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

Main Affiliation

Molecular Biology and Genetics

Sustainable Development Goals Report Points

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Scholarly Output

39

Articles

23

Citation Count

41

Supervised Theses

7 Scholarly Output Search Results

Now showing 1 - 10 of 34

Citation - WoS: 1
Citation - Scopus: 1
Exploring Distinct Binding Site Regions of Beta(2)-Adrenergic Receptor Via Coarse-Grained Molecular Dynamics Simulations
(Scientific Technical Research Council Turkey-Tubitak, 2013) Cakan, Sibel; Akdoğan, Ebru Demet; Akdoğan, Ebru Demet; Molecular Biology and Genetics
beta(2)-Adrenergic receptor (beta(2)AR) is a G protein-coupled receptor that is highly flexible and able to recognize a wide range of ligands through its conformational variations. Active and inactive conformations revealed by recent crystallographic experiments do not provide a complete dynamic picture of the receptor especially in the binding site. In this study molecular dynamics (MD) simulation through a residue-based coarse-grained model is used as an alternative and efficient method to explore a wider conformational search space. The system was composed of beta(2)AR embedded into a 1-palmitoyl-2-oleoyl-phosphatidylcholine membrane bilayer with surrounding water. A total of 6 mu s of simulation at constant NPT was performed for a system of 6868 coarse-grained beads. The system reached equilibrium at around 0.1 mu s. The overall 3-dimensional structure was well preserved throughout the simulation. Local residue-based fluctuations were in good agreement with fully atomistic MD simulations. Four distinct snapshots were selected and reverse-mapped to all-atom representations with around 65000 atoms. Each reverse-mapped system was later subjected to 100 ns of MD simulation for equilibration. Root mean square deviation clustering analysis yielded distinct receptor conformers for the binding site regions which were suggested to be alternative representations of the binding pocket and thus were proposed as plausible targets in docking-based virtual screening experiments for the discovery of novel antagonists.
Citation - WoS: 1
Citation - Scopus: 1
Tunnel-Like Region Observed as a Potential Allosteric Site In Staphylococcus Aureus Glyceraldehyde-3 Dehydrogenase
(Elsevier Science inc, 2024) Guner-Yilmaz, Ozde Zeynep; Akdoğan, Ebru Demet; Kurkcuoglu, Ozge; Akten, Ebru Demet; Molecular Biology and Genetics
Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) catalyzing the sixth step of glycolysis has been investigated for allosteric features that might be used as potential target for specific inhibition of Staphylococcus aureus (S.aureus). X-ray structure of bacterial enzyme for which a tunnel-like opening passing through the center previously proposed as an allosteric site has been subjected to six independent 500 ns long Molecular Dynamics simulations. Harmonic bond restraints were employed at key residues to underline the allosteric feature of this region. A noticeable reduction was observed in the mobility of NAD+ binding domains when restrictions were applied. Also, a substantial decrease in cross-correlations between distant C alpha fluctuations was detected throughout the structure. Mutual information (MI) analysis revealed a similar decrease in the degree of correspondence in positional fluctuations in all directions everywhere in the receptor. MI between backbone and sidechain torsional variations changed its distribution profile and decreased considerably around the catalytic sites when restraints were employed. Principal component analysis clearly showed that the restrained state sampled a narrower range of conformations than apo state, especially in the first principal mode due to restriction in the conformational flexibility of NAD+ binding domain. Clustering the trajectory based on catalytic site residues displayed a smaller repertoire of conformations for restrained state compared to apo. Representative snapshots subjected to k-shortest pathway analysis revealed the impact of bond restraints on the allosteric communication which displayed distinct optimal and suboptimal pathways for two states, where observed frequencies of critical residues Gln51 and Val283 at the proposed site changed considerably.
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; Akdoğan, Ebru Demet; Molecular Biology and Genetics
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.
Citation - WoS: 3
Citation - Scopus: 3
Transmembrane Helix 6 Observed at the Interface of Beta(2)ar Homodimers in Blind Docking Studies
(Taylor & Francis Inc, 2015) Koroğlu, Ayça; Akdoğan, Ebru Demet; Akten, Ebru Demet; Molecular Biology and Genetics
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.
Citation - WoS: 0
Investigation of Allosteric Communication Pathways in Human Beta 2-Adrenergic Receptor
(Wiley-Blackwell, 2015) Akdaş, Başak; Akdoğan, Ebru Demet; Kürkçüoğlu, Özge; Doruker, Pemra; Akten, Ebru Demet; Molecular Biology and Genetics
[Abstract Not Available]
Investigation of Species-Specific Allosteric Binding Sites in Glycolytic Enzymes Via Allosigma and Molecular Dynamics Simulations
(Kadir Has Üniversitesi, 2021) Çelebi, Metehan; Akdoğan, Ebru Demet; Demet Akdoğan, Ebru; Molecular Biology and Genetics
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 - WoS: 17
Citation - Scopus: 20
In Silico Design of Novel and Highly Selective Lysine-Specific Histone Demethylase Inhibitors
(Scientific Technical Research Council Turkey-Tubitak, 2011) Akdoğan, Ebru Demet; Akdoğan, Ebru Demet; Erman, Burak; Yelekçi, Kemal; Yelekçi, Kemal; Molecular Biology and Genetics
Histone lysine-specific demethylase (LSD1) is involved in a wide range of epigenetic processes and plays important roles in gene silencing DNA transcription DNA replication DNA repair and heterochromatin formation. Its active site shows a resemblance to those of 2 homologous enzymes monamine oxidase A and B (MAO-A and MAO-B.) In the present work starting from suitable scaffolds and generating thousands of structures from them 10 potential inhibitors were obtained with structural and physicochemical properties selectively suitable for inhibiting LSD1. iLib Diverse software was used to generate the diverse structures and 3 docking tools CDOCKER GOLD and AutoDock were used to find the most probable potential inhibitor based on its binding affinity. The dispositions of the candidate molecules within the organism were checked by ADMET_PSA_2D (polar surface area) versus ADMET_AlogP98 (the logarithm of the partition coefficient between n-octanol and water) and their suitability is discussed. The LSD1 inhibition activities of the candidates were compared with the properties of trans-2-phenylcyclopropylamine (tranylcypromine) and 2-(4-methoxy-phenyl) cyclopropylamine which are the 2 known inhibitors of LSD1.
