Comparative computational investigation of the reaction mechanism for the hydrolytic deamination of cytosine, cytosine butane dimer and 5,6-saturated cytosine analogues

Abstract

A detailed computational investigation of the mechanism for the hydrolytic deamination of cytosine, its cyclobutane cytosine dimer CC, and other 5,6-saturated cytosine analogues was undertaken. The rationale behind this work was twofold: to clearly establish the mechanism for the hydrolytic deamination of cytosine and cytosine analogues by comparing calculated and experimentally known activation energies and secondly, to provide a logical basis for the much lower activation energy barriers for 5,6-saturated cytosine analogues versus cytosine monomer.Energies for all relevant species including intermediates and transition states for all pathways studied were determined using B3LYP/6-31G(d,p), B3LYP/6-31+G(d,p) and G3MP2B3 levels of theory and solvent calculations were performed using both the polarizable continuum model (PCM) and the solvation model on density (SMD). Activation energies, Gibbs energies of activation, ΔH of reaction and ΔG of reaction were calculated for each pathway investigated. Deformation energies as well as the total interaction energy of reactant species were determined for the formation of the key transition state (TS2) which decomposes to form a tetrahedral intermediate in all pathways studied.The overall gas phase activation energies found for the deamination of cytosine and dicytosine with three explicit water molecules are in good agreement with the experimental values found in the literature. Such good agreement between calculated and experimental results is very strong evidence that the mechanism for the hydrolytic deamination has been correctly determined. Reduced deformation energy required to form the key transition state TS2 for the C5–C6 saturated cytosine analogues has been found to be the main reason for the significantly lower activation energies for their hydrolytic deamination.