Since its discovery some 40 years ago, cisplatin has evolved for its efficacy in one of the most used drugs in treatment of various cancer types. Huge effort was invested in understanding the action of cisplatin and development of more potent platinum, osmium, and ruthenium based drugs. These potential drugs target mainly neighboring purine bases of nuclear DNA forming covalent intra- or inter-strand cross-links that affect inhibition of replication and transcription, cell cycle arrest, and attempted repair of the damaged nucleotides. If such damage cannot be removed the cell dies [1].
Several structures determined by NMR or X-ray crystallography are now available in the PDB database containing 1,2d(GpG) cisplatin or oxaliplatin (e.g. 1AIO, 3LPV, 1A84). Common structural features of all these structures are: a significant roll (25-60°) of the guanine bases involved in the cross-link, bending and unwinding of the double helix at the site of cross-link and orientation towards the major groove. Also, the platinum-guanine plane angle varies between 19-54°. Although the experimental structures were often used as the starting models for molecular dynamics (MD) simulations [2,3], results of these MD still leave many questions unresolved. In our contribution, we will present an NMR study of a DNA cross-linked with a new highly potent cisplatin-based derivative. Details of the binding site have been cross-examined using complementary solution techniques used in modern structural biology, including Raman spectroscopy with DFT calculations aided interpretation of the obtained vibrational spectra. Moreover, the calculated structure of the DNA duplex was verified using SAXS (Small Angle X-ray Scattering) curve, that has been measured on an in-house bioSAXS.