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Projects / Programmes source: ARIS

FOLDING AND DYNAMICS OF BIOMOLECULAR SYSTEMS

Periods
Research activity

Code Science Field Subfield
1.04.00  Natural sciences and mathematics  Chemistry   

Code Science Field
P351  Natural sciences and mathematics  Structure chemistry 

Code Science Field
1.04  Natural Sciences  Chemical sciences 
Keywords
Proteins, peptides, peptidomimetics, membranes, protein folding, prediction of protein structure, computer simulations, dynamics, NMR spectroscopy, vibrational spectroscopy, X-ray structure determination, molecular interactions, electrostatics, solvation, electrostatic screening, hydrogen bonding, hydrophobicity, conformational entropy, protein design, NOE, NMR relaxation, residual dipolar couplings, flexibility, drug-design.
Evaluation (rules)
source: COBISS
Researchers (15)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  09899  PhD Franc Avbelj  Chemistry  Head  2009 - 2014  72 
2.  29492  PhD Martina Glušič  Chemistry  Junior researcher  2009 - 2012 
3.  08329  PhD Simona Golič Grdadolnik  Chemistry  Researcher  2009 - 2014  323 
4.  08523  PhD Jože Grdadolnik  Chemistry  Researcher  2009 - 2014  258 
5.  00035  PhD Dušan Hadži  Chemistry  Researcher  2009 - 2014  645 
6.  09905  PhD Darko Kocjan  Chemistry  Researcher  2009 - 2014  167 
7.  13627  PhD Franci Merzel  Computer intensive methods and applications  Researcher  2012 - 2014  219 
8.  32103  PhD Andreja Mirtič  Chemistry  Junior researcher  2009 - 2013  12 
9.  34527  PhD Urban Novak  Chemistry  Junior researcher  2011 - 2014  35 
10.  32915  Kaja Pureber    Technical associate  2014 
11.  33237  PhD Slavko Rast  Chemistry  Junior researcher  2011 
12.  28554  PhD Mihael Simčič  Pharmacy  Researcher  2009 - 2012  26 
13.  21557  PhD Tjaša Urbič  Chemistry  Researcher  2009 
14.  06033  Silva Zagorc    Technical associate  2009 - 2012 
15.  32914  PhD Urška Zelenko  Chemistry  Junior researcher  2010 - 2014  20 
Organisations (1)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0104  National Institute of Chemistry  Ljubljana  5051592000  21,271 
Abstract
Life processes are based on cascades of low energy events in which the initial phase is molecular recognition. Molecular recognition is determined by the three-dimensional structure of biomolecules and solvent effects. The most commonly encountered solvent in biomolecular recognition is water; however, lipid environment in membranes is equally important. The low energy level of biological processes is a consequence of non-covalent interactions between biomolecules. These interactions are essential for molecular recognition in three-dimensional molecular organization in which there are no changes in covalent bonding, and in biochemical reactions in which covalent bonding is changed. To understand the structural organization and function of biomolecular systems, it is therefore crucial to determine, as precisely as possible, the nature and energetics of non-covalent inter and intra-molecular interactions of biomolecules. These interactions are: hydrogen bonding, electrostatics, solvation, hydrophobicity, van der Waals forces, etc. One of the numerous recognition processes in living organisms, which excel in importance and complexity, is the protein-folding problem. Protein folding is a process in which a molecule is transformed from denatured state to its biologically active native conformation. The information needed to build the native three-dimensional structure of a one-domain protein is encoded in the sequence of amino-acid residues. The essence of the protein-folding problem is the unraveling of this code. The most important objective of this research program is to quantitatively determine the nature and energetics of non-covalent interactions involved in the protein folding process, formation of ligand-receptor complexes and interactions in complexes between biomolecules and membranes. These interactions will be incorporated in computer simulations of the protein folding process and in the algorithm for predicting native three-dimensional protein structures. Recently we found that solvent screening of hydrogen bonding and local electrostatic interactions between polar backbone atoms are determining the secondary structure of proteins. The nature and energetics of those non-covalent interactions that determine the tertiary and quaternary structure of proteins are still poorly understood. These interactions will be examined by studying the folding process of small proteins and model peptides using NMR and vibrational spectroscopy. Sequences of amino-acid residues of the model peptides will be changed to selectively switch on or off the various non-covalent interactions. Such protein design will enable the verification of our hypothesis. The three-dimensional structure of peptides will be determined by NMR and X-ray spectroscopy. The hydrogen bond is a particularly important non-covalent interaction because of the relatively large energy and directionality. Structure and dynamics of hydrogen bonds in different solvent environments will be studied using nuclear quadrupole resonance, inelastic neutron scattering, infrared spectroscopy and calculations using quantum chemical methods of model molecules. An accurate description of the proton transfer process from donor to acceptor is expected. Recently it has been shown that the denatured state of a protein is far from being a simple random coil. Some proteins are biologically active even in the denatured state.. Using NMR, vibrational spectroscopy and theoretical methods we will study the structure of the denatured state and the mechanism of denaturation by chemical denaturants. NMR and vibrational spectroscopy will be used to study interactions in ligand-receptor complexes and complexes trans-membrane receptor - drug - membrane. Conformational analysis of synthetic peptides and peptide mimetics will be utilized to study the stereo-electronic properties of pharmacophoric patterns. We will also investigate the drug - membrane interactions, because some drugs may reach the t...
