Molecular docking algorithms are computational methods that predict the binding site and docking pose of specified ligands with a protein target. They have proliferated in recent years, due to the explosion of structural data in biology. Oxdock is an algorithm that uses various techniques to simplify this complex task, the most significant being the use of a multiscale approach to analyse the problem using a simple representation in the early stages. Oxdock is shown to be a very useful tool in computational biology, as exemplified by two cases. The first case is the analysis of the NMDA subclass of neuronal glutamate receptors and the subsequent elucidation of their function. The second is the investigation of the newly discovered plant glutamate receptors and the clarification of their natural ligands. The results in both instances open new areas of research into exciting areas of biology. Despite its effectiveness in solving many problems, Oxdock does fail in a number of circumstances. It is thus important to devise a new and improved method for molecular docking. This is achieved by combining the speed of the multiscale approach with the optimising ability of Evolutionary Programming. This yields an algorithm that is shown to be precise, accurate and specific. The new algorithm, Eve, is then modified to illustrate its potential in both lead optimisation and de novo drug design. These capacities, combined with its ability to predict the location of binding sites and the docking pose of a ligand, highlight the promise of computational methods in solving problems in many areas of biological chemistry.

Isopenicillin N synthase (IPNS) is a non-haem iron dependent dioxygenase which catalyses the oxidative conversion of anddelta;-(L-andalpha;-aminoadipoyl)-L-cysteinyl-D-valine (ACV) to isopenicillin N (IPN). Sequence comparisons between IPNS isozymes reveal the complete conservation of two histidine (His214, His270), one aspartate (Asp216) [also known as the '2-His-l-carboxylate' motif] and one glutamine (Gln330) residue. The crystal structure of IPNS (Aspergillus nidulans) active site (in the absence of ACV) revealed an octahedrally coordinated manganese atom surrounded by these four protein ligands and two water molecules. The role of the four conserved metal binding ligands was investigated using site directed mutagenesis. The results demonstrated that ligation of the iron with Gln330 was not essential for the catalytic activity of IPNS. In contrast, ligation of the iron with the three remaining metal ligands was indispensable for catalytic activity. Additionally, it was demonstrated that the conserved Asp216 residue may be substituted by a glutamate residue (D216E) with significant retention of catalytic activity. Crystallographic and spectroscopic evidence suggested that the D216E mutant bound both iron and ACV in a similar way to wild-type IPNS. The inactivation of wild-type IPNS was examined under in vitro assay conditions. This study showed that inactivation of IPNS results (minimally) from a slow non-oxidative pathway (in buffer alone) and a fast oxidative pathway via Udenfriend's chemistry (ferrous iron, ascorbate, and oxygen). The oxidative inactivation pathway was substantially reduced by the inclusion of catalase in the assay mixture, thus indicating that oxidative IPNS inactivation results (in part) from the generation of hydrogen peroxide in solution. Inactivation was also accompanied by a slow fragmentation of intact IPNS into (at least) five oligopeptides (observed by sodium dodecyl sulphate polyacrylamide gel electrophoresis). N-Terminal sequencing analyses confirmed that the fragmentation resulted from at least two cleavage sites within the active site (between Asp216-Val217 and Val272-Lys273).

This thesis contains the synthesis of a series of novelligands that include the enantiomerically pure 2-oxazoline moiety. The thesis also considers the application of new nucleophiles for the palladium catalysed allylic substitution reaction. The synthesis of enantiomerically enriched analogues of y-amino butyric acid (GABA) is presented. The first series of ligands are designed as analogues of acetyl acetonate (acac). The ligands include the enantiomerically pure 2-oxazoline ring and a carbonyl moiety. The ligands are available in good yield in two steps. The second series of ligands include a ligating sulfur atom. The synthesis of novel oxazoline-sulfide ligands is detailed. The diastereoselective oxidation of these ligands is considered. Diastereomerically pure oxazoline-sulfoxide ligands are prepared in good yield. New nucleophiles are applied to the palladium catalysed allylic substitution reaction. The substitution products are available in good yield and with excellent stereoselectivity. The synthesis of analogues of GABA is considered. The preparation of enantiomerically enriched a-substituted-y-amino butyric acids is presented. The stereocentre is introduced in the first step of the synthesis. The analogues are subsequently isolated in good yield after six steps.

This thesis reports the spectroscopic and computational studies of a number of Cu(I), Re(I) and Ru(II) complexes of polypyridyl ligands. The ligands considered in this study were 1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline, dibenzo[b,j][1,10]phenanthroline, dipyrido[2,3-a:3�,2�-c]phenazine, dipyrido[2,3-a:3�,2�-c]-6,7-dichlorophenazine and dipyrido[2,3-a:3�,2�-c]-6,7-dimethylphenazine. Density functional theory calculations were carried out on the polypyridyl ligands. Validation of the calculations was carried out by comparison of the predicted values to observables. The structures were compared to previously published X-ray crystal data. Calculated bond lengths were typically calculated to be within 0.02 Å of those in the crystal structure. The calculated vibrational spectra were compared to measured IR and Raman spectra. The correspondence between calculated and measured frequencies was quantified using the mean absolute deviation between the two sets of frequencies. This was typically found to be less than 10 cm⁻�. The robustness of the calculation was further tested by calculations on perdeuterated analogues of some of the ligands. The calculations were extended to metal moieties and validated as for the ligands. Resonance Raman and infrared spectra of the reduced states of some Re(I) complexes are reported. The structure and spectra have been modelled by considering the radical anion of the polypyridyl ligand and the reduced state of the complex. There is improvement in the mean absolute deviation, between calculated and observed frequencies, upon incorporation of the metal moiety into the calculation. Spectra are successfully modelled confirming the validity of the modelled structures. The resonance Raman and infrared spectra of the metal-to-ligand charge transfer excited states of some Cu(I), Re(I) and Ru(II) complexes are reported. Density functional theory calculations on the lowest energy triplet states aided in the spectral assignment of bands. Cu(I) complexes were successfully modelled with mean absolute deviations, between calculated and observed frequencies, of less than 10 cm⁻�. The spectra of the Re(I) and Ru(II) complexes were less successfully modelled. Incorporation of the Ru(II) centre into the calculation of the vibrational frequencies of dipyrido[2,3-a:3�,2�-c]phenazine complexes offers no improvement over modelling the radical anion of this polypyridyl ligand. The excited state lifetimes of a number of polypyridyl complexes have been reported. The changes in lifetimes of similar complexes were found to be consistent with the energy gap law or changes in the conjugation of the involved polypyridyl ligand. This project has allowed the excited state structures of a number of polypyridyl complexes to be determined using vibrational spectroscopy to validate density functional theory calculations. This has provided a study strategy that may be applied to other metal polypyridyl complexes.

Typescript (photocopy) / x, 110 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physical and Inorganic Chemistry, 1983

Thesis (M.S.)--Rochester Institute of Technology. / Includes bibliographical references (leaf 131).

Thesis (Ph. D.)--University of Texas at Austin, 2007. / Vita. Includes bibliographical references.

Thesis (M.S.)--Wake Forest University. Dept. of Chemistry, 2007. / Vita. Includes bibliographical references.

Thesis (Ph. D.)--University of Adelaide, Dept. of Physical and Inorganic Chemistry, 1986. / Includes bibliographical references.

Thesis (Ph. D.)--University of Hong Kong, 2007.