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Molecular mechanics simulations on covalent complexes between polycyclic carcinogens and B-DNA
S N Rao1, T Lybrand, D Michaud
1Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.
Carcinogenesis
|January 1, 1989
Summary
Molecular mechanics simulations reveal how carcinogen diol-epoxides bind to DNA. The (+)trans isomer of benzo[a]pyrene is the most stable DNA adduct, aligning with experimental data.
Area of Science:
- Chemical carcinogenesis
- Molecular modeling
- DNA adducts
Background:
- Polycyclic aromatic hydrocarbons (PAHs) are environmental carcinogens.
- Metabolic activation of PAHs forms diol-epoxides, which are reactive intermediates.
- These intermediates can covalently bind to DNA, forming adducts that lead to mutations.
Purpose of the Study:
- To investigate the molecular mechanisms of DNA adduct formation by diol-epoxides of benzo[a]pyrene, benzo[e]pyrene, and benzo[c]phenanthrene.
- To compare the binding preferences and energetic favorability of different carcinogen-DNA adducts.
- To correlate theoretical findings with experimental observations on carcinogen reactivity and biological activity.
Main Methods:
- Molecular mechanics simulations were employed to model covalent complexes.
- Simulations focused on the interaction between carcinogen diol-epoxides and a DNA pentamer (d(GCGCG).d(CGCGC)).
- Analysis of adduct structures, binding sites (minor groove), and alkylation targets (guanine exocyclic amino group) was performed.
Main Results:
- All modeled carcinogen diol-epoxides bind to the minor groove of DNA, alkylating guanine.
- For benzo[a]pyrene, the (+)trans isomer adduct is energetically most favored, consistent with experimental reactivity.
- Benzo[e]pyrene adducts show similar energetic preferences to benzo[a]pyrene, but theoretical calculations do not explain its lack of biological activity.
- Benzo[c]phenanthrene adducts show energetically favored structures with significant biological activity, inducing greater DNA helix distortions.
Conclusions:
- Molecular mechanics simulations provide insights into the structural and energetic aspects of carcinogen-DNA adducts.
- The study highlights the importance of stereochemistry in determining the stability and potential carcinogenicity of PAH-DNA adducts.
- Discrepancies between theoretical and experimental findings for benzo[e]pyrene warrant further investigation into its biological activity.