3. Electronic Theses and Dissertations (ETDs) - All submissions
Permanent URI for this communityhttps://wiredspace.wits.ac.za/handle/10539/45
Browse
2 results
Search Results
Item A molecular mechanics study for selective complexation of metal ions in medical applications(1994) Chantson, Tracy, ElizabethMolecular mechanics calculations are used to interpret and predict metal ion discrimination by coordinating ligands. Of particular interest are chelates exhibiting characteristics that Single them out for potential medical application; Selectivity patterns for several series of ligands are investigated with the help of strain energy profiles as a function of metal-donor atom bond distance. Ligands include simple; open-chain oxygen- and nitrogen-donors ana triaza- and tetraazamacrocyeles. Results are compared with X-ray crystallographic and solution data. Factors such as chelate ring size, conformational flexibility and preferred metal coordination geometry are found to influence metal specificity. Addition of pendent donor groups to macrocyoles leads to rigid structures and selectivity predictions according to cavity size. Interpretation of specific. metal ion recognition by polyetner antibiotics is attempted. Structural and steric factors are probed as possible determinants of metal choice. both covalent and ionic bonding models are explored. The covalent approach results in predictions of metal selectivity which correlate with mown selectivity patterns. Unfortunately, inability to optimise force field parameters in the ionic bonding approach forced us to abandon this model. The main force field used is the TRIPOS (1992,1993) force field. It performs well in calculations involving a univariate scanning technique but has to be modified to obtain reasonable structure reproduction with the large antibiotics, Errors in thermodynamic data predictions are obtained, nonbonding parameters have yet to be properly parameterized and the allocation of partial atomic charges warrants closer examination . All of these factors contribute to the poor performance of the force field when ionic interactions between metal and donor atoms of the polyethers are assumed.Item A conformational analysis of signal peptides(1998) Chantson, Tracy, ElizabethConformational analysis of portions of functionally-active and functionally-inactive signal peptides (incorporating the wild-type and mutants thereof) has been performed using a variety of computational prediction techniques based on both statistics and molecular mechanics. Molecular mechanics conformational studies are generally plagued by the problem of combinatorial explosion; this problem was addressed with a systematic searching procedure as well as a recently developed genetic algorithm, both utilising tile ECEPP/3 force field. The genetic algorithm, in combination with a gradient minimiser, proved to be successful in finding low-energy conformations for each peptide sequence studied. Analysis was performed in both simulated hydrophobic and hydrophilic environments, under distance-constraints. The molecular mechanics results and statistical predictions generated from the study were compared With existing experimental observations. The reliability of statistical predictions proved to be dependent on prediction method; the more consistent predictions were produced by methods based on membrane proteins, as opposed to those based on globular proteins. The physical property of hydrophobicity of signal peptide sequences, explored in these statistical predictions, was determined to be an important factor in relating sequence to functional activity. Molecular mechanics calculations produced either interrupted or non interrupted a-helical secondary structures both for functionally-efficient and for functionally-inefficient signal peptides, indicating that cc-helixformation alone cannot be correlated with protein export competence. It was concluded from our overall results that both a-helicity and hydrophobicity are required for the efficient functioning of signal peptides.