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Title: Computational modelling off the mechanisms of heme and non-heme enzymes and metathesis reactions
Author: Pandian, Shanthi
ISNI:       0000 0004 2669 7723
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2009
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Computational modelling has far exceeded the expectations of chemists in understanding many subtle factors that cannot be identified experimentally. The present study emphasizes the importance and the key role of computational methods in studying the mechanisms of enzyme catalysed and olefin metathesis reactions. The catalytic mechanism of a non-heme halogenase enzyme that uniquely performs substrate chlorination rather than the usual hydroxylation reaction as catalyzed by the other members of the same class of enzymes is solved. In contrast to the experimental findings of exclusive chlorination, density functional calculations on an isolated cluster model show that the hydroxylation reaction is favoured over substrate chlorination. The effect of external factors like the presence of crystallographic water molecules and amino acid residues (in the second coordination sphere of the active site) were evaluated in an attempt to account for the preference of chlorination by the enzyme. A proton shuttle mechanism is proposed that supports the fact that the amino acid residue responsible for the proton transfer is not conserved in the hydroxylases, which makes the halogenases able to perform the unique catalytic activity. Similarly, the catalytic mechanism of a heme dioxygenase- Indoleamine 2,3- dioxygenase enzyme is studied. Density functional methods have been used to study a prcviously proposed mechanism with further analysis of two other electrophilic addition pathways. The newly proposed mechanisms are found to be more feasible compared to that of the conccrted hydrogen transfer pathway proposed previously. Furthcrn10rc, the reaction mechanism of olefin metathesis reactions is evaluated for the fonnation of various cycloalkcncs catalyzcd by the Grubbs second-generation catalyst.Initially, the performance of certain functionals on the energetics of the smallest ring closing reaction is evaluated. The energy changes during cyclization are analyzed for each individual step on the potential energy surface as a function of ring size. Furthermore, the formation of E- and Z-oligomers is studied and the efficiency of cyclization of each ring is compared with the dimerization reaction, together with an estimate of the effective molarities (EM). Additionally, the effect of certain substituents on the reaction sequence leading to the formation of cyclooctene is studied. The presence of the gem-dimethyl group in addition to other substituents is shown to increase the rate of cyclization over its analogue that is devoid of the dimethyl moiety. Various dimerization reactions that differ by the position of the substituents are compared and the less energetic dimer formation is presented. Similar to the un substituted systems, the effective molarities are evaluated for these substituted systems and the values are shown to agree well with the experimentally measured EM values.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available