Significance for science
The genomes of many organisms have been published recently, from viruses to humans. The main goal of these efforts is to find the sequences of all proteins encoded in the genomes of organisms. Numerous new proteins have been uncovered using the genetic code; however, their structures and biological functions are generally unknown. To understand how the cell works it is crucial that three-dimensional structures and biological functions of all proteins encoded in DNA sequence are known. Determinations of three-dimensional structures and functions of proteins is extremely difficult and time consuming task. It would be much faster and less expensive if we could predict three-dimensional structures of proteins with computers. Biological function and other properties of proteins can then be deduced from their three-dimensional structures. Solving the protein folding problem is extremely important, because it will make possible to predict three dimensional structures and functions of all proteins encoded in the human genome and genomes of other living organisms. It is expected that solution of the protein folding problem would have a huge impact on science, particularly on chemistry, biology and medicine. For solving the protein folding problem it is crucial to develop the potential force field, which will correctly describe structure and dynamics of proteins. Detailed knowledge of the molecular events in protein folding is important for understanding causes of hundreds of diseases including some of the most dreadful disorders like: Alzheimer's and Parkinson's diseases, some types of cancer, type II diabetes, cystic fibrosis, transmissible prion diseases (“mad cow” disease), etc. The reason for these disorders is misfolding of proteins into alternative three-dimensional forms. Successful method for predicting three-dimensional structures of proteins will become an indispensable tool for modeling ligand-receptor complexes, enzyme-substrate and other protein interactions, which will enable the design of novel drugs. The anticipated results of the studies of ligand-receptor interactions will offer the basis for development of more efficient methodology for drug design. We have to understand how dynamic processes affect the ligand binding, so we can develop new and efficient structure-dynamic-based methods for drug design. Proper treatment of dynamic effects is currently the hot topic in drug-design community and will enable the establishment of the so called “flexibility era” in drug discovery.
Significance for the country
The proposed research program is original and is based on our previously published research. The results of this research have been published in the scientific journals with very high impact factors (Proc. Natl. Acad. Sci. USA; J. Am. Chem. Soc.; Phys. Rev. Lett.), which shows that our research is of high quality. With these results we promote Slovenian science. The research team is experienced, highly qualified and have all the necessary equipment to successfully execute and complete the proposed research program. Based on these credentials we obtained industrial projects. We have performed a series of projects for the pharmaceutical companies Lek in which we study new drugs using modern methodology. Developing and using new methods of NMR and vibrational spectroscopy we solve actual problems encountered by the pharmaceutical companies Lek and Krka in production and analysis of their drugs, which directly influences the development project of our partners from the pharmaceutical industry. At the investigation of ligand-receptor interactions the selected receptors will enable the design of new leads, which can have immediate effect on the development of certain classes of urgently required therapeutic agents including new antibiotics and antimycotics. In the EU two million patients in hospitals catch bacterial infections every year and almost 200 thousand of them die, because the existent antibiotics do not help. The fungal resistance is also becoming critical, especially considering high mortality rates of systemic fungal infections, which threaten patients, whose immune system is compromised, including AIDS, cancer, transplant patients, and many others. Theoretical solution of the protein-folding problem will accelerate the development of science and technology in Slovenia (particularly in pharmaceutical firms Lek and Krka). The largest improvement is expected in drug-design. Current drug-design techniques are largely unsuccessful due to the approximations imposed by the simple “lock and key” model of drug action. The interactions of receptor and ligand molecules are often accompanied by changes in their conformations. Such changes will be predicted by the new algorithms, which would considerably decrease the cost of developing new drugs. Implementation of modern methods of computer simulations of biomolecular systems, NMR and vibrational spectroscopy is in our national interest. The development of these techniques is crucial for technological progress of some branches in Slovenia. Young researchers participate in the research. Young researchers are acquiring important knowledge required for realization of basic research project as well as development project in pharmaceutical industry. We cooperate in the international experiments CASP. Formally, this is the competition among research groups in predicting protein three-dimensional structures; however, the main goal of these experiments is to improve general knowledge in this field of research (CASP; Critical Assessment of Techniques for Protein Structure Prediction; http://predictioncenter.gc.ucdavis.edu). On CASP2 and CASP4 we were among the best in the ab initio prediction of the three-dimensional structures of proteins, which was awarded with two invited lectures.
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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