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Projects / Programmes source: ARIS

Computer Algorithm Development for Simulations of Complex Macromolecular Systems

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Research activity

Code Science Field Subfield
1.07.00  Natural sciences and mathematics  Computer intensive methods and applications   

Code Science Field
P000  Natural sciences and mathematics   

Code Science Field
1.01  Natural Sciences  Mathematics 
Keywords
Molecular Modeling, Computer Simulations, Algorithms, Molecular Dynamics, Symplectic Methods, Normal Mode Analysis, Parallel Computational Methods, Parallel Molecular Visualization, Protein-Protein Binding Sites, Biologically Active Compounds
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 (13)
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  Researcher  2013 - 2014  339 
3.  02287  PhD Milan Hodošček  Natural sciences and mathematics  Researcher  2013 - 2016  279 
4.  06734  PhD Dušanka Janežič  Natural sciences and mathematics  Researcher  2013  495 
5.  32869  Matej Janežič  Natural sciences and mathematics  Junior researcher  2013  32 
6.  25435  PhD Janez Konc  Natural sciences and mathematics  Researcher  2013 - 2016  228 
7.  19576  PhD Gregor Mlinšek  Medical sciences  Researcher  2013 - 2014  169 
8.  34598  Mitja Ogrizek  Natural sciences and mathematics  Technical associate  2013 - 2015  18 
9.  19037  PhD Matej Praprotnik  Natural sciences and mathematics  Researcher  2013 - 2016  317 
10.  33209  MSc Kati Rozman  Natural sciences and mathematics  Junior researcher  2013  15 
11.  01661  PhD Tomaž Šolmajer  Natural sciences and mathematics  Head  2013 - 2016  380 
12.  33303  Ivana Uršič    Technical associate  2013  11 
13.  34530  PhD Julija Zavadlav  Natural sciences and mathematics  Researcher  2013 - 2016  37 
Organisations (2)
no. Code Research organisation City Registration number No. of publications
1.  0104  National Institute of Chemistry  Ljubljana  5051592000  20,965 
2.  2790  University of Primorska, Faculty of mathematics, Natural Sciences and Information Technologies  Koper  1810014009  16,821 
Abstract
Computer intensive methods and applications is extremely propulsive area of scientific research in which the use of supercomputers and computer clusters is used to solve the most demanding computational problems in theoretical and applied research in natural and technical sciences. We deal with solving of various types of problems, such as, structure and dynamics of molecules, bulk matter research, chemical and biochemical reactions, and the development of new drugs. Development of new computational methods is closely related to the development of new algorithms and the development of modern computers. This project stands at the cutting edge of today's research trends in the field of molecular modeling. It concentrates on some of the most relevant research areas within development and application of computer simulation techniques and approaches. The current state of the art and important historical contributions are briefly sketched, and our main research goals, based on the past results and contributions of the project participants, are stated. These goals include development of new methods and new improvements for molecular modeling and the simulation of complex macromolecular systems that increase the accuracy and efficiency of present-day computation approaches. We will use and develop molecular modeling methods, especially the simulation of molecular dynamics and chemical graph theory, a branch of mathematical chemistry concerned with discrete structures in chemistry. We primarily aim to: improve algorithms for integration of classical and quantum equations of motion by further developing symplectic algorithms based on analytical treatment of high frequency motions; improve the treatment of the solvent in molecular dynamics simulation by developing explicit/implicit solvent methods in which the hydration water is represented explicitly while the surrounding bulk water is represented implicitly. Special emphasis will be given to development of new algorithms for protein binding sites prediction as well as to development of web tools for modeling of pharmaceutically interesting molecules. The proposed methodological improvements should significantly extend the scope of presently used algorithms in terms of length- and time-scales, and thus contribute to the general applicability of computer simulation algorithms. The simulation results of selected examples will facilitate the understanding of some fundamental problems in molecular biology, especially in the study of protein hydration, protein binding sites prediction, and discovery of new biologically active compounds for the development of new drugs . In spite of large potentials for concrete use of our results in certain branches of technology and industry, the main focus of our research remains development of general, new mathematical methods and algorithms in the field of molecular modeling, and as such, represents a contribution to overall scientific knowledge. The project involves a number of researchers with excellent publishing records, currently active in Slovenia, guaranteeing research at the highest possible level. Nevertheless, a collaboration with two research institutions from USA and one from Malaysia, where some of the most renowned world experts in the field of computer simulations of biological macromolecules are based, is planed too. This further enhances our research. The intensity of this collaboration together with their formal inclusion in the project depends on the financial situation ("a bigger project").
Significance for science
