Ebru Demet Akdoğan

Akdoğan, Ebru Demet

Name Variants

Akdoğan, E.
Akdoğan, EBRU DEMET
E. D. Akdoğan
A., Ebru Demet
Ebru Demet Akdoğan
Akten E.
Akdoğan,E.D.
AKDOĞAN, EBRU DEMET
Akdogan,Ebru Demet
Akdogan,E.D.
Akdogan, Ebru Demet
Ebru Demet AKDOĞAN
E. Akdoğan
EBRU DEMET AKDOĞAN
Ebru Demet, Akdogan
Akdoğan, Ebru Demet
Akdoğan, E. D.
A.,Ebru Demet
AKDOĞAN, Ebru Demet
Demet Akdoğan, Ebru
Akten, Ebru Demet
Akdoğan, Ebru Demet
Akdoğan, Ebru Demet
Akdoğan, Demet Akten

Job Title

Prof. Dr.

Email Address

demet.akten@khas.edu.tr

ORCID ID

0000-0002-0358-3171

Scopus Author ID

6507297154

Full item page

Scholarly Output

37

Articles

22

Citation Count

41

Supervised Theses

7 Scholarly Output Search Results

Now showing 1 - 10 of 33

Citation Count: 6
Structural Analysis of Peptide Fragments Following the Hydrolysis of Bovine Serum Albumin by Trypsin and Chymotrypsin
(Taylor & Francis Inc, 2016) Özyiğit, İbrahim Ethem; Akten, Ebru Demet; Pekcan, Önder
Peptide bond hydrolysis of bovine serum albumin (BSA) by chymotrypsin and trypsin was investigated by employing time-resolved fluorescence spectroscopy. As a fluorescent cross-linking reagent N-(1-pyrenyl) maleimide (PM) was attached to BSA through all free amine groups of arginine lysine and/or single free thiol (Cys34). Time-resolved fluorescence spectroscopy was used to monitor fluorescence decays analyzed by exponential series method to obtain the changes in lifetime distributions. After the exposure of synthesized protein substrate PM-BSA to chymotrypsin and trypsin it is observed that each protease produced a distinct change in the lifetime distribution profile which was attributed to distinct chemical environments created by short peptide fragments in each hydrolysate. The persistence of excimer emission at longer lifetime regions for chymotrypsin as opposed to trypsin suggested the presence of small-scale hydrophobic clusters that might prevent some excimers from being completely quenched. It is most likely that the formation of these clusters is due to hydrophobic end groups of peptide fragments in chymotrypsin hydrolysate. A similar hydrophobic shield was not suggested for trypsin hydrolysis as the end groups of peptide fragments would be either arginine or lysine. Overall in case the target protein's 3D structure is known the structural analysis of possible excimer formation presented here can be used as a tool to explain the differences in activity between two proteases i.e. the peak's intensity and location in the profile. Furthermore this structural evaluation might be helpful in obtaining the optimum experimental conditions in order to generate the highest amount of PM-BSA complexes.
Exploring Distinct Conformers of B2-Adrenergic Receptor Via Coarse-Grained Molecular Dynamics Simulations
(Kadir Has Üniversitesi, 2012) Çakan, Sibel; Akdoğan, Demet Akten
ß2AR, G protein bağlantılı reseptör ve birçok ilaç için hedef moleküldür. Reseptörünson derece esnek olan yapısı bir çok ligant molekülünü tanıma özelliği sağlar. Sonyıllarda yapılan kristalografik çalışmalar reseptörün aktif ve inaktif yapısını ortayaçıkarmasına rağmen bu çalışmalar reseptörün tüm dinamiğini çözmek için yeterlideğildir. Moleküler dinamik (MD) metodu reseptörün tüm dinamiğini anlamak içinalternatif ve verimli bir yöntemdir. Ancak geleneksel atomistik simülasyonlar birçokbiyolojik olayın gerçekleştiği zaman aralığı olan milisaniye seviyelerine ulaşamaz.Bu nedenle, bu calışmada serbestlik derecesini azaltan kaba taneli modellemekullanıldı. Sistem POPC membran tabakası içine gömülü ß2AR ve sulardanoluşturuldu. CG model kullanılmasının asıl amacı atomistik modellerde mümkünolmayan daha geniş yapısal alanı ortaya çıkarmaktır. Reseptörün bölgesel hareketleriatomistik simülasyonlarla uyum içindedir. CG simülasyondan dört görüntü seçilmişve geri eşleme yöntemi ile atomistik modele çevrilmiştir. Daha sonra herbiri 100 nsuzunluğunda bir MD simülasyonuna tabi tutulmuştur. Enerjik ve yapısal olarak farklıreseptör yapıları ortaya çıkmıştır. CG MD simülasyonunun PCA analizi, ilk beşbirincil bileşenin tüm dinamiğin %50 sini açıklarken, atomistik simülasyonların %85ini açıkladığını göstermiştir. CG ve atomistik öz-vektörlerin maksimum örtüşmedeğeri 0.46 dır. CG modelde atomistik modele göre korelasyonlar daha zayıftır.
Citation Count: 6
Potential allosteric sites captured in glycolytic enzymes via residue-based network models: Phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase and pyruvate kinase
(Elsevier, 2022) Celebi, Metehan; Inan, Tugce; Kurkcuoglu, Ozge; Akten, Ebru Demet
