M.S. Theses
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Browsing M.S. Theses by Subject "Allosteric proteins."
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Item Computational study on allostery in bacterial ribosome(Thesis (M.S.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2019., 2019.) Yıldırım, Hatice Zeynep.; Kurnaz, M. Levent.Molecular machines in a cell have signal processing to perform their function using specific sites such as active or allosteric sites. Ligand binding to active sites or signal transferring from allosteric sites affect their function and dynamics. In this thesis, firstly crystal structure of bacterial ribosome (4kdk-4kdj) and its conformers which are generated by ClustENM are investigated to determine allosteric communication pathways. Targets on ribosome are determined as the Decoding Center (DC) – the Sarcin Ricin Loop (SRL), DC - the Peptidyl Transferase Center (PTC) and the PTC – Tunnel. On the allosteric pathways between DC and SRL, EF-G stands out with critical sites on its domains IV which has a significant function in blocking back translocation of tRNA. Some significant nucleotide and aminoacid like A1493 and Met580 appear on pathways between DC-SRL, which help EF-G hydrolysis. On the DC-PTC pathways drug binding site is observed. On the PTC-ribosomal tunnel pathway has a highly conserved non-Watson-Crick base pair and binding pocket for antibiotic is found. Secondly, the bacterial ribosome of E.coli, 4v5h, is analyzed to investigate allostery between Secretion Monitor (SecM)–PTC and TF-Ribosomal Tunnel. A76 of tRNA and nascent chain which consists of alanines seems significant between U2585 and A2451 to provide allosteric communication between SecM and PTC. On the shortest pathways on the TF-Ribosomal Tunnel, GLY91 from L22 has a high frequency of occurrence on all pathways. GLY91 is significant for elongation arrest and for the turn of the β-hairpin of L22 which is important since antibiotic resistance appears when a mutation on the β-hairpin occurs.Item Determination of species-specific allosteric binding sites in pyruvate kinase and its use in drug design studies(Thesis (M.S.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2020., 2020.) Özhelvacı, Mehmet Fatih.; Kurnaz, M. Levent.; Akten, E. Demet.Knowledge of structural and sequential differences in allosteric regions and con formational changes occurring in catalytic sites as a result of allosteric coupling had a great impact in the design of species-specific allosteric inhibitors. It is the most critical strategy to design effective drugs by targeting the disease-causing organism only without harming the infected organism. Glycolytic pathway is the most essential metabolic pathway in almost all living organisms which converts glucose into pyruvate to produce energy, thus it is often targeted in drug design studies. The objective of this study was to develop a new approach to identify all possible species-specific allosteric binding sites that will inhibit the activity of critical allosteric enzyme in the glycolytic pathway which was Pyruvate Kinase (PK) . The ultimate goal was to propose drug molecules that will bind to the proposed allosteric sites and inhibit the activity of bac terial/parasitic PK without effecting human PK. In addition to sequence and structural comparisons, the computational approach con sists of several steps; computational solvent-mapping to identify all possible ligand binding sites, identification of interface regions, elastic network modeling (ENM) to predict the regions which would have the highest effect on global or essential dynamics upon ligand binding; screening approved drug molecules via docking studies using GOLD tool to propose possible drug candidates. Accordingly, several FDA approved and world - wide used molecules were identified that bind to bacterial PK with high binding affinities without much effect on human PK.