adduct s produced by cisplatin and oxaliplatin are consistent with:the observation that they are differentially recognized by the DNA mismatch repair system.