Glutamate and Glycine Binding to the NMDA Receptor

• Published in: Structure (London) Vol. 26; no. 7; pp. 1035 - 1043.e2
• Main Authors: Yu, Alvin, Lau, Albert Y.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 03.07.2018
• Subjects: Animals; Binding Sites; Crystallography, X-Ray; free energy calculations; glutamate receptors; Glutamic Acid - metabolism; Glycine - metabolism; Humans; ligand binding; Molecular Dynamics Simulation; molecular dynamics simulations; NMDA receptors; Protein Binding; Protein Domains; Protein Structure, Tertiary; Receptors, N-Methyl-D-Aspartate - chemistry; Receptors, N-Methyl-D-Aspartate - metabolism; molecular dynamics simulations; NMDA receptors; free energy calculations; ligand binding; glutamate receptors
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2018.05.004

At central nervous system synapses, agonist binding to postsynaptic ionotropic glutamate receptors (iGluRs) results in signaling between neurons. N-Methyl-D-aspartic acid (NMDA) receptors are a unique family of iGluRs that activate in response to the concurrent binding of glutamate and glycine. Here, we investigate the process of agonist binding to the GluN2A (glutamate binding) and GluN1 (glycine binding) NMDA receptor subtypes using long-timescale unbiased molecular dynamics simulations. We find that positively charged residues on the surface of the GluN2A ligand-binding domain (LBD) assist glutamate binding via a “guided-diffusion” mechanism, similar in fashion to glutamate binding to the GluA2 LBD of AMPA receptors. Glutamate can also bind in an inverted orientation. Glycine, on the other hand, binds to the GluN1 LBD via an “unguided-diffusion” mechanism, whereby glycine finds its binding site primarily by random thermal fluctuations. Free energy calculations quantify the glutamate- and glycine-binding processes. [Display omitted] •Glutamate binds to NMDA receptors via a guided-diffusion mechanism•Glycine binds to NMDA receptors via an unguided-diffusion mechanism•All-atom simulations locate metastable sites that assist glutamate binding•Binding of glutamate can occur in two orientations In the N-methyl-D-aspartic acid receptor family of ionotropic glutamate receptors, the agonist glutamate and its co-agonist glycine bind to their respective subunits by different dynamic mechanisms. Glutamate binding is assisted by structural features on the receptor surface. Glycine binding does not receive such assistance.