Activation barriers for methylation of DNA bases by dimethyl sulfate

Highlights: • Methylation of DNA bases. • Density functional theory and SM8 universal solvation model. • Dimethyl sulfate and S_N2 mechanism. • Solvent effects and steric interference. • Activation energies and hydrogen bonding. The S_N2 transition states of the methylation reaction of DNA bases with dimethyl sulfate were examined employing DFT/ M06-2X/6-31+G^∗ and DFT/B3LYP-D3/6-311+G (2df, 2p) levels of theory. Solvation effects were examined using the conductor-like polarizable continuum model (CPCM). Calculation results and feedback from electrostatic potential maps show that in water, charge separation lowers the activation barriers relative to the gas phase for the reactions at N7 of guanine, N3 of adenine and cytosine. Also, the reaction at the O⁶ site of guanine is governed by steric interference and exhibits a higher activation barrier in water.