Şebnem Eşsiz

Eşsiz, Şebnem

Name Variants

Eşsiz, Şebnem
Eşsiz, Sebnem
E., Sebnem
Sebnem Eşsiz
Eşsiz, Ş.
Essiz, Sebnem
Essiz,Sebnem
Şebnem Eşsiz
S. Eşsiz
Essiz,Ş.
E., Şebnem
Eşsiz, S.
DAVUTYAN N.
Eşsiz, ŞEBNEM
Ş. Eşsiz
Şebnem EŞSIZ
Eşsiz,Ş.
EŞSIZ, Şebnem
E.,Sebnem
Essiz,S.
ŞEBNEM EŞSIZ
Sebnem, Essiz
Davutyan N.
EŞSIZ, ŞEBNEM
Gökhan, Şebnem Eşsiz
Eşsiz, Şebnem
Eşsiz Gökhan, Şebnem
Gökhan Eşsiz, Şebnem
Gökhan, Şebnem Eşsiz
Essız, Sebnem
Eşsiz, Şebnem
Essız, Sebnem
Eşsiz Gökhan, Şebnem

Job Title

Dr. Öğr. Üyesi

Email Address

sebnem.gokhan@khas.edu.tr

Main Affiliation

Molecular Biology and Genetics

Scholarly Output

23

Articles

13

Citation Count

135

Supervised Theses

7 Scholarly Output Search Results

Now showing 1 - 10 of 22

Citation - WoS: 2
Citation - Scopus: 2
Correlated conformational dynamics of the human GluN1-GluN2A type N-methyl-D-aspartate (NMDA) receptor
(SPRINGER, 2021) Eşsiz, Şebnem; Servili, Burak; Aktolun, Muhammed; Demir, Ayhan; Carpenter, Timothy S.; Servili, Burak
N-Methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels found in the nerve cell membranes. As a result of overexcitation of NMDARs, neuronal death occurs and may lead to diseases such as epilepsy, stroke, Alzheimer's disease, and Parkinson's disease. In this study, human GluN1- GluN2A type NMDAR structure is modeled based on the X-ray structure of the Xenopus laevis template and missing loops are added by ab-initio loop modeling. The final structure is chosen according to two different model assessment scores. To be able to observe the structural changes upon ligand binding, glycine and glutamate molecules are docked into the corresponding binding sites of the receptor. Subsequently, molecular dynamics simulations of 1.3 mu s are performed for both apo and ligand-bound structures. Structural parameters, which have been considered to show functionally important changes in previous NMDAR studies, are monitored as conformational rulers to understand the dynamics of the conformational changes. Moreover, principal component analysis (PCA) is performed for the equilibrated part of the simulations. From these analyses, the differences in between apo and ligand-bound simulations can be summarized as the following: The girdle right at the beginning of the pore loop, which connects M2 and M3 helices of the ion channel, partially opens. Ligands act like an adhesive for the ligand-binding domain (LBD) by keeping the bi-lobed structure together and consequently this is reflected to the overall dynamics of the protein as an increased correlation of the LBD with especially the amino-terminal domain (ATD) of the protein.
Citation - WoS: 47
Citation - Scopus: 51
New Azole Derivatives Showing Antimicrobial Effects and Their Mechanism of Antifungal Activity by Molecular Modeling Studies
(Elsevier France-Editions Scientifiques Medicales Elsevier, 2017) Doğan, İnci Selin; Eşsiz, Şebnem; Saraç, Selma; Sarı, Suat; Kart, Didem; Eşsiz, Şebnem; Vural, İmran; Dalkara, Sevim
Azole antifungals are potent inhibitors of fungal lanosterol 14 alpha demethylase (CYP51) and have been used for eradication of systemic candidiasis clinically. Herein we report the design synthesis and biological evaluation of a series of 1-phenyl/1-(4-chlorophenyl)-2-(1H-imidazol-1-yl) ethanol esters. Many of these derivatives showed fungal growth inhibition at very low concentrations. Minimal inhibition concentration (MIC) value of 15 was 0.125 mu g/mL against Candida albicans. Additionally some of our compounds such as 19 (MIC: 0.25 mu g/mL) were potent against resistant C. glabrata a fungal strain less susceptible to some first-line antifungal drugs. We confirmed their antifungal efficacy by antibiofilm test and their safety against human monocytes by cytotoxicity assay. To rationalize their mechanism of action we performed computational analysis utilizing molecular docking and dynamics simulations on the C. albicans and C. glabrata CYP51 (CACYP51 and CGCYP51) homology models we built. Leu130 and T131 emerged as possible key residues for inhibition of CGCYP51 by 19. (C) 2017 Elsevier Masson SAS. All rights reserved.
Structural Study of Gaba Type a Receptor : the Effect of Intrasubunit Disulphide Bridges on Dynamics
(Kadir Has Üniversitesi, 2014) Ayan, Meral; Eşsiz, Şebnem; Gökhan Eşsiz, Şebnem
In the mammalian brain the gamma-aminobutyric acid type A receptor is the most commonly expressed subtype of receptor family. Although there is a rich pharmacological activity of R, specific molecular features are still not well known. In this study, we developed a new homology model based on a recently available X-Ray structure of the glutamate-gated chloride channel. When it is compared with previous homology models of the based on lower sequence identity templates, there are three additional disulphide bridges occurring in between membrane spanning alpha helices namely two in the alpha and one in the gamma subunits. These new disulphide bridges are occurring due to the differences in the sequence alignments of template and target structures. Additionally, we performed molecular dynamics simulations with two models, one with the disulphide bridges in the transmembrane domanin, and the other without disulphide bridges. To analyze simulation results, minimum pore radius along the pore, root-mean-square deviation of proteins and root mean square fluctuation of alpha are analyzed. Finally principal component analysis of the 100 nanosecond long trajectory is calculated to compare the differences in the correlated motions of two models
