Abstract
Radiation damage of biomolecules is a signicant contributor to both the onset and
also possible curing of cancer. Such damage is largely the result of free radicals
that can be created by the interaction of high-energetic photons or ions with water
within cells. Understanding the details of this interaction is therefore of vital
importance to the medical community, but even after decades of thorough investigation
the breakdown pattern of radiation damage has not yet been completely
deciphered.
This thesis represents a very comprehensive attempt at drawing conclusions
on the initial step in the reaction mechanism for the reaction between the OH
radical and the DNA/RNA nucleobases. These conclusions are not only based on
calculations of energies of the various intermediates as is the standard procedure in
many investigations, but instead they are supported by computational calculations
of rate constants based on transition state theory. The investigations are performed
with methods of increasing complexity ranging from pure gas-phase, through PCM
solvation up to the very accurate and explicit QM/MM models of nucleobase water
clusters through which also the importance of making conformational averages is
highlighted.
The results in the literature have up till now only supported a reaction mechanism
in which the OH radical adds onto the aromatic systems of the nucleobases,
and disregard any hydrogen abstraction pathway to be of little if any importance
for the overall reaction mechanism. Considering this there is much novelty in the
results drawn from the present study, as conclusions based also on the kinetics of
the system imply that the hydrogen abstraction pathways are of equal importance
for the possible reactions preceding the radiation damage.
The purine nucleobases are found to favour addition onto C8 in accordance
with the literature, and the calculated rate constants suggest that also abstraction
of amine hydrogens are important. For the pyrimidine nucleobases it is concluded
that only additions onto C5 and C6 are contributing factors to the overall reaction
mechanism as also shown in the previous literature, except for thymine for which
the kinetic evaluation shows that abstraction of the methyl hydrogens has by far the
largest reaction rate constant. It is furthermore shown by the QM/MM calculations
that the conformations of the water clusters have a very signicant in
uence on how energetically favourable a certain reaction pathway is through the size of the
reaction barriers and the reaction energies.
also possible curing of cancer. Such damage is largely the result of free radicals
that can be created by the interaction of high-energetic photons or ions with water
within cells. Understanding the details of this interaction is therefore of vital
importance to the medical community, but even after decades of thorough investigation
the breakdown pattern of radiation damage has not yet been completely
deciphered.
This thesis represents a very comprehensive attempt at drawing conclusions
on the initial step in the reaction mechanism for the reaction between the OH
radical and the DNA/RNA nucleobases. These conclusions are not only based on
calculations of energies of the various intermediates as is the standard procedure in
many investigations, but instead they are supported by computational calculations
of rate constants based on transition state theory. The investigations are performed
with methods of increasing complexity ranging from pure gas-phase, through PCM
solvation up to the very accurate and explicit QM/MM models of nucleobase water
clusters through which also the importance of making conformational averages is
highlighted.
The results in the literature have up till now only supported a reaction mechanism
in which the OH radical adds onto the aromatic systems of the nucleobases,
and disregard any hydrogen abstraction pathway to be of little if any importance
for the overall reaction mechanism. Considering this there is much novelty in the
results drawn from the present study, as conclusions based also on the kinetics of
the system imply that the hydrogen abstraction pathways are of equal importance
for the possible reactions preceding the radiation damage.
The purine nucleobases are found to favour addition onto C8 in accordance
with the literature, and the calculated rate constants suggest that also abstraction
of amine hydrogens are important. For the pyrimidine nucleobases it is concluded
that only additions onto C5 and C6 are contributing factors to the overall reaction
mechanism as also shown in the previous literature, except for thymine for which
the kinetic evaluation shows that abstraction of the methyl hydrogens has by far the
largest reaction rate constant. It is furthermore shown by the QM/MM calculations
that the conformations of the water clusters have a very signicant in
uence on how energetically favourable a certain reaction pathway is through the size of the
reaction barriers and the reaction energies.
| Originalsprog | Engelsk |
|---|
| Forlag | Department of Chemistry, Faculty of Science, University of Copenhagen |
|---|---|
| Status | Udgivet - 2016 |
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