Model transition states for methane diazonium ion methylation of guanine runs in oligomeric DNA.
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.
Ekanayake
Kaushalya S
KS
Department of Chemistry, University of Illinois, Chicago, Illinois 60607-7061, USA.
Lebreton
Pierre R
PR
D004247:DNA / Q000737:chemistry*; D003979:Diazonium Compounds / Q000737:chemistry*; D006147:Guanine / Q000737:chemistry*; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry; D008745:Methylation; D008958:Models, Molecular; D009154:Mutation; D011789:Quantum Theory; D013816:Thermodynamics
D003979:Diazonium Compounds; D006147:Guanine; D004247:DNA; D008697:Methane