Density functional theory (DFT) and combined quantum mechanics/molecular mechanics (QM/MM) calculations have been used to model inter- and intra-molecular non-covalent interactions of transition metal complexes and where applicable their interactions with DNA. Two DFT functionals, BHandH and B97-D, which have shown to be efficient in modelling systems containing non-covalent interactions, have been tested against high level ab initio calculations on test transition metal complexes, designed to represent the intermolecular interactions present in the benzene dimer and methane benzene systems. The DFT functionals above show good agreement with the benchmark calculations and have been used to study ruthenium arene 'piano stool' type complexes, of the general form [h6(arene)Ru(en)Cl]+, which have shown potential as anticancer agents. The intramolecular interactions of these ruthenium complexes through coordination to guanine and adenine through the N7 nitrogen, has been explored using a selection of pure DFT, hybrid DFT, and post Hartree-Fock approaches against benchmark correlated wavefunction methods, where the best methods were found to be BHandH, B97-D2, and MP2(0.25). The B97-D2 functional was used to model these ruthenium complexes, with a selection of extended aromatic ligands with potential to act as intercalators, interacting with base pair steps. Calculated binding energies show a sensitivity to the nature of the arenes, where the more flexible ligands form more non-covalent interactions with DNA, as demonstrated by QTAIM analysis. Conformations and binding energies of a relatively new platinum anticancer drug, kiteplatin, with small single strand fragments of DNA, have been studied using B97-D and semi-empirical methods and compared to established drugs cisplatin and oxaliplatin. Isotropic shielding values and J coupling constants have also been calculated for these systems to relate these values to conformational data. Extended dual strand kiteplatin-DNA adducts have been studied using the QM/MM method ONIOM, combining BHandH with AMBER, to calculate binding energies and optimised structures. These results show that as the DNA adduct increases in size the values of the kiteplatin energies start to converge and comparison of base pair parameters show that around the site of coordination all fragments show comparable geometrical distortions.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:571730 |
| Date | January 2013 |
| Creators | Mutter, Shaun Thomas |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/46973/ |
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