Key steps of the cis-platin-DNA interaction: Density functional theory-based molecular dynamics simulations

We present a fully ab initio molecular dynamics study of the interaction of cis-diamminedichloroplatinum(II) (cis-platin) with water and with a model for the DNA adduct in water. Calculations use the Car-Parrinello method, wh ich is based on density-functional theory with gradient-corrected functiona ls. Structural, electronic, and dynamical properties are determined for cis -platin and for the monoaquo complex in water. The mechanism of the first s tep of the cis-platin hydrolysis, namely, the Cl-H2O substitution reaction, is characterized. The free-energy barrier, calculated at room temperature via constrained molecular dynamics simulations, compares remarkably well wi th the value obtained in several independent experiments. As a model for th e simulation of the drug-DNA interaction, the GpG cross-link adduct is cons idered. Results are reported for the structural and vibrational properties in the aqueuos solution and compared with experiment whenever possible. An attempt to characterize the final step of the binding of cis-platin to DNA is also discussed.