Molecular modelling has become widely used in chemistry and biology. The aim of this project is to use a range of molecular modelling techniques to study enzymic actions. This thesis consists of two parts.
Part A of this thesis describes computational studies conducted for the calpain-calpastatin system. Calpain is a cysteine protease. Over-expression of calpain is associated with many diseases. Calpastatin is the naturally occurring specific regulator of calpain activity. In this part of the thesis, the dynamic conformational preferences of region B of the inhibitory domain in calpastatin were examined in detail by using molecular dynamics simulations and stochastic dynamic simulations with Monte Carlo sampling.
Part B of the thesis explores the structure and function of the enzyme 3-dexoy-D-arabino-heptulosonate 7-phosphate synthase from Mycobacterium tuberculosis (MtuDAH7PS). MtuDAH7PS catalyses the first reaction of the shikimate pathway and is a target for the development of anti-tuberculosis drugs. MtuDAH7PS is found to be synergistically inhibited by combinations of aromatic amino acids (Trp+Phe or Trp+Tyr), but not by any single aromatic amino acids. In this part of the thesis, this unique
mechanism of allosteric regulation in MtuDAH7PS was investigated by using a range molecular modelling techniques. Firstly protein crystal structure refinements were conducted and those crystal structures of MtuDAH7PS in
complex with various ligand molecules are described in Chapter 4. Secondly, the reaction mechanism and roles of active site residues were investigated in Chapter 5, through docking calculations (both rigid docking and induced fit docking) of a series of designed active site inhibitors. Finally, Chapter 6 discusses the molecular basis of the communication mechanism of allosteric
regulation in MtuDAH7PS.
| Identifer | oai:union.ndltd.org:canterbury.ac.nz/oai:ir.canterbury.ac.nz:10092/6257 |
| Date | January 2011 |
| Creators | Jiao, Wanting |
| Publisher | University of Canterbury. Department of Chemistry |
| Source Sets | University of Canterbury |
| Language | English |
| Detected Language | English |
| Type | Electronic thesis or dissertation, Text |
| Rights | Copyright Wanting Jiao, http://library.canterbury.ac.nz/thesis/etheses_copyright.shtml |
| Relation | NZCU |
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