The lecture focuses on food safety in the context of chemical carcinogens, which are often present in raw or thermally processed foods and, after initial activation, alkylate DNA, usually guanine at position N7. Recently, important biochemical phenomena have been discovered, such as DNA catalysis of genetic damage, biomolecular cooperativity, in-vivo persistence of DNA adducts and the mutational propensity of DNA polymerases, which still lack an adequate mechanistic explanation. To elucidate their molecular basis, we used a range of state-of-the-art computer simulation techniques in conjunction with free energy calculations and the corresponding thermodynamic cycles. Since microwaves have been shown to catalyze numerous chemical reactions, we are concerned about the possibility of increased reactivity of chemical carcinogens, which also offers an explanation for why microwaves were recently classified as potentially carcinogenic by the World Health Organization. Therefore, we considered the reactions between chemical carcinogens and DNA in the context of our recently proposed physical mechanism of microwave catalysis, based on rotationally excited polar reaction species. Moreover, microwave irradiation has been shown to accelerate peptide misfolding and aggregation, processes that are generally associated with the occurrence of certain cancer types, e.g. amyloidosis. The microwave-irradiated solution thus through rotationally excited water molecules presents a less polar and less protic medium, thereby accelerating the harmful misfolding of peptides and their aggregation. We tested this hypothesis using molecular dynamics simulations in combination with a dedicated integrator, which is capable of efficiently decoupling individual degrees of freedom of water molecules and connecting them with the corresponding thermostats. Furthermore, we have used quantum chemical approaches to study the reactions between chemical carcinogens and polyphenols, secondary metabolites from fruits and vegetables. As a general rule for preventing DNA damage, a chemical carcinogen should react faster with a polyphenol scavenger than with DNA. Since the activation free energy represents a direct measure of reactivity, the reaction of a chemical carcinogen with a scavenger should have a lower activation barrier than the competitive alkylation of DNA. The long-term goal is to discover natural compounds or their mixtures with high antigenotoxic activities that could, after optimization, serve as functional dietary supplements and thus significantly contribute to cancer prevention.
https://indico.ijs.si/event/3605/