**8. Acknowledgements**

JWG, JL and EACB acknowledge the Natural Sciences and Engineering Research Council (NSERC, Canada) for funding and CGS & PGSD scholarships (EACB) and JL and LAE thank the Swedish Science Research Council (VR) for funding. LAE also acknowledges the National University of Ireland (Galway) for financial support. SHARCNET (Canada) and the National Supercomputing Centre (Linköping, Sweden) are acknowledged for additional computational resources.

#### **9. References**

Almatarneh, M. H., Flinn, C. G., Poirier, R. A., & Sokalski, W. A. (2006). "Computational study of the deamination reaction of cytosine with H2O and OH." *J. Phys. Chem. A*, 110(26), 8227-8234.

The final step in the demethylation of 3me4amPym+ is decomposition of the hydroxylated intermediate to give 4–amino pyrimidine, the model for the demethylated nucleobase, and formaldehyde (**Figure 9**). In this step an active site Glu136 residue acts as a general base and deprotonates the Ade–CH2OH hydroxyl with concomitant cleavage of the AdeN—CH2OH bond.(Liu et al. 2009) This reaction proceeds via **5TS3** at the modest cost of 10.3 kcal mol–1. It is noted that in **5TS3** the AdeN…CH2OH and Ade-CH2O—H bonds have lengthened to 1.58 and 1.22 Å, respectively, highlighting their concomitant cleavage. The product-bound complex **5PC** lies 45.1 kcal mol–1 lower in relative energy than the initial reactant complex **5IC1**. Thus, demethylation of 1-methyladenine is calculated to be a quite exothermic process.

In this chapter the application of density functional theory (DFT)-based methods to the

In particular, it was shown how they may be used to provide accurate detailed insights into the thermochemistry of fundamental chemical processes such as electron and proton transfers and thus, help to explain a number of experimental observations. Furthermore, through such studies they were able to show differences in the preferred oxidation pathways for the various DNA nucleobases. Similarly, by the careful examination of calculated hyperfine coupling constants, the nature *and* structure of radicals that may be formed upon exposure of DNA to radiation were deduced. Such an understanding also aids in determining the mechanism by which they may be formed. Finally, their versatility for the investigation of damage and repair mechanisms was highlighted. Indeed, by examining several pathways using seemingly quite simple chemical models, we have been able to deduce the preferred mechanism by which the deamination of cytosine radical may occur including (i) the preferred proton source(s), (ii) the order in which they are added to the leaving nitrogen centre, and (iii) the thermodynamically preferred products. Finally, similar methods in combination with much larger chemical models were used to also elucidate the oxidative dealkylation repair mechanism of AlkB. Together, these studies highlight the versatility and accuracy of DFT methods when used in combination with well-chosen

JWG, JL and EACB acknowledge the Natural Sciences and Engineering Research Council (NSERC, Canada) for funding and CGS & PGSD scholarships (EACB) and JL and LAE thank the Swedish Science Research Council (VR) for funding. LAE also acknowledges the National University of Ireland (Galway) for financial support. SHARCNET (Canada) and the National Supercomputing Centre (Linköping, Sweden) are acknowledged for additional

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**Part 4** 

**Insights into Therapeutic Strategies** 