Citation - WoS: 26
Citation - Scopus: 26
Sustainable production of formic acid from CO2 by a novel immobilized mutant formate dehydrogenase
(Elsevier, 2023) Eşsiz, Şebnem; Servili, Burak; Servili, Burak; Essiz, Sebnem; Binay, Baris; Yildirim, Deniz
Formate dehydrogenase (NAD+-dependent FDH) is an enzyme that catalyzes the reversible oxidation of formate to CO2 while reducing NAD+ to NADH. The enzyme has been used in industrial and chemical applications for NADH regeneration for a long time. However, discovering the unique ability of FDHs, which is to reduce CO2 and produce formic acid, leads studies focusing on discovering or redesigning FDHs. Despite using various protein engineering techniques, these studies mostly target the same catalytic site amino acids of FDHs. Here, for the first time, the effect of an Asp188 mutation on a potential allosteric site in NAD+-dependent CtFDH around its subunit-subunit interface was studied by molecular modelling and simulation in the presence of bicarbonate and formate. Biochemical and kinetic characterization of this Asp188Arg mutant and wild type CtFDH enzymes were performed in detail. Both enzymes were also immobilized on newly synthesized MWCNT-Ni-O-Si/Ald and MWCNT-Ni-O-Si/Glu supports designed to overcome well-known CtFDH stability problems including thermostability and reuse resistance. Integrating mutation and immobilization provided about a 25-fold increase in catalytic efficiency for carbonate activity. The one-way ANOVA analysis also ensured significant effect of the mutation and immobilization on kinetic constants. After characterizing the immobilization of highly purified wild type and mutant enzyme with instrumental analysis techniques, the thermal stability of MWCNT-Ni-Si@wtCtFDH and MWCNT-Ni-Si@mt-CtFDH was found to increase about 11-and 18-fold, respectively, compared to their free counterparts at 50 degrees C. The mutant CtFDH and its immobilized counterpart produced around 2-fold more formic acid than those of wild type CtFDH and its immobilized counterpart under the same conditions. MWCNT-Ni-Si@wt-CtFDH and MWCNT-Ni-Si@mt-CtFDH remained around 82 % and 86 % of their initial activities respectively after lots of recycling. Integration of subunit interface amino acid position of NAD+ dependent FDHs engineering and immobilization provides a new insight can be scientifically and rationally employed for this current application FDHs as a solution to produce formic acids from renewable sources.
Citation - WoS: 0
Soman as a Wrench in the Works of Human Acetylcholinesterase: Soman Induced Conformational Changes Revealed by Molecular Dynamics Simulations
(Amer Chemical Soc, 2014) Bennion, Brian J.; Eşsiz, Şebnem; Eşsiz, Şebnem; Lau, Edmond Y.; Fattebert, Jean-Luc; Emigh, Aiyana; Lightstone, Felice C.
[Abstract Not Available]
Citation - WoS: 1
Citation - Scopus: 1
Modelling of C-Terminal Tail of Human Sting and Its Interaction With Tank-Binding Kinase 1
(Tubitak Scientific & Technical Research Council Turkey, 2022) Ata Ouda Al-Masri, Rahaf; Eşsiz, Şebnem; Audu-Bida, Hajara; Essiz, Sebnem
Stimulator of interferon genes (STING) plays a significant role in a cell's intracellular defense against pathogens or self DNA by inducing inflammation or apoptosis through a pathway known as cGAS-cGAMP-STING. STING uses one of its domains, the C-terminal tail (CTT) to recruit the members of the pathway. However, the structure of this domain has not been solved experimentally. STING conformation is open and more flexible when inactive. When STING gets activated by cGAMP, its conformation changes to a closed state covered by 4 beta-sheets over the binding site. This conformational change leads to its binding to Tank-binding kinase 1 (TBK1). TBK1 then phosphorylates STING aiding its entry to the cell's nucleus. In this study, we focused on the loop modeling of the CTT domain in both the active and inactive STING conformations. After the modeling step, the active and inactive STING structures were docked to one of the cGAS-cGAMP-STING pathway members, TBK1, to observe the differences of binding modes. CTT loop stayed higher in the active structure, while all the best-scored models, active or inactive, ended up around the same position with respect to TBK1. However, when the STING poses are compared with the cryo-EM image of the complex structure, the models in the active structure chain B displayed closer results to the complex structure.