The effective simulation of biomolecular systems is largely hampered by the disparity of length and time scales involved in these systems. Nowadays, simulations of such systems are mostly carried out in separate scales using simulation approaches such as molecular dynamics. Significant advances in computer hardware have provided unprecedented physical insight in the dynamics of biomolecular systems. However, advances in computer hardware alone are not sufficient to reach the experimental length and time scales in these systems. Therefore, it is essential to develop multiscale methods that can resolve the wide range of length and time scales associated with the dynamics of biomolecular systems. Of particular interest is the coupling of these models and algorithms. This coupling is the subject of intense research efforts by several groups around the world and is considered as one of the most important areas for the advancement of computational physics and chemistry. We have developed several multiscale models of water and salt solutions, as the most important solvents in biomolecular systems, that will speed up biomolecular simulations up to an order of magnitude. Our multiscale approaches bridge the hydrodynamics from the atomic to macroscopic scale and enable the study of biophysical phenomena that are beyond the scope of either atomistic, mesoscopic, or macroscopic simulations. The development of algorithms for binding sites detection on protein structures provides new insights into the mode of action of these molecular machines and is fundamental to our understanding of the processes that govern binding of small ligands and biomolecules such as proteins or nucleic acids. The result of our research are new tools for pharmaceutical modeling, free to researchers worldwide, available from our web server ProBiS (Protein Binding Sites) at http://probis.cmm.ki.si, distinguished for its comprehensible graphical interface. The developed tools enable researchers to predict binding of molecules to proteins, and to evaluate their binding affinity using molecular modeling methods. Developed tools are used to resolve outstanding issues in drug design. New molecular targets and development of novel drugs directed at these targets are a challenge for scientists in the field of biomedicine. Growing number of cancer patients worldwide presents a pressing need in human medicine for introduction of novel drugs into therapy. The contribution to the development of science are novel inhibitors of DNA topoisomerase IIa and DNA gyrase B as validated targets for the development of anticancer and antimicrobial drugs. The most important result is the discovery of inhibitors of the human enzyme topoisomerase IIa and DNA gyrase B as potential anticancer and antibacterial compounds and knowledge about their mode of action.
Significance for the country
The successful work of our program group gives the opportunity to perform excellent research and transfer our knowledge and experience to other users, both from the research community and industry. We also participate in the educational process, by mentoring diploma and doctoral students, and collaborate with users to solve their given problems. Functional knowledge obtained and developed by the project team is a foundation on which in perspective hightech biotechnological companies can be organized. The resulting products which can be commercialized are an important contribution towards the economic exploitation of existing infrastructure of academic research institutions. Novel knowledge obtained by this project contributes to further development of the field of pharmacy, biotechnology and biomedicine in Slovenia. Indirectly, the project results will influence the national identity as a consequence of publication of scientific achievements in international journals and patents. Within the project we have developed and carried out multiscale simulations of biomolecular systems combining various numerical approaches. e.g., all atom and coarse grained molecular dynamics methods as well as computational fluid dynamics techniques. The developed methods we employ in the pedagogical environment and use for popularization of the scientific field. The project group members have been mentors/comentors for several doctoral thesis in physics, computer science, pharmaceutical science, and chemistry. The project group members are also lecturers at the Faculty of Mathematics and Physics, University of Ljubljana, Faculty of pharmacy , Ljubljana and Faculty for chemistry Maribor. The multiscale methods, which we have developed and employed in this project, should pave the way for simulation based studies of pharmaceutical and medical interest. Since the project group members collaborate with the Slovenian pharmaceutical industry, i.e., Lek (Sandoz) and Krka, we envisage that our biomolecular simulation results may be of interest for potential applications in the pharmaceutical industry. The advance of basic science is one of the most important driving forces of the development of modern society. Namely, basic science enables and facilitates the proliferation of applied science and thus eventually also fuels the technological advance and economic growth. A timely and effective implementation of the evolution and growth of inter and multidisciplinary basic research is one of the leading trends of modern science. It is therefore vital that Slovenia keeps up with the leading European and worldwide scientific trends. The research also importantly contributes to top quality education of young researchers and other aspiring young scientists (graduate and postgraduate students). An important integral part of the program are close international collaborations with leading scientific institutions. The program is thus also important in terms of strengthening and enhancing Slovenia’s recognition and reputation within the international scientific community. The research activity directed towards development of a novel chemical entities to the end of preclinical research has been completed successfully in this laboratory for a variety of biological systems in which enzymatic targets and rational design of inhibitor molecules of diversified chemical classes were performed. There is also a continuously growing interest of the world pharmaceutical industry to promote an intense collaboration with innovative groups in academia. Such collaboration is potentially a basis for formation of hightech biotechnological companies that has been a priority for the Slovenian economic development of the 21st century. Indirectly, the programme will influence the national identity as a consequence of publication of scientific achievements in international journals and conferences.
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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