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

The structure and binding of cisplatin to DNA in aqueous solution are investigated via a QM/MM methodology. In our approach, the platinated moiety is treated at the density functional level and the biomolecular frame with the AMBER force field. The calculations are based on X-ray structures of platinated DNA in the free form (cispt-d(CCTCTG*G*TCTCC)-d(GGAGACCAGAGG) [Takahara, et al. Nature 1995,377,649-652](1)) and in complex with HMG protein domain A (cispt-d(CCUCTCTG*G*ACCTTCC)-d(GGAGAGACCTG-GAAGG) [Ohndorf et al. Nature 1999, 399, 708 -712](2) as well as on a cisplatin docked DNA model. During the QM/MM simulation, the structure of the platinated DNA dodecamer rearranges significantly toward structural determinants of the solution structure as obtained by NMR spectroscopy [Gelasco et al. Biochemistry 1998, 37, 9230-9239].(3) The calculated Pt-195 chemical shifts of the QM/MM structure relative to cisplatin in aqueous solution are in qualitative agreement with the experimental data [Bancroft et al. J. Am. Chem. Soc. 1990, 112, 6860-6871. Miller et al. Inorg. Chem. 1985, 24, 2421-2425].(4,5) The QM/MM structure of the platinated/DNA HMG complex, on the other hand, remains rather similar to the X-ray structure, consistent with its relatively low flexibility. Docking of Pt(NH3)(2)(2+) onto DNA in its canonical B-conformation causes a large axis bend and a rearrangement of DNA as experimentally observed in the platinated adducts, with NMR chemical shifts in qualitative agreement with the values in aqueous solution(4,5).