Projects / Programmes
FOLDING AND DYNAMICS OF BIOMOLECULAR SYSTEMS
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 |
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.
Researchers (11)
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
0104 |
National Institute of Chemistry |
Ljubljana |
5051592000 |
20,997 |
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 Human Genome project has been successfully completed and the genomes of many other organisms have been published recently. The main goal of these efforts is to find the sequences of all proteins encoded in the genomes of living 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. It is expected that solution of the protein folding problem would have a huge impact on science, particularly on chemistry, biology and medicine. Detailed knowledge of the molecular events in protein folding is important for understanding causes of hundreds of diseases (Alzheimer's and Parkinson's diseases, some types of cancer, type II diabetes, cystic fibrosis, transmissible prion diseases). The structure prediction algorithms will be used also for modeling bio-molecular systems like ligand-receptor and enzyme-substrate complexes and other protein interactions, which will assist drug-design.
Significance for the country
Theoretical solution of the protein-folding problem will accelerate the development of science and technology in Slovenia. 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 bio-molecular modeling, NMR and vibrational spectroscopy is in our national interest. The development of these new techniques is crucial for technological progress of some branches in Slovenia. The results of our research are published in the scientific journals with very high impact factors, which promote Slovenian science. Using 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. 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.
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