Computational analysis of the effects of site‐specific phosphate alkylation in the DNA oligomer {d‐[GGAATTCC]}₂

Alkylation of the sugar–phosphate backbone of DNA can result upon exposure to several potent carcinogens, inducing DNA misfunction. In order to assess the structural and energetic changes in DNA helices induced by such alkylation, we have performed AMBER‐based analyses on phosphotriester containing analogues of {d‐[GGAATTCC]}₂. Fourteen analogues of the nonalkylated oligomer were examined, each bearing a single alkylation of known stereochemistry. Results indicate that although there is minimal effect on the aromatic bases, the presence of a phosphotriester disturbs the sugar–phosphate backbone in complex ways. For most analogues, total minimum energies are lower for the S_p‐alkylations than for the R_p‐alkylations which point directly into the major groove of the helix; however, different energetic contributions follow different, or no, trends in dependence on alkylation site and/or stereochemistry. Where data is available, experimental nmr results agree with the calculations reported here.