Mutagenicity of Polycyclic Aromatic Hydrocarbons and Amines: A Conformational Hypothesis a

Polycyclic aromatic hydrocarbons and amines are chemical carcinogens that are widespread in the environment. It is believed that they initiate cancer after metabolic activation by linking covalently to DNA. This may cause a conformational distortion of the genetic material. If the lesion is not repaired in time, a mutation that can ultimately cause cell transformation may occur during replication. Whether or not the adduct is, in fact, repaired depends on whether the damage is recognized by the appropriate enzymes. This recognition is likely to be determined by the adduct conformation. However, detailed atomic resolution data on carcinogen-DNA adduct conformations are virtually nonexistent because of the difficulty associated with synthesizing and crystallizing these substances. Consequently, we perform minimized semiempirical potential energy calculations for model carcinogen-DNA adduct systems, which yield molecular views. Computational methods that have been described in detail previously are employed.’ We have studied’.’ two adducts that have been identified as mutagenic lesions4? 2-aminofluorene (AF) linked to guanine (2-8. and the (+) anti-benzo [a] pyrene diol epoxide (BP) adduct to guanine N’. The deoxydinucleoside monophosphate dCpdG is used as a model for DNA. Such dimeric subunits are suitable models for the larger polymer because they are the conformational building blocks. Two interesting low-energy conformations were computed that are common to both adducts (FIGURES 1 and 2). One form places the carcinogen at the exterior of a normal A or B helix, in a groove. In the second form the covalently bound carcinogen is stacked with an adjacent base. The energies of the two states differ by less than three kcal/mole. Furthermore, the conformational alterations to the DNA needed to go from one state to the other are small, with each rotation remaining near the domain preferred in B DNA in both conformers. In addition, model building shows that the interconversion is, in fact, facile, indicating a reasonable activation barrier. We suggest that both states might occur in vivo. Neither conformation causes severe kinking or denaturation of the DNA duplex. Consequently, the repair enzymes