Citation - WoS: 10
Citation - Scopus: 10
Ligand-Binding Affinity of Alternative Conformers of Human Beta(2)-Adrenergic Receptor in the Presence of Intracellular Loop 3 (icl3) and Their Potential Use in Virtual Screening Studies
(Wiley, 2019) Dilcan, Gonca; Akdoğan, Ebru Demet; Doruker, Pemra; Akten, Ebru Demet; Molecular Biology and Genetics
This study investigates the structural distinctiveness of orthosteric ligand-binding sites of several human beta(2) adrenergic receptor (beta(2)-AR) conformations that have been obtained from a set of independent molecular dynamics (MD) simulations in the presence of intracellular loop 3 (ICL3). A docking protocol was established in order to classify each receptor conformation via its binding affinity to selected ligands with known efficacy. This work's main goal was to reveal many subtle features of the ligand-binding site presenting alternative conformations which might be considered as either active- or inactive-like but mostly specific for that ligand. Agonists inverse agonists and antagonists were docked to each MD conformer with distinct binding pockets using different docking tools and scoring functions. Mostly favored receptor conformation persistently observed in all docking/scoring evaluations was classified as active or inactive based on the type of ligand's biological effect. Classified MD conformers were further tested for their ability to discriminate agonists from inverse agonists/antagonists and several conformers were proposed as important targets to be used in virtual screening experiments that were often limited to a single X-ray structure.
Citation - WoS: 39
Citation - Scopus: 41
A Docking Study Using Atomistic Conformers Generated Via Elastic Network Model for Cyclosporin A/Cyclophilin A Complex
(Taylor & Francis Inc, 2009) Akten, Ebru Demet; Akdoğan, Ebru Demet; Cansu, Sertan; Doruker, Pemra; Molecular Biology and Genetics
Anisotropic network model is used to generate a set of distinct conformations for cylophilin A (CypA). The native structure is deformed to different extents along each of the lowest-frequency modes (first 7 modes) both in negative and positive directions. Each node of the elastic network represents either a single atom in the high-resolution model or a single residue in the low-resolution model. Realistic conformations with energies close to or lower than the crystal structure and with satisfactory internal geometry are recovered by energy minimization using implicit solvation model. These conformations are then used for ensemble docking to the ligand cyclosporin A for both a further test of accuracy of generated conformers and exploration of different binding modes. Higher number of correctly docked ligands are obtained for conformations with low deformation factors as a result of lower root mean square distances with respect to crystal structure. Yet Surprisingly the lowest binding energy is obtained for one of the highly deformed conformations as a result of its special contact with arginine side chain oriented towards binding site. Considering the fact that the cyclic ligand's backbone and protein's side chains are held rigid during docking the conformers generated by high- and low-resolution elastic network models are almost equally successful in providing the correct binding mode. The shape of the binding pocket that incorporates crucial interaction sites for hydrogen bond formation is found to be another important determining factor for the success of the dock. Also the small backbone variations of a few angstrom ngstroms in magnitude at the loop regions surrounding the binding pocket can cause amino acids' side chains to be displaced by magnitudes of up to 10 angstrom and therefore have a strong influence on the efficiency of the conformational search during docking.
Citation - WoS: 2
Citation - Scopus: 2
Information Transfer in Active States of Human ?2-Adrenergic Receptor Via Inter-Rotameric Motions of Loop Regions
(Mdpi, 2022) Sogunmez, Nuray; Akdoğan, Ebru Demet; Akten, Ebru Demet; Molecular Biology and Genetics
Featured Application Loop regions in beta(2)AR are critical hot spot regions, likely in other GPCRs, and can be used as potential allosteric drug targets. Two independent 1.5 mu s long MD simulations were conducted for the fully atomistic model of the human beta2-adrenergic receptor (beta(2)AR) in a complex with a G protein to investigate the signal transmission in a fully active state via mutual information and transfer entropy based on alpha-carbon displacements and rotameric states of backbone and side-chain torsion angles. Significant correlations between fluctuations in alpha-Carbon displacements were mostly detected between transmembrane (TM) helices, especially TM5 and TM6 located at each end of ICL3 and TM7. Signal transmission across beta(2)-AR was quantified by shared mutual information; a high amount of correspondence was distinguished in almost all loop regions when rotameric states were employed. Moreover, polar residues, especially Arg, made the most contribution to signal transmission via correlated side-chain rotameric fluctuations as they were more frequently observed in loop regions than hydrophobic residues. Furthermore, transfer entropy identified all loop regions as major entropy donor sites, which drove future rotameric states of torsion angles of residues in transmembrane helices. Polar residues appeared as donor sites from which entropy flowed towards hydrophobic residues. Overall, loops in beta(2)AR were recognized as potential allosteric hot spot regions, which play an essential role in signal transmission and should likely be used as potential drug targets.