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

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• 作者：Tereza Such&#225 ; nkov&#225 ; ^a ; Karel Kubí ; č ; ek^b ; Jana Kaš ; p&#225 ; rkov&#225 ; ^a ; Viktor Brabec^a ; Jiř ; í ; Kozelka^b ; ^c ; ^{kozelka.jiri@gmail.com}
• 关键词：Anticancer drugs ; Cisplatin ; DNA binding ; Interstrand crosslinks ; Lone&ndash ; pair&ndash ; 蟺 interactions ; Molecular dynamics simulations
• 刊名：Journal of Inorganic Biochemistry
• 出版年：2012
• 期刊代码：53_01620134
• 类别：ch
• 出版时间：March, 2012
• 卷：108
• 期：Complete
• 页码：69-79
• 文件大小：1485 K

摘要

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.