Likelihood of new allosteric sites for glycolytic enzymes, phosphofructokinase (PFK), glyceraldehyde-3phosphate dehydrogenase (GADPH) and pyruvate kinase (PK) was evaluated for bacterial, parasitic and human species. Allosteric effect of a ligand binding at a site was revealed on the basis of low-frequency normal modes via C alpha-harmonic residue network model. In bacterial PFK, perturbation of the proposed allosteric site outperformed the known allosteric one, producing a high amount of stabilization or reduced dynamics, on all catalytic regions. Another proposed allosteric spot at the dimer interface in parasitic PFK exhibited major stabilization effect on catalytic regions. In parasitic GADPH, the most desired allosteric response was observed upon perturbation of its tunnel region which incorporated key residues for functional regulation. Proposed allosteric site in bacterial PK produced a satisfactory allosteric response on all catalytic regions, whereas in human and parasitic PKs, a partial inhibition was observed. Residue network model based solely on contact topology identified the 'hub residues' with high betweenness tracing plausible allosteric communication pathways between distant functional sites. For both bacterial PFK and PK, proposed sites accommodated hub residues twice as much as the known allosteric site. Tunnel region in parasitic GADPH with the strongest allosteric effect among species, incorporated the highest number of hub residues. These results clearly suggest a one-to-one correspondence between the degree of allosteric effect and the number of hub residues in that perturbation site, which increases the likelihood of its allosteric nature.
Classification of Distinct Conformers of Beta-2 Adrenergic Receptor Based on Binding Affinity of Ligands Through Docking Studies
(Kadir Has Üniversitesi, 2017) Dilcan, Gonca; Akten, Ebru Demet
?2AR is an important drug target and plays a critical role in the relaxation of pulmonary tissues and cardiovascular physiology. We have developed a strategy for classifying various ?2AR conformers as active or inactive states based on binding mode of selected ligands with known activities. Previously distinct conformational states of the ligand’s binding pocket were obtained from a 2.8 µs MD simulation. Snapshots were clustered based on RMSD value of five key residues at the binding site. Clustering analysis yielded a total of 13 distinct conformers to which five agonists four inverse agonists and four antagonists were docked separately using seven different scoring functions. Best ligand poses with the highest score value were selected and evaluated based on their vicinity to five key residues. Poses that were not in this neighborhood were discarded and remaining ones were sorted based on their score. Before treating MD conformers this classification scheme was applied first to both active/inactive state crystal structures for critical assessment. MD conformers found in top five in all scoring functions were selected and assigned to be either active or inactive. Finally selected MD conformers were used to screen a small database to further investigate their discriminatory power. As a result MD conformers performed more selective screening than inactive state crystal structure for antagonists/inverse agonists. Generating alternative conformations of the receptor and classifying them as active or inactive is an important practice in the drug design studies that were often limited to one snapshot obtained from X-ray studies.
Investigation Of Allosteric İnhibition Effect İn Pyruvate Kinase By Constrained Molecular Dynamics Simulation Method Piruvat Kinazın Allosterik Olarak İnhibe Edilmesinin Kısıtlanmış Moleküler Dinamik Similasyon Methodu Kullanılarak İncelenmesi
(Kadir Has Üniversitesi, 2021) Akkaya, Reyhan; Akdoğan, Ebru Demet
In previous studies, our research group identified species-specific allosteric sites in glycolytic enzymes from different organisms and identified candidate inhibitory molecules that strongly interact with the residues at these sites. In this study, a Molecular Dynamics simulation study was performed on one of the glycolytic enzymes, bacterial pyruvate kinase (S. aureus PK), by employing bond restraints between selected pairs of residues at the suggested allosteric region in order to mimic the presence of a drug molecule. At the same time, interacting residues in an ex- perimentally identified allosteric region were also restricted and compared with the proposed area. Three 100 ns long independent runs were conducted for each of three different states of the receptor; apo state (no restraints), constr-1 (restriction on proposed allosteric site) and constr-2 (restriction on known allosteric site) which amount to a total of nine runs, e.g., 900 ns. Several analytical methods were used to elucidate the effect of restricted regions on protein dynamics and the allosteric character of pyruvate kinase. While structural changes were examined with RMSD-RMSF analysis, correlations between