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Quantum chemical studies of DNA and metal-DNA stuctures : H-bonding and P-stacking

Robertazzi, Arturo. 2006. Quantum chemical studies of DNA and metal-DNA stuctures : H-bonding and P-stacking. PhD Thesis, Cardiff University.

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Abstract

Metal complexes interact with many different sites of nucleic acids, stabilising the structure or, in some cases, leading to severe distortion or non-canonical forms of DNA such as triplexes, quadruplexes, junctions etc. Remarkably, several transition metals are considered potentially active anti-cancer drugs. Among these the most studied is certainly cis-diamminodichloroplatinum(II), or cisplatin, which after an activation process, attacks DNA in guanine-rich regions leading to strong distortion of DNA structure. Theoretical and experimental works suggest 7t-stacking disruption and GC pair distortion as the most relevant effects. In this work, ab initio and DFT calculations are extensively employed in order to explore the role of basic forces in DNA and metal-DNA adducts. To do so, Atoms in Molecules (AIM) theory has been used as a tool to decompose binding energies into contributions of covalent bond, H-bond and rc-stack energies, leading to a clearer picture of the studied systems. Firstly, DFT methods were employed to investigate the hydrolysis mechanism of cisplatin, a key step in the activation of the drug. Subsequently, an ADM based approach has been proposed to estimate H-bond energies in metal-DNA complexes. This allowed us to investigate the effect of platination on GC pair and, more generally, the role of H-bonding in such systems. A large study of transition metal- purine complexes, from Ti to Hg, has been discussed, providing a systematic analysis of the effect of metallation on the GC pair. As well as H-bonding, 7c-stacking plays a fundamental role in DNA and metal-DNA structures. In order to avoid use of expensive and, in certain cases, prohibitive methods such as MP2 and CCSD calculations, a new hybrid DFT functional, BHandH, has been applied to stacked model complexes (from benzene to DNA nucleobases). In addition, AIM analysis was shown to be useful tool in estimating it-stacking interactions in these systems. Thus, QM/MM calculations (QM = BHandH, MM = AMBER) were employed in order to investigate the role of H-bonding and -stacking in DNA and cisplatin-DNA adducts, the interplay between those being our main focus. One example of realistic platinated octamer was also studied with the BH&H/AMBER/AIM approach, leading to general agreement with experimental data.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Chemistry
Subjects: Q Science > QD Chemistry
ISBN: 9781303205118
Date of First Compliant Deposit: 30 March 2016
Last Modified: 10 Jan 2018 04:53
URI: http://orca.cardiff.ac.uk/id/eprint/56075

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