A computational investigation of selective DNA methylation

Methane diazonium ion methylation at nucleophilic sites of the free DNA bases and at N7 and O6 of guanines in nucleotides containing guanine runs have been examined. Relative reactivities at different DNA sites were calculated from quantum mechanical self-consistent field and density functional descriptions of reaction transition states. Methane diazonium ions are the reactive intermediates formed from several carcinogenic methylating agents. For some alkylating agents, DNA reaction patterns correlate with mutation patterns measured in human tumors.; The results from an investigation of ten DNA base reactions in the gas phase and in a reaction field that models an aqueous environment indicate that oxygen center reactions have transition states that are tighter, and occur later along the reaction pathways than nitrogen center reactions. Activation barriers of these reactions are greatly influenced by solvation. In order to calculate accurate descriptions of the relative reactivities of different DNA base sites, it is necessary to consider interactions between the base-methane diazonium ion reaction system and discrete water molecules. When explicit water molecules are incorporated into the reaction field, a comparison of the relative barrier heights for reactions at ten base sites yields results that are consistent with the experimentally observed relative reactivities.; An investigation of the sequence specific reaction patterns of the methane diazonium ions at N7 and O6 sites of guanines in double-stranded nucleotides containing two, three, or four stacked guanines and counterions show that for both N7 and O6 reactions, the calculated reactivity of the guanine at the 3'-end is greater than that at the 5'-end. Furthermore, calculated reactivities of the interior guanines are higher than those at the ends. The calculated reaction patterns agree with most available experimental data.; Gas-phase interaction energy decomposition analysis on a double-stranded dinucleotide containing two GC base pairs and counterions shows that for both N7 and O6 reactions, the electrostatic interaction makes the largest contribution to the selectivity at the 3'-guanine. The present results also provide evidence that in aqueous solution orbital interactions are likely to strongly influence guanine N7 selectivity in DNA regions containing stacked guanines.