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Projects / Programmes source: ARIS

COMPUTER SIMULATION OF MOLECULAR STRUCTURE AND DYNAMICS

Periods
Research activity

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

Code Science Field
P170  Natural sciences and mathematics  Computer science, numerical analysis, systems, control 

Code Science Field
1.07  Natural Sciences  Other natural sciences 
Keywords
Molecular Modeling, Computer Simulations, Algorithms, Molecular Dynamics, Symplectic Methods, Normal Mode Analysis, Integral Equation Theory, QM/MM methods, DFT methods, Hamiltonian Systems, Force Fields, Electronic Structure, Density Functionals, Multicomponent Reactions, Reaction Mechanisms, Parallel Computers
Evaluation (rules)
source: COBISS
Researchers (25)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  31147  PhD Staš Bevc  Computer intensive methods and applications  Researcher  2009 - 2014  21 
2.  23422  PhD Urban Borštnik  Computer intensive methods and applications  Researcher  2009 - 2011  36 
3.  25434  PhD Urban Bren  Chemistry  Researcher  2009 - 2014  367 
4.  28560  PhD Nejc Carl  Computer intensive methods and applications  Researcher  2009 - 2012  23 
5.  37458  PhD Martin Gladović  Chemistry  Junior researcher  2014  21 
6.  02287  PhD Milan Hodošček  Chemistry  Researcher  2009 - 2014  281 
7.  06734  PhD Dušanka Janežič  Computer intensive methods and applications  Researcher  2009 - 2013  503 
8.  32869  Matej Janežič  Natural sciences and mathematics  Junior researcher  2010 - 2013  32 
9.  25435  PhD Janez Konc  Computer intensive methods and applications  Researcher  2009 - 2014  236 
10.  37452  PhD Samo Lešnik  Pharmacy  Junior researcher  2014  57 
11.  13627  PhD Franci Merzel  Computer intensive methods and applications  Researcher  2009 - 2011  212 
12.  19576  PhD Gregor Mlinšek  Cardiovascular system  Researcher  2010 - 2014  172 
13.  34598  Mitja Ogrizek  Computer intensive methods and applications  Technical associate  2012 - 2014  18 
14.  03455  PhD Matej Penca  Computer intensive methods and applications  Researcher  2009 - 2013  66 
15.  06431  PhD Ksenija Poljanec  Chemistry  Researcher  2009 - 2013  26 
16.  36416  PhD Aleksandar Popadić  Computer intensive methods and applications  Junior researcher  2013 - 2014  20 
17.  19037  PhD Matej Praprotnik  Computer intensive methods and applications  Researcher  2009 - 2014  323 
18.  33209  MSc Kati Rozman  Natural sciences and mathematics  Junior researcher  2010 - 2014  17 
19.  35381  PhD Jurij Sablić  Computer intensive methods and applications  Junior researcher  2012 - 2014  29 
20.  01661  PhD Tomaž Šolmajer  Chemistry  Head  2013 - 2014  380 
21.  34881  PhD Joanna Trykowska Konc  Computer intensive methods and applications  Researcher  2012  13 
22.  33303  Ivana Uršič    Technical associate  2010 - 2013  11 
23.  30286  PhD Blaž Vehar  Computer intensive methods and applications  Junior researcher  2009 - 2012  17 
24.  34530  PhD Julija Zavadlav  Physics  Junior researcher  2011 - 2014  38 
25.  26516  PhD Jernej Zidar  Computer intensive methods and applications  Junior researcher  2009  26 
Organisations (1)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0104  National Institute of Chemistry  Ljubljana  5051592000  21,278 
Abstract
Computer simulation methods have been developing primarily in the areas of increasing the simulation lengths and the size of modeled systems, which allows a greater understanding of the relationship between the structure and function in biological macromolecules. Due to the heterogeneous nature of these macromolecules, an average of several simulations of the same system must be performed. Including a solvent in simulations greatly increases the scope of the simulated system. The length of simulations has to be greater than on the nanosecond scale to study chemically and biologically interesting processes, which occur on the microsecond scale. We expect that the development of new methods for molecular modeling and their implementation on parallel computers will increase the speed of computer simulations for several orders of magnitude. This will allow a more detailed examination of known problems as well as allow the examination of new problems. The program has the following goals: a) Further development and use of the SISM (Split Integration Symplectic Method) and HANA (Hydrogens ANAlytically) symplectic methods for molecular dynamics simulations of macromolecules that will allow integrating equations of motion with a long time step while remaining stable, computationally economical and being efficiently parallelizable. The methods are based on the factorization of the Liouville operator and differ from other methods using a split scheme in their analytical treatment of high frequency oscillations. Their benefit will be demonstrated on some biologically interesting examples, especially proteins. b) Further development and use of the combination of molecular dynamics methods, normal mode vibrational analysis, and quasiharmonic analysis of proteins in solutions for studying protein hydration. c) Further development and use of QM/MM methods, which allow computer simulations using a combination of a classical and quantum potential, allowing for more accurate simulations of large biological molecules at the ab initio level. d) Further development of computationally