Kemijska karcinogeneza: mehanistični vpogled / Chemical Carcinogenesis: Mechanistic Insights

Chemical Carcinogenesis represents a complex multi-stage process that begins with the exposure to harmful chemicals and ends with the formation of neoplastic cells. The proposed research project will for the first time computationally address the entire process of early carcinogenesis. It will also include possible human interventions in the form of omnipresent microwave irradiation and dietary polyphenols. Research proposal concerns food safety with emphasis on chemical carcinogens that are present either in raw or in thermally processed foods and which after initial activation alkylate DNA, typically at the N7 atom of guanine. Important biochemical phenomena like DNA catalysis of the resulting genetic damage, biomolecular cooperativity, DNA adduct longevity or DNA polymerase mutational propensity were recently discovered and still lack an appropriate mechanistic understanding. A range of state-of-the-art computer simulation techniques in conjunction with free-energy calculations and dedicated thermodynamic cycles will be applied to elucidate their molecular basis. Because microwaves are reported to catalyze a variety of chemical reactions, we are concerned with microwave enhanced reactivity of chemical carcinogens, which has the potential to explain why microwaves were recently classified as potentially carcinogenic to humans by the World Health Organization. Therefore, reactions between chemical carcinogens and DNA will be modeled in the context of our newly proposed physical mechanism of microwave catalysis based on rotationally excited reactive species. Moreover, microwave irradiation is also reported to enhance protein folding and aggregation, events which are generally associated with several neurodegenerative disorders as well as with certain cancer types like amyloidoses. Molecular dynamics simulations in conjunction with homedeveloped Split Integration Symplectic Method (SISM), which is able to effectively decouple individual degrees of freedom of water molecules and to connect them with corresponding thermostats, will be applied to test the hypothesis that the microwaved aqueous solution through the rotationally hot water molecules represents a less polar and less protic medium thereby promoting the processes of aberrant protein folding and aggregation. Furthermore, reactions between chemical carcinogens and polyphenols – natural compounds abundant in fruits – will be studied using quantumchemical approaches. The underlying concept is that, in order to prevent DNA damage, chemical carcinogen has to react faster with its polyphenolic scavenger than with DNA. Since activation free energy presents a direct measure of reactivity, the free-energy barrier for the reaction of chemical carcinogen with its scavenger has to be lower than for the competing DNA alkylation. Finally, our novel inverse molecular docking protocol will be applied to discern polyphenols which inhibit protein targets involved in oncogenic signaling cascades. The ultimate goal is to discover natural compounds or their mixtures with high antigenotoxic activities which, after subsequent optimization, could serve as food supplements contributing much towards the prevention of cancer. We will seek experimental verification of the calculated results from our long-term collaborators whenever possible in order to establish a validated computational platform offering clear advantages over the wet-lab experiments that are in the field of Chemical Carcinogenesis inevitably associated with high health and environmental hazards.