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Molecular mechanics explanation for the stereochemical and shape selectivity of B-DNA for "bay-region" carcinogens
L Von Szentpaly1, I L Shamovsky
1Chemistry Department, University of the West Indies, St. Andrew, Kingston 7, Jamaica.
Abstract:
The equilibrium structures of 20 intercalated physical complexes of "bay-region" triol carbocations of polycyclic aromatic hydrocarbons (PAHs) with B-DNA are obtained by AMBER molecular modeling. The complexes with highly potent carcinogens are found (i) to undergo only minor conformational changes upon complexation, (ii) to be stabilized by hydrogen bonds between two hydroxyl groups of the triol carbocations and N3 atoms of the adjacent guanine residues, and (iii) to be "preorganized" for covalent bonding. A new explanation for the absolute stereochemical and shape dependence of carcinogenesis by PAHs is presented. The biologically active conformers of both carcinogenic stereoisomers (anti and syn) of triol carbocations are characterized by a quasi-diaxial orientation of the neighboring hydroxyl groups and fulfill the spatial requirements for hydrogen bonding to the adjacent guanine residues of B-DNA. The striking dependence of potency on the shape of the PAHs is largely caused by repulsion from the C2'-methylene groups of the deoxyribose residues of DNA. This interaction may shift the intercalated triol carbocation, thereby enhancing or reducing the preorganization for covalent bonding. The molecular modeling study is augmented by benchmark ab initio calculations on the bay-region triol carbocation of phenanthrene.
Insights
Polycyclic aromatic hydrocarbons (PAHs) form complexes with DNA, influencing carcinogenicity. Molecular modeling reveals these complexes are preorganized for bonding, explaining shape-dependent cancer risks.
Area of Science:
- Computational chemistry
- Molecular modeling
- Biochemistry
Background:
- Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants and potent carcinogens.
- The "bay-region" triol carbocation is a key intermediate in PAH-induced DNA damage.
- Understanding the interaction between PAHs and DNA is crucial for explaining carcinogenesis.
Purpose of the Study:
- To elucidate the equilibrium structures of intercalated PAH triol carbocation-B-DNA complexes.
- To explain the stereochemical and shape dependence of PAH carcinogenesis.
- To present a new model for PAH-DNA interactions and their role in cancer.
Main Methods:
- AMBER molecular modeling was used to simulate 20 intercalated complexes.
- Ab initio calculations were performed on the phenanthrene bay-region triol carbocation.
- Analysis of hydrogen bonding, conformational changes, and steric interactions was conducted.
Main Results:
- Complexes with potent carcinogens showed minor conformational changes upon intercalation.
- Hydrogen bonds between hydroxyl groups and guanine N3 atoms stabilized the complexes.
- Biologically active conformers exhibited quasi-diaxial hydroxyl groups, facilitating DNA binding.
- Repulsion from deoxyribose C2'-methylene groups influenced PAH shape-dependent potency.
Conclusions:
- PAH triol carbocation-DNA complexes are preorganized for covalent bonding.
- The study provides a new mechanistic explanation for the stereochemical and shape dependence of PAH carcinogenesis.
- Steric interactions with DNA significantly modulate the carcinogenic potential of PAHs.