A model study of the enzyme-catalyzed cytosine methylation using ab initio quantum mechanical and density functional theory calculations: pKa of the cytosine N3 in the intermediates and transition states of the reaction

Ab initio quantum mechanical and density functional theory calculations, along with an isodensity surface-polarized continuum model, were used to examine cytosine methylation reaction. An approach for estimating the pKa of the cytosine N3 in the reaction intermediates and transition states and on the calculated reaction profiles is also introduced. According to pKa calculations, the pKa of N3 of the ring increases from five to 18 during the attack of methyl thiolate on C6 of the cytosine. This declines from 17 to five in the next reaction stage where C5 of the cytosine is methylated. Proton transfers in cytosine methylation are believed to occur between Glu119 of the active site and N3 of the cytosine.