global movements and structural components were analysed with principal component analysis. From PCA results, it was observed that both restricted allosteric regions led to decreased correlations of positional fluctuations in comparison to apo state. Investigation of changes in the secondary structure at the catalytic site showed that the α′6 helix, which has an essential role in the stabilization of the active structure, shifted to a coil-turn structure in the apo state more frequently than in the con- strained states. Additionally, domain rotations identified via principal axes analysis, showed that the constrained state disrupted the domain rotations more often. Finally, the distance fluctuation analysis was performed to observe the effect of the restricted residues in the allosteric signal transduction. The communications be- tween residues increased in the constr-1 state while there was slight decrease in the communications of the constr-2 state.
Pharmacophore- Based Screening and Docking for the Discovery of Novel Antagonists of Beta-2 Adrenergic Receptor
(Kadir Has Üniversitesi, 2013) Yakar, Rüya; Akdoğan, Ebru Demet
ß2AR which is the member of rhodopsin-like GPCR is the target system for the discovery of novel antagonists using structure-based pharmacophore modeling and docking methods. initially a shared pharmacophore model is obtained using the structure of five known inactive ß2AR complex (PDB ids: 2HR1 3D4S 3NY8 3NY9 and 3NYA). in order to test the discriminatory power of pharmacophore model a small database consisting of 117 known molecules (53 antagonists against 64 agonists) was screened using LigandScout software tool. The screening yielded 44 antagonists (72% true positives) against 17 agonists (18% false positives) which was found satisfactory. Then under the same screening conditions the second database that is the clean drug-like subset of ZiNC database was screened. -- Abstract'tan.
The Prediction of 3d Structure of the Dimeric State of Human Β2-Adrenergic Receptor
(Kadir Has Üniversitesi, 2016) Koroğlu, Ayça; Akdoğan, Ebru Demet
A significant amount of experimental and computational data points out a possible role of TM6 in the dimerization of ?2-adrenergic receptor (?2AR). Peptide– and protein–protein docking experiments guided by this assumption were conducted in order to confirm the potential participation of TM6 at the interface region of ?2AR dimers. Firstly a derived peptide consisting of 23 residues of TM6 was blindly docked to ?2AR monomer using a rigid body approach. The resulting complexes in which the peptide preferred to be near TM5 and TM6 regions have also the highest scores. Secondly a total of seven peptides were derived from each TM regions and were blindly docked to ?2AR using the same rigid body approach. TM6 was found to be the most preferred binding site region in the receptor for each peptide. As for the protein-protein dockings a full rigid-body docking returned a total of 16000 dimer conformations and is followed by a membrane topology filtering. 149 complexes fit the topology requirements. A root mean-squared deviance (RMSD) value of 6 Å was used to cluster all 149 complexes and it is observed that the highest populated cluster of conformers have the highest score value and moreover TM6 presents at the interface region. Finally an information-driven semi flexible docking approach used by given the interface residue data for seven TM regions. interface residue data derived from the SASA values of residues in each TM region. The generated complexes were filtered due to membrane topology requirements. The complex with the TM6 interface was the highest scored docking pose among the complexes with a proper membrane topology.
Poz- Adrenerjik Reseptörün Kaba Taneli Moleküler Dinamik Simülasyonu ile Farklı Konformasyonlarının Araştırılması
(Kadir Has Üniversitesi, 2012) Cakan, Sibel; Akten, Ebru Demet
ß2 adrenergic receptor (ß2AR) is a G protein-coupled receptor, which belongs to thelargest family of membrane proteins and is the target of many drugs. ß2AR is highlyflexible and, able to recognize a wide range of ligands through its conformationalvariations. Although recent crystallographic experiments have revealed active andinactive conformations, they are not sufficient for deciphering the whole receptor?sdynamics. Molecular dynamics (MD) simulation is an alternative and efficientmethod to understand the protein dynamics. However, traditional all-atomsimulations do not reach the millisecond time scales at which many biologicalprocesses occur. Thus, coarse-grained (CG) modeling is used to reduce the numberof degrees of freedom. The system was composed of ß2AR embedded into apalmitoyl-oleoyl-phosphatidylcholine (POPC) membrane bilayer with surroundingwater. Main purpose of using a CG