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Projects / Programmes source: ARIS

Microwave Catalysis and Chemical Carcinogenesis

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Research activity

Code Science Field Subfield
1.04.02  Natural sciences and mathematics  Chemistry  Structural chemistry 

Code Science Field
P003  Natural sciences and mathematics  Chemistry 

Code Science Field
1.04  Natural Sciences  Chemical sciences 
Keywords
computer simulations, free-energy calculations, preorganized electrostatics, ultimate carcinogens, polyphenols, DNA damage, microwave catalysis, mobile telephony
Evaluation (rules)
source: COBISS
Citations Citations for bibliographic records in COBIB.SI that are linked to records in citation databases
source: WoS source: Scopus source: COBISS
Researchers (22)
no. Code Name and surname Research area Role Period No. of publications
1.  31147  PhD Staš Bevc  Natural sciences and mathematics  Researcher  2013 - 2016  21 
2.  25434  PhD Urban Bren  Natural sciences and mathematics  Head  2013 - 2016  339 
3.  22616  PhD Tina Eleršek  Natural sciences and mathematics  Researcher  2013 - 2016  248 
4.  09892  PhD Metka Filipič  Natural sciences and mathematics  Researcher  2013 - 2016  584 
5.  37458  PhD Martin Gladović  Natural sciences and mathematics  Junior researcher  2015 - 2016  21 
6.  02287  PhD Milan Hodošček  Natural sciences and mathematics  Researcher  2013 - 2016  279 
7.  06734  PhD Dušanka Janežič  Natural sciences and mathematics  Researcher  2013  495 
8.  32869  Matej Janežič  Natural sciences and mathematics  Junior researcher  2013  32 
9.  36794  PhD Martin Klvana  Biotechnical sciences  Researcher  2014 - 2016  11 
10.  25435  PhD Janez Konc  Natural sciences and mathematics  Researcher  2013 - 2016  228 
11.  15669  PhD Jurij Lah  Natural sciences and mathematics  Researcher  2013 - 2016  318 
12.  29398  PhD Andrej Lajovic  Natural sciences and mathematics  Researcher  2014 - 2015  38 
13.  27882  PhD Miha Lukšič  Natural sciences and mathematics  Researcher  2013 - 2016  208 
14.  34598  Mitja Ogrizek  Natural sciences and mathematics  Technical associate  2013 - 2015  18 
15.  19037  PhD Matej Praprotnik  Natural sciences and mathematics  Researcher  2013 - 2016  317 
16.  33209  MSc Kati Rozman  Natural sciences and mathematics  Junior researcher  2013 - 2014  15 
17.  01661  PhD Tomaž Šolmajer  Natural sciences and mathematics  Researcher  2014 - 2016  380 
18.  38409  Eva Španinger  Natural sciences and mathematics  Researcher  2015 - 2016  12 
19.  33303  Ivana Uršič    Technical associate  2013  11 
20.  02563  PhD Vojeslav Vlachy  Natural sciences and mathematics  Researcher  2013 - 2016  368 
21.  34530  PhD Julija Zavadlav  Natural sciences and mathematics  Researcher  2013 - 2016  37 
22.  20767  PhD Bojana Žegura  Natural sciences and mathematics  Researcher  2013 - 2016  315 
Organisations (5)
no. Code Research organisation City Registration number No. of publications
1.  0103  University of Ljubljana, Faculty of Chemistry and Chemical Technology  Ljubljana  1626990  22,621 
2.  0104  National Institute of Chemistry  Ljubljana  5051592000  20,965 
3.  0105  National Institute of Biology  Ljubljana  5055784  13,066 
4.  0794  University of Maribor, Faculty of Chemistry and Chemical Engineering  Maribor  5089638012  12,498 
5.  2790  University of Primorska, Faculty of mathematics, Natural Sciences and Information Technologies  Koper  1810014009  16,824 
Abstract
Research proposal concerns food safety with emphasis on chemical carcinogens that are present either in raw or in thermally processed foods. A variety of computer simulation techniques will be used to elucidate the physicochemical basis of high reactivity and related carcinogenicity of chemical carcinogens. DNA catalysis through preorganized electrostatics of its microenvironment provides a plausible explanation. In addition, reactions between chemical carcinogens and polyphenols – natural scavengers of chemical carcinogens abundant in fruits – will be studied from first principles. The underlying concept is that, in order to prevent DNA damage, chemical carcinogen has to react faster with its scavenger than with DNA. Since activation free energy presents a direct measure of reactivity, free-energy barrier for the reaction of chemical carcinogen with its scavenger has to be lower than for the competing reaction with DNA. Our long-term goal is to find an effective natural scavenger of chemical carcinogens which, after subsequent optimization, could serve as food supplement. We believe that such studies will contribute much towards prevention of cancer – a very relevant