Platinum–DNA interstrand crosslinks: Molecular determinants of bending and unwinding of the double helix

Platinum diamine complexes are able to crosslink the guanines of d(GC)2 dinucleotides within double-stranded DNA. The interstrand crosslink thus formed causes a bend of the double helix toward the minor groove and the helical sense changes locally to left-handed, resulting in a considerable unwinding. The bend and unwinding angles have been shown to depend on the platinum ligands. Here, we have used molecular dynamics simulations to investigate the DNA 20-mer d(C1T2C3T4C5C6T7T8G*9C10T11C12T13C14C15T16T17C18T19C20)-d(G21A22G23A24A25G26G27A28G29A30G*31C32A33A34G35G36A37G38A39G40) with the G* guanines crosslinked by cis-Pt(NH3)22+, Pt(R,R-DACH)2+, or Pt(S,S-DACH)2+. Previous investigations on cisplatin interstrand adducts indicated that the structure is similar in solid state and in solution; thus, we used the reported X-ray structure of a cisplatin adduct as a starting model. Replacing in the MD-relaxed model for the DNA duplex crosslinked with cis-Pt(NH3)22+ the two NH3 platinum ligands by R,R-DACH or S,S-DACH led to clashes between the DACH residue and the deoxyribose of C12. Confrontation of MD-derived models with gel shift measurements suggested that these clashes are avoided differently in the adducts of Pt(R,R-DACH)2+versus Pt(S,S-DACH)2+. The R,R-isomer avoids the clash by untwisting the T11/A30–C12/G29 step, thus increasing the global unwinding. In contrast, the S,S-isomer modifies the shift and slide parameters of this step, which dislocates the helical axis and enhances the bend angle. The clash that leads to the differentiation of the structures as a function of the diamine ligand is related to a hydrogen bond between the platinum complex and the T11 base and could be characteristic of interstrand crosslinks at d(pyG*Cpy)-d(puG*Cpu) sequences.

DNA interstrand crosslinks formed by cisplatin (yellow), oxaliplatin (red), and its S,S-enantiomer (blue) have different structures. The differences are related to an H-bond (cyan) linking the Pt-complex with a nearby nucleotide (C12), and requiring adaptation of the DNA-helix to avoid a clash between the DACH-residue and the C12H4′ atom (sphere).Figure optionsDownload as PowerPoint slideHighlights
► MD simulations show how Pt-ligands affect structure of Pt-DNA interstrand crosslinks.
► The bulky DACH ligand of oxaliplatin causes clashes with DNA backbone.
► Pt-DNA adducts adapt to the ligand bulkiness by modifying bend angle or unwinding.
► Pt-DNA interstrand crosslinks are stabilized by lone-pair–π interactions.