Binding and dynamics demonstrate the destabilization of ligand binding for the S688Y mutation in the NMDA receptor GluN1 subunit

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dc.contributor.authorChen, JZen_AU
dc.contributor.authorChurch, WBen_AU
dc.contributor.authorBastard, Ken_AU
dc.contributor.authorDuff, APen_AU
dc.contributor.authorBalle, Ten_AU
dc.date.accessioned2024-10-03T21:26:39Zen_AU
dc.date.available2024-10-03T21:26:39Zen_AU
dc.date.issued2023-05-15en_AU
dc.date.statistics2024-09-18en_AU
dc.description.abstractEncephalopathies are brain dysfunctions that lead to cognitive, sensory, and motor development impairments. Recently, the identification of several mutations within the N-methyl-D-aspartate receptor (NMDAR) have been identified as significant in the etiology of this group of conditions. However, a complete understanding of the underlying molecular mechanism and changes to the receptor due to these mutations has been elusive. We studied the molecular mechanisms by which one of the first mutations within the NMDAR GluN1 ligand binding domain, Ser688Tyr, causes encephalopathies. We performed molecular docking, randomly seeded molecular dynamics simulations, and binding free energy calculations to determine the behavior of the two major co-agonists: glycine and D-serine, in both the wild-type and S688Y receptors. We observed that the Ser688Tyr mutation leads to the instability of both ligands within the ligand binding site due to structural changes associated with the mutation. The binding free energy for both ligands was significantly more unfavorable in the mutated receptor. These results explain previously observed in vitro electrophysiological data and provide detailed aspects of ligand association and its effects on receptor activity. Our study provides valuable insight into the consequences of mutations within the NMDAR GluN1 ligand binding domain. © 2023 by the authors. Licensee MDPI, Basel, Switzerland. Open access CC BY.en_AU
dc.description.sponsorshipThis work was supported by the National Computational Merit Allocation Scheme (NCMAS) 2022 (Grant number NCMAS 2022-154) and the Sydney Informatics Hub HPC Access Scheme 2022 and 2023. J.Z.C is in receipt of an Australian Government Research Training Program (RTP) Scholarship.en_AU
dc.format.mediumElectronicen_AU
dc.identifier.articlenumber4108en_AU
dc.identifier.citationChen, J. Z., Church, W. B., Bastard, K., Duff, A. P., & Balle, T. (2023). Binding and dynamics demonstrate the destabilization of ligand binding for the S688Y mutation in the NMDA receptor GluN1 subunit. Molecules, 28(10), 4108. www.mdpi.com/1420-3049/28/10/4108en_AU
dc.identifier.issn1431-5157en_AU
dc.identifier.issn1420-3049en_AU
dc.identifier.issue10en_AU
dc.identifier.journaltitleMoleculesen_AU
dc.identifier.urihttps://doi.org/10.3390/molecules28104108en_AU
dc.identifier.urihttps://apo.ansto.gov.au/handle/10238/15711en_AU
dc.identifier.volume28en_AU
dc.languageEnglishen_AU
dc.language.isoenen_AU
dc.publisherMDPIen_AU
dc.subjectLigandsen_AU
dc.subjectMutationsen_AU
dc.subjectReceptorsen_AU
dc.subjectGermaniumen_AU
dc.subjectNitrogenen_AU
dc.subjectEtiologyen_AU
dc.subjectMoleculesen_AU
dc.titleBinding and dynamics demonstrate the destabilization of ligand binding for the S688Y mutation in the NMDA receptor GluN1 subuniten_AU
dc.typeJournal Articleen_AU
dcterms.dateAccepted2023-05-11en_AU
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