Physical association modeling of DNA alkylation

The widespread occurrence of physical binding between biological macromolecules and small molecules has prompted us to hypothesize that physical binding contributes to DNA alkylation specificity. The preferred physical binding sites for a CH⁺₃-like test probe were predicted for several sequences of DNA using molecular mechanics free space calculation methods. Sequences containing $\text{A = T}$ basepairs direct physical binding to the minor groove, whereas sequences containing $\text{G ≡ C}$ basepairs direct physical binding to the major groove. Physical binding calculations were also performed for model ‘unwound’ DNA conformations. The results of the test probe studies were subsequently employed as starting points to predict the preferred physical binding sites for the more complicated case of an actual alkylating agent, the dimethylaziridinium ion. These studies demonstrate that physical binding specificity is highly dependent upon DNA sequence and conformation, and correlates well with the DNA alkylation site specificity observed for alkylating agents in the dimethylaziridine class.