How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors?

• Published in: PloS one Vol. 13; no. 8; p. e0201234
• Main Authors: Palmai, Zoltan, Houenoussi, Kimberley, Cohen-Kaminsky, Sylvia, Tchertanov, Luba
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03.08.2018; Public Library of Science (PLoS)
• Subjects: Allosteric properties; Binding sites; Binding Sites, Glutamic Acid/metabolism, Glycine/metabolism, Humans, Ion Channel Gating, Ligands, Molecular Docking Simulation, Molecular Dynamics Simulation, Protein Binding, Protein Interaction Domains and Motifs, Protein Structure, QuaternaryRe ceptors, N-Methyl-D-Aspartate/agonists, Receptors, N-Methyl-D-Aspartate/chemistry , Receptors, N-Methyl-D-Aspartate/metabolism, Structural Homology, Protein; Biochemistry, Molecular Biology; Bioinformatics; Biology and Life Sciences; Blood-brain barrier; Cancer; Central nervous system; Channel gating; Communication; Computer Science; Computer simulation; Conformation; Crystallography; Docking; Dynamic models; Glutamic acid receptors (ionotropic); Glycine; Hypertension; Ion channels; Ion channels (ligand-gated); Kinases; Life Sciences; Ligands; Medication; Medicine and Health Sciences; Modeling and Simulation; Modular structures; Modulators; Molecular dynamics; N-methyl-D-aspartate; N-Methyl-D-aspartic acid receptors; Neurological diseases; Neuromodulation; Neurotransmission; Pharmaceutical sciences; Physical Sciences; Polyamines; Proteins; Receptors; Research and Analysis Methods; Structural Biology; Synchronism; Synchronization; France
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0201234

NMDA-type glutamate receptors (NMDAR) are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system. NMDAR dysfunction has been found to be involved in various neurological disorders. Recent crystallographic and EM studies have shown the static structure of different states of the non-human NMDARs. Here we describe a model of a human NMDA receptor (hNMDAR) and its molecular dynamics (MD) before and after the binding of agonist ligands, glutamate and glycine. It is shown that the binding of ligands promotes a global reduction in molecular flexibility that produces a more tightly packed conformation than the unbound hNMDAR, and a higher cooperative regularity of moving. The ligand-induced synchronization of motion, identified on all structural levels of the modular hNMDA receptor is apparently a fundamental factor in channel gating. Although the time scale of the MD simulations (300 ns) was not sufficient to observe the complete gating event, the obtained data has shown the ligand-induced stabilization of hNMDAR that conforms the "going to be open state". We propose a mechanistic dynamic model of the ligand-dependent gating mechanism in the hNMDA receptor. At the binding of the ligands, the differently twisted conformations of the highly flexible receptor are stabilized in unique conformation with a linear molecular axis, which is a condition that is optimal for pore development. By searching the receptor surface, we have identified three new pockets, which are different from the pockets described in the literature as the potential and known positive allosteric modulator binding sites. A successful docking of two NMDAR modulators to their binding sites validates the model of a human NMDA receptor as a biological relevant target.