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Correlated conformational dynamics of the human GluN1-GluN2A type N-methyl-D-aspartate (NMDA) receptor

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Date
2021
Author
Esşiz, Şebnem
Gencel, Melis
Aktolun, Muhammed
Demir, Ayhan
Carpenter, Timothy S.
Servili, Burak
Abstract
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.

Source

JOURNAL OF MOLECULAR MODELING

Issue

6

Volume

27

URI

https://hdl.handle.net/20.500.12469/4030

Collections

  • Araştırma Çıktıları / Scopus [1565]
  • Araştırma Çıktıları / WOS [1518]

Keywords

Ligand gated ion channels
Ionotropic glutamate receptors
Molecular dynamics
Principal component analysis
Homology and loop modeling

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DSpace software copyright © 2002-2015  DuraSpace
Contact Us | Send Feedback
Theme by 
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