Projects / Programmes
Chemical Carcinogenesis - A Computational Approach
| Code |
Science |
Field |
Subfield |
| 1.04.00 |
Natural sciences and mathematics |
Chemistry |
|
| Code |
Science |
Field |
| P003 |
Natural sciences and mathematics |
Chemistry |
| Code |
Science |
Field |
| 1.04 |
Natural Sciences |
Chemical sciences |
biomolecular simulations, free-energy calculations, aflatoxins, cytochromes P450, DNA polymerases, biochemical cooperativity, DNA catalysis, DNA adduct longevity, DNA replication fidelity, scavengers of chemical carcinogens, microwave effects
Researchers (23)
Organisations (5)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
0104 |
National Institute of Chemistry |
Ljubljana |
5051592000 |
20,957 |
| 2. |
0381 |
University of Ljubljana, Faculty of Medicine |
Ljubljana |
1627066 |
48,215 |
| 3. |
0481 |
University of Ljubljana, Biotechnical Faculty |
Ljubljana |
1626914 |
66,295 |
| 4. |
0794 |
University of Maribor, Faculty of Chemistry and Chemical Engineering |
Maribor |
5089638012 |
13,112 |
| 5. |
2790 |
University of Primorska, Faculty of mathematics, Natural Sciences and Information Technologies |
Koper |
1810014009 |
17,671 |
Abstract
The proposed 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 (QM/MM) and empirical representations of solvated biomolecular systems with molecular dynamics or Monte Carlo simulations and free-energy calculations in order to elucidate the molecular basis of chemical carcinogenicity. Aflatoxin B1 – one of the most potent mutagens implicated in human carcinogenesis and a major public health risk in several areas of the developing world – will serve as a typical example. Important phenomena like biomolecular cooperativity, DNA catalysis, DNA adduct longevity and DNA polymerase mutational propensity, that still strive for an appropriate mechanistic interpretation, will be addressed. We will seek experimental verification of the calculated results from our long-term collaborators whenever possible and use it in a continuous feedback loop in order to optimize the parameters of the empirical free-energy methods thereby extending the reach of the applied computer simulation techniques. The resulting reliable in silico environment will provide mechanistic insight at a level unattainable experimentally and will offer clear advantages over the wet-lab experiments that are in the field of Chemical Carcinogenesis inevitably associated with high health and environmental hazards. In addition, reactions between chemical carcinogens and polyphenols – natural scavengers of chemical carcinogens abundant in fruits and their products – 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, the free-energy barrier for the reaction of chemical carcinogen with its scavenger has to be lower than for the corresponding 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. Finally, because microwaves are reported to catalyze a variety of chemical reactions, we are concerned with microwave enhanced reactivity of chemical carcinogens. Since microwave irradiation from various sources including mobile telephony, wireless networks, global positioning systems, satellites, radars, and household appliances 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 newly proposed physical mechanism of microwave catalysis based on rotationally excited reactive species. Corresponding enhancement of DNA damage formation has the potential to explain why microwaves have been recently classified as possibly carcinogenic to humans by the World Health Organization. Current microwave irradiation exposure limits based exclusively on equilibrium tissue heating may, consequently, need to be reconsidered.
Significance for science
The finalized research project applied state-of-the-art molecular modeling techniques to the poorly subscribed field of Chemical Carcinogenesis by combining ab initio, mixed QM/MM and empirical representations of solvated biomolecular systems with MD or MC 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 seeked 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 in the field of Chemical Carcinogenesis offer clear advantages over the wet-lab experiments that are inevitably associated with high health and environmental hazards. On the methodological side we would like to emphasize our invention of a dedicated combination of MC simulation and analytical solution to address the issue of microwave catalysis and of a dedicated SISM integrator that in conjunction with MD 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. Our results 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), Chris Oostenbrink (Head of Institute for Molecular Modeling and Simulation, BOKU University Vienna and holder of a prestegeous ERC Starting Grant) and Jan Florian (Head of Laboratory of Biomolecular Simulations, Loyola University Chicago). 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 Associated Editor of the Scientific Reports, Nature Publishing Group (Prof.Dr. Damjana Rozman) 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 finalized research project will have 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 the finalized research project we have advanced the field of cancer prevention 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 properties serve as cancer prophylactic agents and be administered as food supplements. We would 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 initiated. Simultaneously, we wish 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, a 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. Finally, understanding the molecular basis of positive cooperativity in CYP3A4 – the enzyme involved in the metabolism of over 50% of all market drugs – may help to alleviate the often observed adverse drug-drug interactions. The finished research project will also have an indirect impact on the area of education. We have disseminated our research findings to graduate students through lectures at the interdisciplinary programs of Biomedicine, Bioinformatics and Chemistry as well as to the interested general public through organization of round table discussions, radio and television interviews as well as through publication of popular articles. In addition, the finalized research project has contributed towards development of highly-trained personnel, as young researchers of all five collaborating research institutions have been involved in the project related scientific activities. Finally, we have promoted Slovenia and Slovenian science in the capacity of a United Nations Expert Consultant in Combinatorial Chemistry and Molecular Design (Principle Investigator), of a Slovenian representative of the ELIXIR network in the European Strategy Forum on Research Infrastructures (ESFRI) (Prof.Dr. Damjana Rozman), of a coordinator of international COST and NATO projects (Prof.Dr. Nataša Poklar Ulrih), and of an Associate Editor of the Journal of Chemical Information and Modeling, An American Chemical Society Publication (Prof.Dr. Dušanka Janežič).
Most important scientific results
Annual report
2014,
2015,
final report
Most important socioeconomically and culturally relevant results
Annual report
2014,
2015,
final report