model is to explore a wider conformational spacethat would not be reachable via all-atom models. The local fluctuations were in goodagreement with all-atom simulations. Four snapshots were selected and reversemappedto all-atom representations. Each was later subjected to 100 ns MDsimulation for equilibration. RMSD clustering yielded distinct receptor conformersthat are both energetically and structurally acceptable. PCA analysis of CG-MDsimulations showed that the first five principle modes explained only 50% of theoverall dynamics compared to 85% in all-atom simulations. Maximum overlap valuebetween eigenvectors of CG and all-atom was determined as 0.46. Normalizedorientational cross-correlations between residue fluctuations revealed weakercorrelations in CG simulations compared to all-atomAPPEND
Investigation of Species-Specific Allosteric Binding Sites in Glycolytic Enzymes Via Allosigma and Molecular Dynamics Simulations
(Kadir Has Üniversitesi, 2021) Çelebi, Metehan; Demet Akdoğan, Ebru
In previous studies of our research group, allosteric sites have been proposed to be used as drug targets in species-specific drug design studies for phosphofructokinase (PFK), glyceraldehyde-3 phosphate dehydrogenase (GADPH) and pyruvate kinase (PK) that belong to three species bacteria, parasite, and human and are essential enzymes in the glycolytic pathway. In this thesis, they were further investigated by various tools such as AlloSigMA and MD simulations. In addition to proposed allosteric sites, known allosteric sites reported by experimental studies for S. aureus PFK and PK enzymes were also investigated. In the first part, AlloSigMA was used to perturb the residues at the proposed and/or known allosteric sites in order to evaluate their allosteric capacities and their effects on protein dynamics. Accordingly, a reduced dynamics in the catalytic sites indicating allosteric inhibition was observed for most of the proposed allosteric sites whereas either an opposite or no effect was observed for known allosteric sites. In addition, partial allosteric inhibition was observed for some of the proposed allosteric sites in human species. In the second part of this thesis, Molecular Dynamics simulations of a total of nine runs, each 100 ns long, were performed for S. aureus phosphofructokinase enzyme in apo and constrained states which incorporated bond restraints at the proposed and known allosteric sites. Here, the goal was to investigate the effect of restraints on the protein's global dynamics. RMSD/RMSF, principal component analysis, the change in orthogonal principal axes, and the mean square distance fluctuation between each pair of residues were determined. According to PCA analysis, increase in the correlation of positional fluctuations between each pair of residues in the chains and domains were observed. Based on the mean square distance fluctuation between residue pairs, each dimer started to communicate more within itself when switched to constrained state.
Citation Count: 3
Transmembrane Helix 6 Observed at the Interface of Beta(2)ar Homodimers in Blind Docking Studies
(Taylor & Francis Inc, 2015) Koroğlu, Ayça; Akten, Ebru Demet
Peptide- and protein-protein dockings were carried out on beta(2)-adrenergic receptor (beta(2)AR) to confirm the presence of transmembrane helix 6 (TM6) at the interface region between two beta(2)AR monomers thereby its possible role in dimerization as suggested in numerous experimental and computational studies. Initially a portion of TM6 was modeled as a peptide consisting of 23 residues and blindly docked to beta(2)AR monomer using a rigid body approach. Interestingly all highest score conformations preferred to be near TM5 and TM6 regions of the receptor. Furthermore longer peptides generated from a whole TM region were blindly docked to beta(2)AR using the same rigid body approach. This yielded a total of seven docked peptides each derived from one TM helix. Most interestingly for each peptide TM6 was among the most preferred binding site region in the receptor. Besides the peptide dockings two beta(2)AR monomers were blindly docked to each other using a full rigid-body search of docking orientations which yielded a total of 16000 dimer conformations. Each dimer was then filtered according to a fitness value based on the membrane topology. Among 149 complexes that met the topology requirements 102 conformers were composed of two monomers oriented in opposite directions whereas in the remaining 47 the monomers were arranged in parallel. Lastly all 149 conformers were clustered based on a root mean-squared distance value of 6 angstrom. In agreement with the peptide results the clustering yielded the largest population of conformers with the highest Z-score value having TM6 at the interface region.