Projects / Programmes source: ARIS

Folding and dynamics of biomolecular systems

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 
Protein, peptide, protein folding, prediction of protein structure, computer simulations, dynamics, NMR spectroscopy, vibrational spectroscopy, non-covalent interactions, electrostatic screening, solvation, hydrogen bonding, hydrophobicity, flexibility, drug-design
Evaluation (rules)
source: COBISS
Researchers (12)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  09899  PhD Franc Avbelj  Chemistry  Researcher  2015 - 2018  72 
2.  08329  PhD Simona Golič Grdadolnik  Chemistry  Researcher  2015 - 2018  323 
3.  08523  PhD Jože Grdadolnik  Chemistry  Researcher  2015 - 2018  258 
4.  00035  PhD Dušan Hadži  Chemistry  Researcher  2015 - 2018  645 
5.  38292  Tina Hočevar  Chemistry  Technical associate  2016 - 2017 
6.  09905  PhD Darko Kocjan  Chemistry  Researcher  2015 - 2016  167 
7.  13627  PhD Franci Merzel  Computer intensive methods and applications  Head  2015 - 2018  219 
8.  34527  PhD Urban Novak  Chemistry  Researcher  2015 - 2018  35 
9.  50459  Iza Ogris  Chemistry  Technical associate  2017 - 2018  42 
10.  50851  PhD Francesca Paoletti  Chemistry  Researcher  2017 - 2018  41 
11.  32915  Kaja Pureber    Technical associate  2015 
12.  39115  PhD Marko Sever  Chemistry  Junior researcher  2016 - 2018  12 
Organisations (1)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0104  National Institute of Chemistry  Ljubljana  5051592000  21,319 
Protein folding is a process in which a molecule is transformed from the denatured state to its biologically active native conformations. It has long been established that simple soluble monomeric proteins can refold in vitro without any additional biochemical machinery. For such proteins, all the information needed to build the three-dimensional structures resides in the sequence of amino acid residues and the environmental conditions. However, the general problem on how the amino acid sequences dictate the three-dimensional structures remains unsolved. The problem of how proteins fold - the protein folding problem - is one of the top 125 scientific puzzles facing scientists today (Science, 2005, 309, 78). Detailed understanding of the molecular events in folding and misfolding processes of proteins may be important for improving therapies of numerous misfolding diseases.   The main objective of this research program is to quantitatively determine the energetics of non-covalent interactions that are involved in the protein folding process and in the formation of ligand-receptor complexes. The nature and energetics of these interactions are, despite large efforts, still poorly understood. New insights into these interactions may lead us closer to the final solution to the protein folding problem. Recently we have shown that even dipeptides exhibit structural features that are very similar to those of the residues in proteins. This discovery opens prospect for the development of a new force field for predicting protein structures that is based on the structures of peptides in aqueous solution. The energy contributions of individual interactions will be determined from the conformational equilibrium measured by the vibrational and NMR spectroscopy and then gradually incorporated into the new potential force field.   Among the non-covalent interactions, we will focus on the hydrogen bonding and hydrophobic interactions. The energetics of hydrogen bonding will be studied using the experimental stabilities of amide-to-ester mutants, which indicate that hydrogen bonds are the dominant interactions in proteins. On the other hand, hydrophobic interactions are generally considered to be the driving force in protein folding; however, it is still not clear what their molecular origin is. These interactions will be studied using vibrational spectroscopy and theoretical methods. We will use NMR, vibrational spectroscopy, and molecular dynamics simulations to evaluate the flexibility of ligands and receptors in the free and bound state and investigate the influence of flexibility on the stability of ligand-receptor interactions. We will study the mechanisms of formation of amyloid fibers searching for the ways how to inhibit or even prevent the formation of fibers. In the case of misfolding that is a consequence of point mutations, we will study the role of different chaperones that help establishing the native protein function. Through a combination of theoretical and experimental methods we will elucidate general molecular mechanisms responsible for protein function.
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 2015, 2016, 2017, final report
Most important socioeconomically and culturally relevant results Annual report 2015, 2016, 2017, final report
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