Modeling intercalated PAH metabolites: Explanation for the bay region methyl effect

Equilibrium structures of intercalation complexes of different metabolites of polycyclic aromatic hydrocarbons—triol carbocations and diol epoxides—with the dG2 · dC2 dinucleotide are obtained by the AMBER and FLEX empirical force field calculations. Triol carbocations derived from benzo[a]pyrene (BaP) and, especially, 7,12‐dimethylbenz[a] anthracene (DMBA) are stereochemically compatible with the dinucleotide and B‐DNA. The compatibility is caused by two hydrogen bonds between the quasiaxial hydroxyl groups of triol carbocation and the N(3) atoms of successive guanine residues of the DNA fragment, and a van der Waals contact between the C(12) bay region methyl group and methylene group of the deoxyribose residue of the CC strand. This in turn results in better stacking of the reactive centers and, hence, a “preorganization” of the physical complex to subsequent covalent bonding. A substantial out‐of‐plane deformation of the triol carbocations induced by the bay region methyl group plays an important role in the stereochemical compatibility, and explains the high carcinogenicity of the syn diastereoisomeric form of DMBA metabolites. Specific structural features of the physical complexes “preorganized” for covalent bonding are described. © 1995 John Wiley & Sons, Inc.