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

SISSA, International School for Advanced Studies, Trieste INFM-DEMOCRITOS, Modeling center for research in atomistic simulation, Trieste § EPFL, Ecole Polytechnique Federale de Lausanne, Switzerland


ABSTRACT ±La struttura del complesso tra cis-platino e DNA in soluzione acquosa e' stata studiata con metodologie QM/MM. L'intorno del platino e' trattato a un livello DFT mentre il resto della biomolecola ed il solvente col force-field di AMBER. I calculi si basano sulle strutture X-ray del complesso platino-DNA (nella forma libera, cisptd(CCTCTG*G*TCTCC) -d(GGAGACCAGAGG)1 ed in complesso con l'HMGprotein domain A, cispt-d(CCUCTCTG*G*ACCTTCC)-d(GGAGAGACCTGGAAGG)2 ed una struttura modellata tramite docking del cis-platino sul DNA). Durante la dinamica, la struttura del Pt-DNA dodecamero si riarrangia significativamente riproducendo la struttura in soluzione come ottenuta con spettroscopia NMR. Il 195Pt chemical shifts calcolati dalla struttura QM/MM relativa al cis-platino in soluzione acquosasono in accordo qualitativo con i dati sperimentali. Invece la struttura del complesso cis-PtDNA/HMG A rimane stabile. Ildocking del cis-Pt sulDNA induce un piegamento della doppia elica e una transizione dentro la struttura come osservato sperimentalmente in addotti platinati. L'approccio QM/MM si rivela uno strumento nuovo ed utile per studiare complessi Pt-DNA.

Structure and binding ofcisplatin to DNA in aqueous solution is investigated by QM/MM methodologies. In our approach, the platinated moiety is treated at the density functional level and the biomolecular frames with the AMBER force field. The calculations are based on X-ray structures of platinated DNA (in the free form, cisptd(CCTCTG*G*TCTCC) -d(GGAGACCAGAGG)1 in complex with HMG protein domain A,cispt-d(CCUCTCTG*G*ACCTTCC)-d(GGAGAGACCTGGAAGG)2 and on cisplatin docked DNA structure. During the dynamics, the structure of the platinated DNA dodecamer rearranges significantly towards structural determinants of the solution structure as obtained by NMR spectroscopy. The calculated 195Pt chemical shifts of the QM/MM structure relative to cisplatin in aqueous solution are in qualitative agreement with the experimental data.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)22+ onto DNA in its canonical B-conformation causes a large kink and a rearrangement of DNA as experimentally observed
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Takahara, P. M., Rosenzweig, A. C., Frederick, C. A., Lippard, S. J., Nature (1995),377, 649-652. Ohndorf, U. M., Rould M.A., He, Q., Pabo C.O., Lippard, S. J. Nature (1999), 399, 708-712.



in the platinated adducts, with NMR chemical shifts in qualitative agreement with the values in aqueous solution. Thus, the QM/MM approach presented here reveals itself as a novel and useful tool to investigate cispt/DNA adducts.Introduction
The drug cisplatin (cis-diamminedichloroplatinum(II)) is widely used in clinic treatment against a variety of cancer diseases3-4. Its beneficial effects arise from its binding to DNA nucleobases, preferentially to the two N7 atoms belonging to two adjacent G nucleobases or, to a lesser extent, to AG sequences. Due to the high toxicity and intrinsic or acquired resistance, there isgreat interest in developing new cisplatinderived drugs. Therefore understanding of the binding mode and the structural features of cisplatin-DNA adducts is of great importance. So far, structural information are based on X-ray and NMR structures as well as on MD simulations5. Even though the overall distortion is similar in all structures, there are non neglicible differences in the details...
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