Methylation reactions of the DNA bases with the methane diazonium ion, which is the reactive intermediate formed from several carcinogenic methylating agents, were examined. The SN2 transition states of the methylation reactions at N7, N3, and O6 of guanine; N7, N3, and N1 of adenine; N3 and O2 of cytosine; and O2 and O4 of thymine were calculated using the B3LYP density functional method. Solvation effects were examined using the conductor-like polarizable continuum method and the combined discrete/SCRF method. The transition states for reactions at guanine N3, adenine N7, and adenine N1 are influenced by steric interactions between the methane diazonium ion and exocyclic amino groups. Both in the gas phase and in aqueous solution, the methylation reactions at N atoms have transition states that are looser, and generally occur earlier along the reaction pathways than reactions at O atoms. The forming bonds in the transition states in water are 0.03 to 0.13 A shorter than those observed in the gas phase, and the activation energies are 13 to 35 kcal/mol higher. The combined discrete/SCRF solvation energy calculations using base-water complexes with three water molecules yield base solvation energies that are larger than those obtained from the CPCM continuum method, especially for cytosine. Reactivities calculated using barriers obtained with the discrete/SCRF method are consistent with the experimentally observed high reactivity at N7 of guanine.

Electrostatic potentials and local ionization energies have been computedat the HF/6-31G * level on the molecular surfaces of the five nucleotide bases. The potentials are analyzed in terms of their most positive and negative values as well as several statistically defined quantities that reflect their patterns over the entire surface. Considerable charge separation and variability are found for all five molecules. The results are consistent with the base pairing that is known to occur. The observed reactive behavior toward electrophiles can be interpreted in terms of the complementary roles of the surface potential and the local electron lability. Local polarization energies, corresponding to a test charge being placed at specific points above the molecules, are also calculated (HF/6-31+G * ), and their relationship to the local ionization energies is examined.

The DNA reaction pattern of the methane diazonium ion, which is the reactive intermediate formed from several carcinogenic methylating agents, was examined at N7 and O(6) sites in guanine runs occurring in oligonucleotides and model oligonucleotides. Density functional B3LYP/6-31G*, and SCF 3-21G and STO-3G energies of model transition states were calculated in the gas phase and in the CPCM reaction field. For nucleotides containing two, three, and four stacked guanines with counterions in the gas phase, O(6) reactivity is greater than N7 reactivity. In the reaction field, N7 reactivity is 9.0 to 9.8 times greater than O(6) reactivity. For a double-stranded oligonucleotide containing two stacked guanines with counterions in the reaction field, the N7 and O(6) reactivities of the 3'-guanine are 3.9 times greater than the corresponding sites in the 5'-guanine. For double-stranded oligonucleotides with three or four stacked guanines and counterions, the reactivities of the interior guanines are higher than corresponding reactivities of guanines at the ends. These reaction patterns agree with most of the available experimental data. Activation energy decomposition analysis for gas-phase reactions in a double-stranded dinucleotide containing two stacked guanines with counterions indicates that selectivity at O(6) is almost entirely due to electrostatic forces. Selectivity at N7 also has a large electrostatic interaction. However, the orbital interaction also contributes significantly to the gas-phase selectivity, accounting for 32% of the total interaction energy difference between the 3'- and 5'-guanine reactions. In aqueous solution, the relative orbital contribution to N7 selectivity is likely to be larger.