field that is nowadays unjustifiably overlooked. Moreover, since microwaves are reported to catalyze a variety of chemical reactions, we are concerned with microwave enhanced reactivity of chemical carcinogens. Because microwave irradiation emitted from various sources including mobile telephony, microwave appliances, satellites, and radars represents a large portion of the electromagnetic smog, this question should be urgently addressed. Therefore, reactions between chemical carcinogens and DNA will be modeled in the context of our recently proposed physical mechanism of microwave catalysis based on rotationally excited polar reactive species. If microwaves are shown to catalyze DNA damage by chemical carcinogens, it is easy to envision that adverse health effects leading to development of cancer will ensue. Current microwave irradiation exposure limits based exclusively on equilibrium tissue heating may, consequently, need to be reconsidered. Finally, microwave radiation is also reported to enhance protein folding and aggregation, which has been generally associated with Alzheimer’s, Parkinson’s, Huntington’s, and Creutzfeld-Jakob diseases as well as with certain types of cancer. Rotationally excited polar water molecules again provide a plausible explanation, because they are expected to significantly disrupt the hydrogen-bond network around a given protein and, consequently, to hinder its hydration. Such a protein would then be forced to compensate for the lost interactions by interacting more potently with itself as well as with adjacent proteins and thereby enhancing the process of aberrant protein folding and aggregation. In the proposed research project we will seek to verify this hypothesis using molecular dynamics simulations in conjunction with in-house Split Integration Symplectic Method, which is able to effectively decouple rotational, translational, and vibrational degrees of freedom of water molecules.
Significance for science
The research project applies state-of-the-art molecular modeling techniques to the poorly subscribed field of Chemical Carcinogenesis by combining ab initio, mixed quantum-mechanical/molecular-mechanical and empirical representations of solvated biomolecular systems with molecular dynamics or Monte Carlo simulations and free-energy calculations. Computer simulations provide atomistic insight into biochemical processes on characteristic time scales, give access to controlled conditions outside of experimental grasp, and yield results in a cost-efficient and timely manner. On the other hand, we would like to point out that we are aware of significant limitations pertinent to all molecular modeling methods and that we sought experimental verification of the calculated results whenever possible from our long-term collaborators. We firmly believe that only theory working hand in hand with experiment conducted under carefully controlled in silico and in vitro conditions has the potential to elucidate the molecular origin of important phenomena like biomolecular cooperativity, DNA catalysis, DNA adduct longevity or DNA polymerase mutational propensity that still strive for an appropriate mechanistic interpretation. Moreover, experimental results were used in a continuous feedback loop in order to optimize the parameters of the empirical free-energy methods thereby extending the reliability of the applied computer simulation techniques. The ultimate goal is to elucidate the molecular basis of chemical carcinogenicity and to establish a reliable in silico platform which would offer clear advantages over the wet-lab experiments that are in the field of Chemical Carcinogenesis inevitably associated with high health and environmental hazards. On the methodological side we would like to emphasize our invention of a dedicated combination of Monte Carlo simulation and analytical solution to address the issue of microwave catalysis and of a dedicated SISM integrator that in conjunction with molecular dynamics simulations facilitates decomposition of individual degrees of freedom of water molecules and, thereby, elucidates microwave effects on the hydration of prototypical solutes. Both approaches represent the first computational tools in the field of microwave-enhanced chemistry and require further development to allow for application to biomolecular systems. In addition, the novel methodological techniques like third-power fitting and BRFE are likely to find their use also outside biomolecular simulations in the fields of material science and chemical engineering. The results of our work were published in high ranking journals and presented at international scientific conferences. Open