Quantum chemical studies of metal-DNA interactions

A series of density functional theory (DFT) and quantum mechanics/molecular mechanics (QM/MM) calculations are used to investigate the binding of platinum and ruthenium anticancer drugs to DNA. The qualitative and quantitative features of Becke's half-and-half (BHandH) functional for calculating geometries, binding energies and harmonic frequencies of non- covalently bound systems are tested and the intermolecular interactions are characterised and quantified using the QTAIM electron densities. Application of this DFT-QTAIM approach to complexes of the type (n6-arene)Ru(en)(nucleobase) 2+ shows a clear preference for binding at guanine over any other base both in gas phase and in aqueous solution, a trend explained on the basis of QTAIM and molecular orbital data. Key parameters of the QM/MM methodology within the ONIOM scheme and efficient geometry optimisation strategies are examined for applications involving DNA oligonucleotides. Calculations on cis- Pt(NH3)2 2+ (cisplatin) bound to d(CpCpTpGpGpTpCpC).(GpGpApCpCpApGpG) reveal that proper consideration of the electrostatics between the QM an MM regions can lead to acceptable geometries, especially when explicit solvent molecules are present. This approach is used to explore the effects of methyl substitution on the binding of a series of Pt(en)2+ (en: ethylenediamine) complexes to dinucleotides. Among the examined methyl derivatives, significant differences are observed for the variants whose en nitrogen atoms are multiply methylated. Binding energies are found to be in excellent correlation with in vitro cytotoxicity data expressed as -log(IC5o). The above mentioned cisplatin-oligonucleotide complex is compared against three clinically approved platinum drugs (carboplatin, heptaplatin and lobaplatin). Calculations on truncated models show a stronger binding for cisplatin among the four complexes and numerous intermolecular interactions are located via QTAIM analysis in the lobaplatin and heptaplatin complexes. Additionally, subtle differences in key geometrical parameters are observed among the complexes around the sites of platination, with the exception of unusually short interplanar base - base distances in the complexes of loba- and heptaplatin. Finally, the same QM/MM methodology is applied to oligonucleotide sequences of five base pairs that contain difluorotoluene or mismatched base pairs, which are shown to be too flexible to be optimised at reliable structures at the chosen level of truncation. Comparisons among obtained structures using different input parameters further validate the followed QM/MM approach