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

ORCID ID

0000-0002-5476-4722

Scopus Author ID

7801565973

Full item page

Scholarly Output

23

Articles

13

Citation Count

135

Supervised Theses

7 Scholarly Output Search Results

Now showing 1 - 10 of 22

Citation Count: 28
A Wrench in the Works of Human Acetylcholinesterase: Soman Induced Conformational Changes Revealed by Molecular Dynamics Simulations
(Public Library Science, 2015) Bennion, Brian J.; Eşsiz, Şebnem; Lau, Edmond Y.; Fattebert, Jean-Luc; Emigh, Aiyana; Lightstone, Felice C.
Irreversible inactivation of human acetylcholinesterase (hAChE) by organophosphorous pesticides (OPs) and chemical weapon agents (CWA) has severe morbidity and mortality consequences. We present data from quantum mechanics/molecular mechanics (QM/MM) and 80 classical molecular dynamics (MD) simulations of the apo and soman-adducted forms of hAChE to investigate the effects on the dynamics and protein structure when the catalytic Serine 203 is phosphonylated. We find that the soman phosphonylation of the active site Ser203 follows a water assisted addition-elimination mechanism with the elimination of the fluoride ion being the highest energy barrier at 6.5 kcal/mole. We observe soman-dependent changes in backbone and sidechain motions compared to the apo form of the protein. These alterations restrict the soman-adducted hAChE to a structural state that is primed for the soman adduct to be cleaved and removed from the active site. The altered motions and resulting structures provide alternative pathways into and out of the hAChE active site. In the soman-adducted protein both side and back door pathways are viable for soman adduct access. Correlation analysis of the apo and soman adducted MD trajectories shows that the correlation of gorge entrance and back door motion is disrupted when hAChE is adducted. This supports the hypothesis that substrate and product can use two different pathways as entry and exit sites in the apo form of the protein. These alternative pathways have important implications for the rational design of medical countermeasures.
Citation Count: 12
Sustainable production of formic acid from CO2 by a novel immobilized mutant formate dehydrogenase
(Elsevier, 2023) Tulek, Ahmet; Gunay, Elif; 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 Count: 2
Correlated conformational dynamics of the human GluN1-GluN2A type N-methyl-D-aspartate (NMDA) receptor
(SPRINGER, 2021) Esşiz, Şebnem; Gencel, Melis; 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.
Homology Modeling and Normal Mode Analysis of Human Nr1-Nr2a Nmda Type Receptors
(Kadir Has Üniversitesi, 2017) Demir, Ayhan S.; Gökhan Eşsiz, Şebnem
N-Methyl-D-Aspartate (NMDA) receptors are ionotropic glutamate receptors located in the membrane of the nerve cells. The normal receptor activity has a vital importance in consciousness and normal brain functions. Neuronal death occurs as a result of overstimulation of NMDA-type glutamate receptors and leads to diseases such as stroke epilepsy Alzheimer's and Parkinson's. There are two recently available x-ray structures one from Xenopus laevis and the other one from Rattus norvegicus. First the structures were analyzed and compared especially for ion channel parts by considering the general problems that arise when crystallizing structures of membrane proteins. Then human GluNR1-GluNR2A type NMDA receptor structure was modeled by homology modeling based on the Xenopus laevis template. NMDA receptor structure is a large membrane protein complex thus we followed a couple of different strategies such as modeling by the individual monomer modeling as a tetramer and modeling as a tetramer without loops then adding loops with loop modeling. Final models were chosen according to the model assessment scoring function. Subsequently elastic network analysis was used to understand the dynamics of the structural variations which govern the function of the protein. 20 slowest modes of NMDA receptor were examined according to 8 parameters which are found to be functionally important in previous NMDA studies. The 3th slowest mode was noticeable regarding to gating mechanism. in Mode 3 a twist motion of the TMD part rotates clockwise parallel to the membrane while LBD and TMD together rotate counter-clock wise parts cause opening of the channel. Mode 3 showed the relationship between TMD girdles LDB and M3-TMD linker. Similarly Mode 9 like Mode 3 showed the same relationship. in addition Mode 9 showed like a breathing motion or expansion motion along the channel axis. We hope that these modes will be tested by a more through all atom molecular dynamics study of apo and ligand bound human NMDA structure in the near future.
