Almatarneh, Mansour Hussein (2007) Computational study of the deamination reaction of cytosine. Doctoral (PhD) thesis, Memorial University of Newfoundland.
- Accepted Version
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The decomposition reaction of formamidine yielding hydrogen cyanide and ammonia has been studied first as a simple model for the intramolecular and intermolecular hydrogen rearrangement of cytosine. The gas phase decomposition of formamidine predicted a high activation energy of 259 kJ mol⁻¹ at the G3 level of theory. Adding one and two water molecules catalysed the reaction by forming a cyclic hydrogen bonded transition state, reducing the barrier to 169 and 151 kJ mol⁻¹ at the G3 level, respectively. The PCM solvent model predicts a significant lowering of the free energy of activation. -- The mechanism for the deamination reaction of cytosine with H₂O, OH-, and H₂O/OH- to produce uracil was investigated using ab initio (HF and MP2) levels and B3LYP DFT calculations. All pathways in the cytosine deamination produce an initial tetrahedral intermediate followed by several conformational changes. The final intermediate for all pathways dissociates to products via a 1 - 3 proton shift. Two pathways for the deamination reaction of cytosine with H₂O and OH- were found. The activation energy for the rate determining steps of deamination of cytosine with H₂O for pathways A and Bare 221 and 260 kJ mol⁻¹ at the G3MP2 level of theory, respectively. The deamination of cytosine with H₂O by either pathway is therefore unlikely because of the high barriers involved. Deamination with OH⁻ through pathway C resulted in the lowest activation energy, 203 kJ mol⁻¹ at the G3MP2 level of theory. -- The deamination with H₂O/OH- and 2H₂O/OH- in which the water molecules acted as a solvent and a catalyst was also investigated. Seven pathways for the deamination reaction for these systems were found. We found that the barrier for the water-mediated 1-3 proton shift is reduced by 46 kJ mol⁻¹ at the G3MP2 level of theory. We also found that the addition of the second water molecule reduces the barriers for both rate-determining steps by 31 kJ mol⁻¹. The activation energy for the rate-determining step, the formation of tetrahedral intermediate for pathway D is 115 kJ mol⁻¹ at the G3MP2 level of theory, in excellent agreement with the experimental value. This work shows, for the first time, a plausible mechanism for the deamination of cytosine and accounts for the observed experimental activation energy (117 ± 4 kJ mol⁻¹)
|Item Type:||Thesis (Doctoral (PhD))|
|Additional Information:||Includes bibliographical references.|
|Department(s):||Science, Faculty of > Chemistry|
|Library of Congress Subject Heading:||Deamination--Computer simulation; Deamination; DNA damage--Data processing; DNA damage.|
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