access journals were also considered due to their extended outreach. Access to foreign expertise was provided through collaboration with Professors Frederick Peter Guengerich (Director of Center in Molecular Toxicology, Vanderbilt University School of Medicine and Awardee for Outstanding Achievements in Chemistry in Cancer Research of American Association for Cancer Research), Arieh Warshel (Head of Laboratory of Theoretical Chemisty and Biophysics, University of Southern California and Nobel Laureate in Chemistry), and Chris Oostenbrink (Head of Institute for Molecular Modeling and Simulation, BOKU University Vienna and holder of a prestegeous ERC Starting Grant). The project group members finally promoted Slovenian science in the capacity of a United Nations Expert Consultant in Combinatorial Chemistry and Molecular Design (Prof.Dr. Urban Bren), of an Adjunct Professor at the Department of Pharmaceutical Chemistry, University of California, San Francisco (Prof.Dr. Vojeslav Vlachy), of a member of the Scientific panel on contaminants in food chain at European Food Safety Authority EFSA (Prof.Dr. Metka Filipič), and of an Associate Editor of the Journal of Chemical Information and Modeling, An American Chemical Society Publication (Prof.Dr. Dušanka Janežič).
Significance for the country
The research project has a direct impact on the areas of Health and Food Safety – both of which represent the first-priority research fields of the Research and Development Resolution of Republic of Slovenia. Although cancer together with the coronary diseases claims the most human lives, its frontline treatment with chemotherapy and radiotherapy remains largely ineffective as well as very toxic, while its prevention is unjustifiably overlooked. However, a significant shift from this general trend has been observed lately through advocacy of a healthy life style and through introduction of a vaccine against human papillomavirus. In this research project we advanced the field of cancer prevention further by testing a variety of natural scavengers of ultimate carcinogens for their ability to prevent damage of the genetic material. The final goal is to find successful candidates, which would after subsequent optimization in terms of chemical reactivity and ADMET (absorption, distribution, metabolism, excretion and toxicity) properties serve as cancer prophylactic agents and be administered as food supplements. We will of course have to rely on Slovenian food industry for both financial support and expertise in the later stages of the development process – collaboration with Ljubljanske mlekarne (Slovenian largest diary) has already been secured. Simultaneously, we helped to elucidate the nature of microwave catalysis, which remains poorly understood despite much speculation in the scientific and popular literature. In a wider context this contribution opens new perspectives concerning the exposure of living organisms to omnipresent microwave irradiation emitted from mobile telephony, wireless networks, radars, satellites, GPS and household appliances, since altered biochemical reactivity could lead to carcinogenesis and since enhanced protein folding and aggregation have been generally associated with neurodegenerative disorders as well as with certain cancer types like amyloidoses. Consequently, current microwave irradiation exposure limits based exclusively on equilibrium tissue heating may need to be reconsidered. Moreover, mechanistic interpretation of the microwave catalytic effect is in fact indispensable for optimization of synthetic processes in terms of selection of the appropriate reaction medium, microwave power, and frequency. Furthermore, understanding the molecular basis of positive cooperativity in cytochrome P450 3A4 – the enzyme involved in metabolism of over 50 % of all market drugs – may help to alleviate the often observed adverse drug-drug interactions. Finally, the research project has an indirect impact on the area of education, because the project group members included its findings in their lectures to undergraduate and postgraduate students of all three Slovenian public universities: University of Maribor, University of Ljubljana and University of Primorska. We also disseminated our research findings to the interested general public through organization of round tables, radio, newspaper and television interviews, and through publication of popular articles.
Most important scientific results Annual report 2013, 2014, 2015, final report
Most important socioeconomically and culturally relevant results Annual report 2013, 2014, 2015, final report
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