Browsing by Author "Balle, T"

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    Binding and dynamics demonstrate the destabilization of ligand binding for the S688Y mutation in the NMDA receptor GluN1 subunit
    (MDPI, 2023-05-15) Chen, JZ; Church, WB; Bastard, K; Duff, AP; Balle, T
    Encephalopathies 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.
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    Effects of mutations in the NMDA receptor GluN1 subunit on binding and dynamics: a computational approach
    (International Union of Crystallography, 2021-08-14) Chen, Z; Church, WB; Bastard, K; Duff, AP; Balle, T
    N-methyl-D-aspartate receptors (NMDARs) are central to the pathophysiology of neurodegenerative diseases such as schizophrenia [1], however despite significant structural insights of the receptor [2,3,4,5] the importance of mutations in the NMDAR have been poorly described in the literature. Here we present molecular dynamics simulation data combined with modelling and binding free energy calculations to outline the effects of mutations [6] in the GluN1 subunit of the NMDAR on agonist binding affinity and ligandreceptor interactions. Our data demonstrates the changes caused by the positioning of an introduced tyrosine residue at the binding pocket and its associated changes in the conformation upon ligand binding. Furthermore, molecular dynamics simulations demonstrate the changes in ligand environment in the ligand-receptor complex leading to a loss of key interactions and an associated instability of the bound complex. Lastly, binding free energy calculations show that it is no longer energetically favourable for ionic interactions to form and an associated overall increase in Gibbs free energy for ligand binding. These data are important in explaining the changes in behaviour for mutations in the GluN1 ligand binding region and are consistent with previously reported experiments [7]. We are also pursuing experimental approaches to further understand the action of ligand binding. © 2021 The Authors