Projects / Programmes
Molecular Simulations and Bioinformatics
January 1, 2004
- December 31, 2008
| Code |
Science |
Field |
Subfield |
| 1.04.00 |
Natural sciences and mathematics |
Chemistry |
|
| Code |
Science |
Field |
| P351 |
Natural sciences and mathematics |
Structure chemistry |
computer simulations, molecular dynamics, Monte Carlo method, quantum simulations, bioinformatics, genomics, new active compounds, proton transfer, hydrogen bond, enzyme reactions, enzyme-inhibitor complex
Researchers (12)
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
0104 |
National Institute of Chemistry |
Ljubljana |
5051592000 |
21,007 |
Abstract
New methods and new applications of molecular simulations of biologically and technologically relevant systems and processes will be developed. At lower-most lewel we shall use quantum chemical ab initio and density functional methods which lead us to the Born-Oppenheimer potential surface which can be used for the study of chemical reactions. These methods also provide us with the distribution of the electric charges on the molecules what is needed in the studies of the solvatation phenomena. The semiempirical methods will be used when the sizes of the molecules preclude the use of ab initio methods. Quantum mechanics will be used to study the formation and decay of van der Waals and hydrogen bonds and the courses of proton transfer reactions. The approach will be based upon the special choice of generalized coordinates that will be custom tailored according to the type of the process. Among the more important applications of this methodology will be the study of the mechanism of some enzyme reactions where a strong hydrogen kinetic isotope effect was found and was not yet explained so far.
We shall continue with the study of the mechanisms of inhibition of various enzymes and binding of ligands to the active site of bioreceptor molecules. We shall also search for new chemical entities with biological activity. Chemical synthesis and biological testing will take place in our partner's organisations.
In the field of bioinformatics in silico experiments will be the basic research methodology. We shall focus our attention to the sequences with low information content whose mutability contributes a predominant share to the genetic diversity. The point mutational events and extensions and shortenings of short simple repeats through the DNA polymerase slippage processes will be the central point of our investigation.
Significance for science
The main goal of the proposed program was to improve the understanding of dynamical aspects of processes associated with biological macromolecules. The key questions concerning enzymatic reactions are not yet properly understood and issues like role of long-range electrostatic interactions, fluctuations and tunneling remain unclear. In particular, we quantifed the relevance of hydrogen tunneling in biocatalysis and hydrogen bonds. From proper understanding of the rate limiting step one can devise the structure and charge distribution of the transition state that is used for drug design based on transition state analogs. In parallel we studied hydrogeden bonded systems that are useful as model systems for enzyme centers with much smaller conformational space. We found similarities between zeolite catalysts and enzymes. A systematic comparison between the factors that contribute to their activity will represent an important contribution for the development of science. We pioneered ab initio computational studies of DNA modification with the ultimate carcinogens of the epoxide and quinone type. We developed a microscopic model for microwave catalysis and applied it to neutral hydrolysis of ester bond. Our bioinformatics studies gave additional insight into biological evolution on molecular level giving rise to additional knowledge relevant to pathology and treatment of various diseases, including cancer. We worked toward novel molecular targets relevant for discovery and development of novel antibiotics. The field is highly relevant for medicine in the spirit of resistant pathological strains. Our research gave important information concerning design of new lead compounds for antibiotics. Moreover calculations of the transition state structure gave additional insight into the nature of catalytic step and inhibitor binding. The results of our work were and will be published in high rank journals and were reported at international conferences.
Significance for the country
Our studies gave additional insight into structure, binding and reactivity of enzymes and DNA, what is a necessary condition for drug design. We are the only group in this country dealing with computational aspects of DNA reactivity. We reported the first ab initio calculations of DNA with the ultimate carcinogens of the epoxide type, a chemical reaction responsible for initial step of carcinogenesis. We combined our knowledge of chemical reactivity including microwave catalysis with researchers in the field of oncology to better understand carcinogenesis and hopefully cancer will be one day prevented and treated more successfully than today. We are the only group in Slovenia where tunneling in the systems of biological relevance is studied. Nobody else is offering advanced computational support to vibrational spectroscopy and zeolite catalysis. Research collaboration with pharmaceutical industry during the entire duration of the research program was maintained. The preservation of research capacity in pharmaceutical industry is a national priority cited in strategic documents of Republic of Slovenia. In hospitals and public health organisations primarily classification and taxonomy research of resistant specific bacterial strains and rationalization of use of antibiotics are performed, and to a lesser degree discovery of novel antibiotics is studied. Lek – pharmaceutical company is traditionally one of the technologically most advanced industrial units. As such it has recognized the importance and high added value of research on novel chemical entities(NCE), in particular in the antimicrobial and cardiovascular area. These activities were focused and established an international collaboration network. However, most recently the new owner has stopped this reseach and our successful studies have been left without conclusive stages. Thus it was of key importance to restore the work and enable young researchers to continue their goal – novel drug molecule – oriented research. On the other hand, the current trends in big pharmaceutical industry point toward partner collaboration of multinational companies with academic research group programs or small biotech companies. These smaller, flexible groups provide for innovative step to the end of preclinical development what forms subsequently the basis for further development in clinic, regulatory documentation activities and marketing of the substance performed by the big pharma. Continuation of research in the area of NCE's would solidify the excellency in application research what has been repeatedly stressed in our national strategy since Slovenia is still lacking high tech research-based biotech companies. The group members are teaching at the University of Ljubljana and/or are mentors of students at undergraduate and graduate level at various faculties (chemistry, pharmacy, physics, biomedicine). Thus the efficacy of graduate studies is enhanced and a comparative advantage of such program is a potential for creation of new working places for young researchers. Introduction of modern technology and focused knowledge is a key feature for further development of pharmacy and biotechnology e.g in spin-off biotech in Slovenia.
Most important scientific results
Final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Final report,
complete report on dLib.si
