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(C(1)T(2)C(3)T(4)C(5)C(6)T(7)T(8)G*(9)C(10)T(11)C(12)T(13)C(14)C(15)T(16)T(17)C(18)T(19)C(20))-d(G(21)A(22)G(23)A(24)A(25)G(26)G(27)A(28)G(29)A(30)G*(31)C(32)A(33)A(34)G(35)G(36)A(37)G(38)A(39)G(40)) with the G* guanines crosslinked by cis-Pt(NH(3))(2)(2+), 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(NH(3))(2)(2+) the two NH(3) platinum ligands by R,R-DACH or S,S-DACH led to clashes between the DACH residue and the deoxyribose of C(12). 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 T(11)/A(30)-C(12)/G(29) 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 T(11) base and could be characteristic of interstrand crosslinks at d(pyG*Cpy)-d(puG*Cpu) sequences.
Department of Biophysics, Faculty of Sciences, Palacky University, Olomouc, Czech Republic.
Tereza
T
Suchánková
Karel
K
Kubíček
Jana
J
Kašpárková
Viktor
V
Brabec
Jiří
J
Kozelka
D004247:DNA / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009944:Organoplatinum Compounds / Q000737:chemistry*; D010984:Platinum / Q000737:chemistry
D009944:Organoplatinum Compounds; D010984:Platinum; D004247:DNA