Browsing by Author "Aktolun, Muhammed"

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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.
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.