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, which is based on density-functional theory with gradient-corrected functionals. Structural, electronic and dynamical properties are determined for cis-platin and for the monoaquo complex in water. The mechanism of the first step of the cis-platin hydrolysis, namely, the Cl-H(2)O substitution reaction, is characterized. The free-energy barrier, calculated at room temperature via constrained molecular dynamics simulations, compares remarkably well with the value obtained in several independent experiments. As a model for the simulation of the drug-DNA interaction, the GpG crosslink adduct is considered. 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.