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
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.
Structural Studies of Nmda Receptor and Xanthine Oxidase Enzyme
(Kadir Has Üniversitesi, 2019) Gencel, Melis; Gökhan Eşsiz, Şebnem
The first part of the thesis deals with the structural studies of N-Methyl-D-Aspartate receptors (NMDARs). NMDARs are ionotropic ligand-gated receptors that have pivotal roles at the central neuronal system but, hyperactivity of NMDARs could contribute to neurodegenerative diseases. Therefore, understanding the activation mechanism of NMDARs is important as it may lead to the development of new treatments for neurodegenerative diseases. In this thesis, human GluN1/GluN2A type NMDAR is modeled based on GluN1/GluN2B type NMDA structures that were resolved in 2014. To observe the dynamics of NMDA, 1.3 microseconds molecular dynamics simulations are performed for ligand-free and ligand-bound structures in the physiological environment. RMSD, RMSF, and PCA have been used to analyze the trajectory to understand the di↵erences in ligand-free and ligand-bound structures collective motions. From these analyses, the di↵erences in between ligand-free and ligand-bound simulations can be summarized as the following: Ligand-binding domain closure is observed, and these rearrangements are reflected to the transmembrane linkers upon ligand binding. Correlation maps from PCA analysis display more correlated motions in ligand-bound simulations. As a summary, mainly ligands act like an adhesive for the binding-domain by bringing the bi-lobe structures together and consequently, this is reflected in the overall dynamics of the protein. In the second part of this thesis, Xanthine Oxidase (XO) enzyme has been studied for the potency of bis-chalcones compounds. 8 bis-chalcones compounds that were provided to us from Serdar Burmalıo˘glu’s research group, showed high inhibition behavior on XO. These 8 molecules are docked to XO catalytic unit and 1000 run is performed for each compound. All compounds show better results than its approved drug which is allopurinol, however, the best ones are fifth and seventh compounds. In addition, all these compounds have three similar binding modes but, the first pose has the lowest free binding energy
Structural Study of Gaba Type a Receptor : the Effect of Intrasubunit Disulphide Bridges on Dynamics
(Kadir Has Üniversitesi, 2014) Ayan, Meral; 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
Yapısal ve Mutasyonel Çalışmalar: Nmda Tipi Glutamat Reseptörü ve Format Dehidrogenaz Enziminin Moleküler Dinamik Simülasyonları
(2023) Servili, Burak; Eşsiz, Şebnem
Yapısal biyoloji ve moleküler dinamik (MD) simülasyon çalışmaları, moleküler düzeyde moleküller arası/içi etkileşimleri anlamanın temellerinden, ilaç ve protein tasarımının önde gelen yöntemlerinden biridir. Bu tez, iki farklı alandaki protein simülasyonlarından oluşmaktadır: Sinir hücrelerinde elektrik sinyali yayılımında bir iyon kanalı reseptör kompleksi olan N-metil-D-aspartat reseptörü (NMDAR) ve formatın bikarbonata biyokatalizinde format dehidrojenaz enzimi (FDH). Tezin ilk amacı NMDAR iyon kanalının açık yapısını mutasyonlarla elde etmektir. İkinci amaç ise allosterik bölgede Asp188Arg mutasyonu yaparak FDH enziminin hem format hem de bikarbonat substratları ile etkileşimlerini anlamaktır. Bu mutasyon deneysel olarak FDH'nin bikarbonat/CO2 yakalama için kullanımı yönünde olan ters reaksiyon için daha aktif bir enzim yaratmıştır. Bu amaçla, nano ölçekli moleküler