Dramatic 5‘-Residue Effect on Conformer Distribution of Short Oligonucleotide Retro Models of the Cisplatin−DNA Cross-Link:  Implications for the Lippard and Cross-Link Distorted Base Pair Steps Present in Cisplatin−DNA Duplex Adducts

Abstract

The cisplatin anticancer drug preferentially attacks the GG sequence of DNA duplexes. Virtually all DNAs containing the key G*G* lesion (G* = N7 platinated G) have large distortions in the cross-link (G*G*) base pair (bp) step and also in the adjacent Lippard (XG*) bp step, making the adducts very different from B-form DNA in the XG*G* region. The XG*G* strand in duplexes also differs in several ways from single-strand (ss) models with G*G* and XG*G* sequences. In the duplex, the X residue has an N sugar, the 5'-G* and 3'-G* bases have slight "R" canting (3'-G* H8 atom toward the 5'-G* base), and there is no or weak H-bonding by the NH3 ligands. In most XG*G* ss models, X has an S sugar, the 5'-G* base normally cants strongly toward the 3'-G* base (L canting), and the NH3 forms an H-bond. Well-defined ss models exist in the solid state, but dynamic motion obscures the properties of the ss models in solution. In this work, we employ retro models (better defined, less dynamic ss models) to understand the differences between duplex and ss models. The retro models in this study lack carrier ligand NH's, thus eliminating H-bonding. To correlate previous ss solid-state models with our solution work, we constructed hybrid molecules by overlaying parts of known structures. The combined model and experimental information indicates that the X N-pucker is not favorable in L-canted ss models, that X residue steric effects (not H-bonding) favor L canting in ss models, that X N-pucker is needed for favorable WC hydrogen bonding and stacking interactions in duplexes, and that X N-pucker minimizes X base clashes with bases in the complementary strand in duplexes. The R canting minimizing clashes between the X and G* residues of the Lippard bp step (independent of X pucker) and the repositioning of the X residue base caused by the change from S-pucker to N-pucker together lead to the unusual features of the Lippard bp step in the duplex.

2.4-Å Crystal Structure of the Asymmetric Platinum Complex {Pt(ammine)(cyclohexylamine)}2+ Bound to a Dodecamer DNA Duplex

“…The very small differences observed in the G6-G7 base pair step geometry for the cisplatin-, oxaliplatin-, and {Pt(NH 3 )(NH 2 Cy)} 2ϩ -DNA structures may signal a common geometric feature that modulates their recognition by minor groove binding proteins. These results also support the hypothesis that the flanking sequence dependence of proteins binding to platinum-DNA adducts is most likely an inherent property of sequence-dependent protein-DNA contacts, not differential distortion around the platination site (16,36).…”

DNA fragment conformations in adducts with Kiteplatin

“…This 5′-substituent effect favouring the HH1 conformer is well documented. 46,47,61 This finding is further evidence that (cis-1,4-DACH)-Pt(d(TGGT)) is representative of many d(TGGT) adducts with several other carrier ligands used in retro-modelling studies. Although as extensive a study of temperature effects was not conducted for the d(TGGT) adduct derived from cisplatin, this latter adduct has H8 signals at 9.04 ppm (3′-G) and 8.25 ppm (5′-G) at 22°C and a 31 P NMR signal at −3.02 ppm at 15°C.…”

Hydration process as an activation of trans‐ and cisplatin complexes in anticancer treatment. DFT and ab initio computational study of thermodynamic and kinetic parameters

“…[12][13][14][15][16][17][18] As to experimental works, the thermodynamic data for replacement of chloride ligand by water molecules were measured by Hindmarch et al 19 for both hydration steps:…”