Citation - WoS: 5
Citation - Scopus: 7
Computational Analysis of a Zn-Bound Tris(imidazolyl) Calix[6]arene Aqua Complex: Toward Incorporating Second-Coordination Sphere Effects Into Carbonic Anhydrase Biomimetics
(Amer Chemical Soc, 2013) Koziol, Lucas; Eşsiz, Şebnem; Eşsiz, Şebnem; Wong, Sergio E.; Lau, Edmond Y.; Valdez, Carlos A.; Satcher, Joe H. Jr.; Aines, Roger D.; Lightstone, Felice C.
Molecular dynamics simulations and quantum-mechanical calculations were performed to characterize a supra-molecular tris(imidazolyl) calix[6]arene Zn2+ aqua complex as a biomimetic model for the catalyzed hydration of carbon dioxide to bicarbonate H2O + CO2 -> H+ + HCO3-. On the basis of potential-of-mean-force (PMF) calculations stable conformations had distorted 3-fold symmetry and supported either one or zero encapsulated water molecules. The conformation with an encapsulated water molecule is calculated to be lower in free energy than the conformation with an empty cavity (Delta G = 1.2 kcal/mol) and is the calculated free-energy minimum in solution. CO2 molecule partitioning into the cavity is shown to be very facile proceeding with a barrier of 1.6 kcal/mol from a weak encounter complex which stabilizes the species by about 1.0 kcal/mol. The stabilization energy of CO2 is calculated to be larger than that of H2O (Delta Delta G = 1.4 kcal/mol) suggesting that the complex will preferentially encapsulate CO2 in solution. In contrast the PMF for a bicarbonate anion entering the cavity is calculated to be repulsive in all nonbonding regions of the cavity due to the diameter of the calix[6]arene walls. Geometry optimization of the Zn-bound hydroxide complex with an encapsulated CO2 molecule showed that multiple noncovalent interactions direct the reactants into optimal position for nucleophilic addition to occur. The calixarene complex is a structural mimic of the hydrophilic/hydrophobic divide in the enzyme providing a functional effect for CO2 addition in the catalytic cycle. The results show that Zn-binding calix[6]arene scaffolds can be potential synthetic biomimetics for CO2 hydration catalysis both in terms of preferentially encapsulating CO2 from solution and by spatially fixing the reactive species inside the cavity.
Loop Modeling and Molecular Dynamics Simulations of Apo and Ligand-Bound Human Glun1-Hlun2a Nmda Type Receptors
(Kadir Has Üniversitesi, 2017) Aktolun, Muhammed; Eşsiz, Şebnem; Eşsiz, Şebnem
N-Methyl-D-Aspartate receptors (NMDARs) are glutamate-gated ion channels found in the nerve cell membranes. The functioning of the receptor is of crucial importance in consciousness and normal brain functions. As a result of overexcitation of NMDARs neuronal death occurs and may lead to diseases such as epilepsy stroke Alzheimer's and Parkinson's. Understanding the molecular mechanism and structure function relationships of the receptor might lead to discovery of new drug target mechanisms. Recently there are two intact X-ray structures available one is from Xenopus laevis and the other one is from Rattus norvegicus for GluN1-GluN2B type NMDA receptor. First both Xray structures are examined and compared for the ion channel especially by taking the general problems into consideration which arise from crystallization conditions. Human GluN1- GluN2A type NMDAR structure is modeled based on the structure of Xenopus laevis template and missing loops are added by ab-initio loop modeling. Final structure is chosen according to the model assessment scoring function. NMDAR activation requires binding of two coagonists glycine and glutamate. To be able to observe the structural changes upon ligand binding glycine and glutamate molecules are docked into the corresponding binding sites of the receptor. Subsequently Molecular Dynamics (MD) simulations of 1 microsecond are performed for both apo and ligand-bound structures. 10 structural parameters which have been considered as functionally important in previous NMDA studies are developed to understand the dynamics of the conformational changes that is associated with the function of the protein throughout the simulations. Moreover Principal Component Analysis is performed for the equilibrated part of the simulations to classify similar conformations together. in the ligand-bound simulation certain loop regions showed higher mobility. Upon ligand binding closure in LBD clamshell smaller ATD-LBD inter-domain distance and larger LBDTMD linker distance is observed in specific subunits. Opening in the bottom TMD girdle is observed for a short time. Correlated motions of the receptor in the ligand-bound simulation increased. The structure showed rotation-like motion in the apo simulation whereas slidinglike motion within the neighboring heterodimers are observed.
Citation - WoS: 3
Citation - Scopus: 3