efficient methods for determining the time-dependent electronic structure of molecules based on the Kohn-Sham formulation of the density functional theory in which the electron density is calculated using single-electron Green's functions. Since the most computationally demanding operations are only computed locally, the speed of calculating the electronic structure of molecules is significantly increased. e) Further development and application of quantum chemical and classical approaches for calculating reaction mechanisms, especially calculating the ionic reactions of isocyanides. We will determine whether it is generally true that ionic reactions of isocyanides proceed as multicomponent chemical reactions. No such studies have been performed using computational methods and it is not possible to study this problem experimentally. f) Further development and use of the RISM formalism, which is based on the theory of integral equations, which will, in combination with Monte Carlo simulations, enable a deeper understanding of the relationship between the properties of molecules and the macroscopic properties of the matter they form. These relationships are given by distribution functions that are obtained by using the theory of integral equations. g) Further development of new and effective network topologies for connecting personal computers into clusters and that will enable fast parallel performance for molecular dynamics programs and allow for an effective implementation of the newly developed methods on parallel computers.
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. Within the scope of the programme we 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. A theoretical description of fluctuations in nonequilibrium dynamics is a big and important scientific challenge worldwide. While the critical importance of fluctuation out of equilibrium is meanwhile well recognized, the field is still in its infancy phase and thus relatively unexplored. Of highest importance is the understanding of the relationship between the details of micro and/or mesoscopic dynamics, interparticle interactions and the statistics of functionals over trajectories, which might lead to numerous breakthroughs in the understanding of nonequilibrium phenomena in various fields. The research field is strongly interdisciplinary and spans over theoretical and mathematical physics all the way to theoretical physical (bio)chemistry. The highest relevance and timeliness of the proposed research is also reflected in the tight and intense collaboration of the members of the research program with leading scientists across Europe and world wide. The vivid crossfertilization and entanglement of ideas and disciplines enables further breakthroughs and advances in basic science in the future.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 the research program 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. 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 is the study of DNA topoisomerase IIa and protein Mcl1 as targets for the development of anticancer drugs. In particular, new knowledge of general interest will result from experimental determination of structure of the ligand–enzyme complexes which is currently under way and which will enable insights into underlying molecular mechanisms.
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. Novel knowledge obtained by this project contributes to further development of the field of pharmacy, biotechnology and biomedicine in Slovenia. Indirectly, the programme influences the national identity as a consequence of publication of scientific achievements in international journals and patents. Within the programme we develop and carry out multiscale simulations of biomolecular systems combining various numerical approaches. e.g., allatom and coarse-grained molecular dynamics methods as well as computational fluid dynamics techniques. The developed methods we also employ in the pedagogical environment and use for popularization of the scientific field. The programme group members are 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 and Faculty of Pharmacy, University of Ljubljana. The multiscale methods, which were develop and employed in this programme, should pave the way for simulation based studies of pharmaceutical and medical interest, e.g., targeted drug delivery. Since the programme 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 research activity directed towards development of a novel chemical entities to the end ofpreclinical 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. Members of the laboratory are involved in teaching at Faculty of Pharmacy at University of Ljubljana and transfer their knowledge to students. 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 influences the national identity as a consequence of publication of scientific achievements in international journals and patents. Furthermore, the efforts of the research team to develop an original chemical entity into drug contributes to the international distinction of our research.
Most important scientific results Annual report 2009, 2010, 2011, 2012, 2013, final report, complete report on dLib.si
Most important socioeconomically and culturally relevant results Annual report 2009, 2010, 2011, 2012, 2013, final report, complete report on dLib.si
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