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(GGAGAGACCTGGAAGG) [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 195 Pt 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(NH 3 ) 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