Cisplatin binding to DNA oligomers from hybrid Car-Parrinello/molecular dynamics simulations

Cisplatin is widely used in clinic treatment against a variety of cancer diseases. It binds to two adjacent guanine residues and induces a bend in the DNA double helix. It is believed that cell death is induced upon binding of proteins, which recognize platinated DNA and impede replication and cell repair processes. Because of the high toxicity of cisplatin, there exists a great interest in new Pt-derivs., which are less toxic but as efficient as cisplatin. Thus, a profound understanding of the structural characteristics of Pt/DNA complexes is needed. NMR and X-Ray structures of cisplatin/DNA adducts share the overall structural features, but disagree in the local structure at the platinated site. In our work we performed hybrid QM/MM Car-Parrinello mol. dynamics on cisplatin/DNA adducts in the free from and complexed to the HMG protein domain A. Since this method allows for a parameter free treatment of the Pt-moiety and includes as well the DNA environment, we gain accurate insight into the structure of the drug/DNA complex. We conclude that the QM/MM approach described here proves to be a valuable tool for metal-DNA models and it can be used in the future to model the interaction of other platinum-based compds. with DNA, for which a valuable force field parametrization has not yet been developed. [on SciFinder (R)]