Carcinogenesis induced by Aflatoxin B1: A computational study

The reported study represents a nice example of how state-of-the-art molecular modeling techniques can be used to study complicated macromolecular complexes, whose structures have not yet been experimentally determined, and to validate these against the available experimental data. The proposed structure will facilitate future studies on the rational design of successful Aflatoxin B1 (AFB1) modulators or on human subpopulations characterized by specific CYP3A4 polymorphisms that are especially sensitive to AFB1 - the most potent natural carcinogen known to men. We also report a series of ab initio and density functional theory simulations of guanine alkylation by aflatoxin B1 exo-8,9-epoxide and predict that the preference of aflatoxin B1 exo-8,9-epoxide over the endo stereoisomer for the reaction with guanine exists in the aqueous solution and is only further amplified in the DNA duplex. Finally, through comparison with an analogous reaction between 3a, 6a-dihydrofuro[2,3-b]furan exo-4, 5-epoxide and guanine, we show that the large planar body of aflatoxin B1 does not enhance its reactivity and related carcinogenicity. This explains why the planar region of related mycotoxins sterigmatocystin and aflatoxin G1 could have been evolutionarily optimized in a different way.