Conformational evaluation of DNA-carcinogen adducts using semi-empirical potential energy calculations
The covalent attachment of an aromatic amine to guanine C8 can produce a conformational change within the DNA molecule. This conformational change is likely to influence the altered DNA's biological capacity. The author used semi-empirical potential energy calculations to evaluate conformational patterns of DNA-aromatic amine adducts using the series: aniline, 4-aminobiphenyl, 2-aminofluorene and 1-aminopyrene. An exhaustive search was made of the conformational space for carcinogen modified two-base sequences. Information was incorporated into single stranded modified trimers. Modified strands were incorporated in duplex trimers. Nine-base modified duplexes were constructed and evaluated. This procedure produced distinctly different patterns for each aromatic amine investigated. It was apparent that the base sequence in which the carcinogen modification was found was crucial to the conformational change produced. At the dimer level, aniline allows both syn and anti guanine orientations at the carcinogen modification site. There were base-base and base-carcinogen stacked states, suggesting a flexible adduct easily able to assume many conformations. 4-Aminobiphenyl attachment resulted in low energy base-carcinogen stacked states, and a guanine torsion predominantly in a low syn orientation. The flexibility of this adduct was greatly reduced from that of the aniline adduct. 2-Aminofluorene adducts assumed more of a conformational mix. The major portion was base-base stacked with modified guanine anti, with a portion with base-carcinogen stacking and guanine syn or low syn. 1-Aminopyrene adducts were inflexible. The majority assumed a base-carcinogen stack with guanine syn. The conformational profiles of large modified pieces provided details of a unique low energy wedge conformation, in which aminofluorene, particularly, was able to fit into the minor groove with very little helix distortion.
- Research Organization:
- New York Univ., NY (United States)
- OSTI ID:
- 7272751
- Resource Relation:
- Other Information: Thesis (Ph.D.)
- Country of Publication:
- United States
- Language:
- English
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