dinamik (NAMD) uygulaması, kök-ortalama-kare sapması, kök-ortalama-kare dalgalanması ve protein-ligand etkileşim analizi yöntemleriyle birlikte simülasyonları çalıştırmak için kullanılmıştır. İlk durumda, NMDAR iyon kanalının üst kapısındaki Lurcher motifindeki alanin (A7), deneysel çalışmalara dayanarak arginin/tirozin ile değiştirildi. Analiz sonucunda NMDAR iyon kanalının açık yapısı elde edildi. FDH'nin MD simülasyonlarında, bikarbonat bağlı yapı, enzimin subtrat ve koenzim bağlanma bölgelerini ayıran önemli bir tuz köprüsünü korumuştur. Ek olarak, bağlanma bölgesinden substrat taşınımı, vahşi tip ve mutasyona uğramış yapılar için farklı yollar sergilemiştir. Her iki protein sistemi için de MD, harici pertürbasyonların proteinlerin yapısı ve işlevi, yani işlevsel mutasyonlar üzerindeki etkisini incelemek için ana araç olarak kullanılmıştır. Her iki protein de hareketlerin zaman ölçeği, sistem boyutu ve istenen ters reaksiyon yönünde düşük enzim aktivitesi nedeniyle yapısal bir çalışma için karmaşık sistemler oluşturmuştur.
Message-Passing Based Algorithm for the Global Alignment of Clustered Pairwise Ppi Networks
(Kadir Has Üniversitesi, 2013) Yenigün, Doğan Yiğit; 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.
Effects of Nerve Agents on Conformational Dynamics of Acetylcholinesterase
(Kadir Has Üniversitesi, 2021) Güleşen, Sevilay; Gökhan, Şebnem Eşsiz
Human acetylcholinesterase (hAChE), an essential enzyme in the central and peripheral nervous system, hydrolyses acetylcholine (ACh) at the cholinergic synapses. Organophosphorus pesticides (OPs), also called nerve agents, can inactivate the hAChE irreversibly and leads to serious morbidity (such as paralysis, cognitive deficiencies, and seizures) and even mortality consequences based on the amount of exposure and rapidness of treatment. Therefore, understanding the inhibition mechanism of hAChE by OPs, such as soman and sarin, is critical since it may guide developing a new and efficient treatment for poisoning by the nerve agents. The effects of soman inhibition on the dynamics of the hAChE were investigated in comparison with the results of the molecular dynamics study of the apo form and another OP adducted, i.e. soman adducted, form of hAChE in 2005. To understand the changes in the protein structure of hAChE after binding soman, 40 MD data were published. In this thesis, we aimed to find how sarin phosphorylation of the active site Ser203 residue of the hAChE affects the protein dynamics and to compare the result with the previously discovered results of the apo and soman-adducted hAChE. First, 40 classical MD simulations for the sarin adducted hAChE were run with the exact parameters of the apo and soman-adducted hAChE simulations. The sarin adducted hAChE was used for the MD simulations. Resulting trajectories were analyzed with RMSD analysis, principal component analysis (PCA), and K-means clustering algorithm calculations to understand the differences between collective motions of the apo, soman adducted, and sarin adducted hAChE. According to the results, the sarin molecule has an alternative pathway for entering and leaving from the active site of the hAChE like the soman molecule. The back door area when it is calculated from the backbone atoms versus the sidechain atoms shows a significant different behavior. The backbone atoms calculation of the sarin-adducted gives similar results with the apo simulation. However, there is a significant third peak at much larger value observed in the calculation of the sarin-adducted sidechain. That might be an alternative pathway for entrance to the molecule. Also, the gorge entrance and back door motion correlation is affected when hAChE is adducted by sarin, depending on correlation analysis. This disruption and the previous mentioned above area results support the hypothesis about alternative pathways for entrance and exit in the protein. All these motions and alternative pathways are critical for the development of the treatment of sarin poisoning. Keywords: Molecular dynamic simulation, acetylcholinesterase, sarin, soman, principal component analysis