The Neural Gamma(2)alpha(1)beta(2)alpha(1)beta(2) Gamma Amino Butyric Acid Ion Channel Receptor: Structural Analysis of the Effects of the Ivermectin Molecule and Disulfide Bridges
(Springer, 2018) Ayan, Meral; Eşsiz, Şebnem; Eşsiz, Şebnem
While similar to 30% of the human genome encodes membrane proteins only a handful of structures of membrane proteins have been resolved to high resolution. Here we studied the structure of a member of the Cys-loop ligand gated ion channel protein superfamily of receptors human type A gamma(2)alpha(1)beta(2)alpha(1)beta(2) gamma amino butyric acid receptor complex in a lipid bilayer environment. Studying the correlation between the structure and function of the gamma amino butyric acid receptor may enhance our understanding of the molecular basis of ion channel dysfunctions linked with epilepsy ataxia migraine schizophrenia and other neurodegenerative diseases. The structure of human gamma(2)alpha(1)beta(2)alpha(1)beta(2) has been modeled based on the X-ray structure of the Caenorhabditis elegans glutamate-gated chloride channel via homology modeling. The template provided the first inhibitory channel structure for the Cys-loop superfamily of ligand-gated ion channels. The only available template structure before this glutamate-gated chloride channel was a cation selective channel which had very low sequence identity with gamma aminobutyric acid receptor. Here our aim was to study the effect of structural corrections originating from modeling on a more reliable template structure. The homology model was analyzed for structural properties via a 100 ns molecular dynamics (MD) study. Due to the structural shifts and the removal of an open channel potentiator molecule ivermectin from the template structure helical packing changes were observed in the transmembrane segment. Namely removal of ivermectin molecule caused a closure around the Leu 9 position along the ion channel. In terms of the structural shifts there are three potential disulfide bridges between the M1 and M3 helices of the gamma(2) and 2 alpha(1) subunits in the model. The effect of these disulfide bridges was investigated via monitoring the differences in root mean square fluctuations (RMSF) of individual amino acids and principal component analysis of the MD trajectory of the two homology models-one with the disulfide bridge and one with protonated Cys residues. In all subunit types RMSF of the transmembrane domain helices are reduced in the presence of disulfide bridges. Additionally loop A loop F and loop C fluctuations were affected in the extracellular domain. In cross-correlation analysis of the trajectory the two model structures displayed different coupling in between the M2-M3 linker region protruding from the membrane and the beta 1-beta 2/D loop and cys-loop regions in the extracellular domain. Correlations of the C loop which collapses directly over the bound ligand molecule were also affected by differences in the packing of transmembrane helices. Finally more localized correlations were observed in the transmembrane helices when disulfide bridges were present in the model. The differences observed in this study suggest that dynamic coupling at the interface of extracellular and ion channel domains differs from the coupling introduced by disulfide bridges in the transmembrane region. We hope that this hypothesis will be tested experimentally in the near future.
Message-Passing Based Algorithm for the Global Alignment of Clustered Pairwise Ppi Networks
(Kadir Has Üniversitesi, 2013) Yenigün, Doğan Yiğit; Eşsiz, Şebnem; Erten, Cesim; Eşsiz Gökhan, Şebnem; Aşıcı, Tınaz Ekim
Constrained global network alignments on pairwise protein-protein interaction (PPI) networks involve matchings between two organisms where proteins are grouped together in a great number of clusters, produced by algorithms that seek functionally ortholog ones and these organisms are represented as graphs. Unlike balanced global network alignments, this has not gained much popularity in bioinformatics. Only a few methods have been proposed thus far; by assuming specific structures of networks including the clusters themselves and the density of the PPI networks are not too large, then optimal alignments can be encountered. Here, we introduce a general-purpose algorithm that is able to work on any kind of graph structures while taking advantage of the message-passing method, based on propagation between clusters. When these graphs satisfy conditions like continuous interaction connectivity of proteins across all neighbored clusters, in addition to previous explanations, the optimality of alignments can still be achieved. Convergence of the cluster network can occur at the point where the maximum number of conserved interactions are detected. Many experiments were made with balanced GNA algorithms and our algorithm may find more conservations and more importantly, alignments have higher biological quality than other ones in various instances.