Browsing by Author "Gökhan, Şebnem Eşsiz"

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Docking Study of Resveratrol Like Molecules on Histone Deacetylase
(Kadir Has Üniversitesi, 2016) Alnemsi, Fatma; Yelekçi, Kemal; Gökhan, Şebnem Eşsiz
The modulation of histone acetylation plays a pivotal role in the regulation of gene expression by governing the state of lysine residues located on the amino – terminal tails of histone proteins. A dynamic balance of histone acetylation /deacetylation is maintained by histone acetyl transferases(HAT) and histone deacetylases(HDACs) . Due to their fundamental role in gene expression HDAC family have been associated with basic cellular events and disease states such as cell growth differentiation and cancer information. in particular distinct class i and ii are overexpressed in some cancer disease. HDAC inhibitors structurally can be grouped into hydroxamates cyclic peptides aliphatic acids benzamine’s. HDAC inhibitors (HDACi) and histone acetyl transferase activators increase histone acetylation. HDAC8 is a class i HDAC implicated as a therapeutic target for a various disease including disorder cell growth. The structure of this enzyme reaveled unique features as its conformational flexibility. The architecture of the catalytic site and the channel rim of HDAC8 adapt to accommodate various ligands according to their size shape and chemical properties. Ýn this study the native TSA ligand of HDAC8 (code 1T64) re docked to observe the inhibition constant (Ki) with different parameter such as rotatable bonds and X Y Z coordinates. From this approach starting de nova design from resveratrol compound that is suggested to play a role in the preventation of some disease such as inhibition of tumour initiation. The resveratrol scaffold was used to create 100 hundred analogues by substituting chemical groups to observe the changes in the binding energy and inhibition constant by molecular docking using Autodock4.2. These 100 analogues were evaluated in terms of the inhibition constant (Ki) and 20 of them selected due to their lowest inhibition constant (Ki) and binding energy. The fact that HDAC8 is a promising target for cancer therapy these molecules can be potential anticancer agents if additional laboratory assays are carried out to ascertain their inhibitory effects.
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
Homology Modeling and Normal Mode Analysis of Human Nr1-Nr2a Nmda Type Receptors
(Kadir Has Üniversitesi, 2017) Demir, Ayhan S.; Gökhan Eşsiz, Şebnem; Gökhan, Şebnem Eşsiz
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.
Identifying the Working Principles of Human Dna Methyltransferase 3a Enzyme by Computational Methods
(Kadir Has Üniversitesi, 2021) Savaş, Büşra; Eşsiz Gökhan, Şebnem; Karaca Erek, Ezgi; Gökhan, Şebnem Eşsiz; Erek, Ezgi Karaca
DNA metilasyonu, metilasyon deseninin sürdürülmesi ve oluşturulmasından sorumlu epigenetik mekanizmalardan biridir. DNA metiltransferaz 3 (DNMT3) enzim ailesi DNA'nın sıfırdan metilasyonunu düzenler bu nedenle de novo metiltransferazlar olarak adlandırılır. İki üyesi, DNMT3A ve DNMT3B, DNA ve S-Adenosilmetiyonin (SAM) arasındaki reaksiyonu katalize eder. Diğer üyesi olan DNMT3L ise DNA ile doğrudan etkileşime girmese de, DNMT3A ve DNMT3B'ye bağlanarak reaksiyonu allosterik olarak hızlandırır. Ek olarak, reaksiyonun etkinliğinin DNMT3A: DNMT3L kompleksinin oluşumu ile daha da arttığı görülmüştür. DNMT3A: DNMT3L kompleksi, proteinler arasında hidrofobik arayüzün oluştuğu heterodimer ve hem hidrofobik hem de hidrofilik arayüzler içeren heterotetramer formunda olarak bulunur. Bu çalışmada, bu arayüzlerin ve DNMT3L'nin DNMT3A'nın çalışma prensipleri üzerindeki etkisini bulmayı hedefledik. Bu amaç doğrultusunda, DNM3L'nin allosterik etkisini tespit etmek için PCA analizini kullandık. Ek olarak, MD simülasyonu sırasında meydana gelen protein-DNA etkileşimleri hem heterodimer hem de heterotetramer kompleksleri için incelendi.
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; Gökhan, Şebnem Eşsiz
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.
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; Gökhan, Şebnem Eşsiz
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.
Nmda Tipi Glutamat Reseptörlerinin Çalışma Mekanizması ve Açık İyon Kanalı İnhibitörleri ile Etkileşimleri
(2018) Carpenter, Tim; Gökhan, Şebnem Eşsiz
Bu projenin amacı glutamat ve glisin nörotransmitterleri ile aktive olan tetramerik yapıdaki, ligant kapılı iyon kanalı ailesinin bir üyesi olan NMDA (N-metil-D-Aspartat) tipi glutamat reseptör iyon kanalının, iyon iletimine kapalı ve açık hallerinin hesaplamalı metotlar ile karakterize edilmesi üzerinedir. Projede bilgisayar bazlı sayısal metotlar kullanılarak reseptörde ligant bağlanması sonucu gerçeklesen lokal ve global hareketler hakkında bilgi elde edilmiştir. Projenin ilk basamağında NMDA reseptörünün yeni çözümlenmiş olan iki X- Ray yapısı baz alınıp, homoloji modellemesi yöntemi kullanılarak insan tipi NMDA modeli elde edilmiştir. Daha sonrasında proteinin dominant hareketlerini belirlemek icin normal mod analizini kullanılmıştır. Proteinler dinamik bir sistem olduğundan sayısal benzetim yöntemi olan moleküler dinamik metoduyla ligand-olmayan ve ligand-bağlı iki sistem simüle edilmiştir. 1300 nanosaniye koşturulan sistemlerde ligand bağlandığı bölgede kapanmaya sebep olurken, bu hareketin bağlayıcılar tarafından iyon kanalına iletildiği gözlemlenmiştir. Bu simülasyonların sonucunda gözlemlediğimiz bir diğer etki ise, ligant bağlandığı bölgeyi daha stabil hala getirerek reseptörün diğer bölgeleri ile etkileşimleri artırmaktadır.
Structural Studies of Nmda Receptor and Xanthine Oxidase Enzyme
(Kadir Has Üniversitesi, 2019) Gencel, Melis; Gökhan Eşsiz, Şebnem; Gökhan, Şebnem Eşsiz
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; Gökhan, Şebnem Eşsiz
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