Conformational Changes of the NMDA Receptors Associated with Ethanol-Induced Inhibition

Alcohol addiction ranks among the leading global causes of preventable death and disabilities in human population. Understanding the sites of ethanol action that mediate its acute and chronic effects is critical to develop appropriate treatment options for this disorder. The N-methyl-D-Asparate (NMDA) receptors are ligand- and voltage-gated heterotetrameric ion channels, which not only play a key role in the development and function of the brain but are also known to directly interact with alcohol in a concentration-dependent manner. However, the exact molecular mechanisms and conformational dynamics of this interaction are not yet well understood. Computational studies may shed light at spatiotemporal dimensions that pose limitations to experimental investigations and thereby improve our understanding of the molecular interactions of alcohol with the NMDA receptors in a hypothesis-free manner. Here, we conducted a series of molecular dynamics simulations of the interaction of ethanol molecules at a moderate concentration (20 mM) with the wild-type ligand-free crystal structure GluN1-GluN2B NMDA Receptor of rat (4 Å resolution) under physiological conditions. The co-agonists glutamate and glycine were distributed randomly within the simulation box at concentrations reflecting the active zone of vesicular release. In total, eight configurations were simulated (100 ns/configuration) to investigate sites of action of ethanol as well the conformational dynamics of the NMDA receptor in absence/presence of each co-agonist or ethanol and any combination thereof. The simulations suggest that by a double hydrogen-bond (−2.9 kcal/mol) with tryptophan 635 and phenylalanine 638 located at the transmembrane M3 helix of the GluN2B subunit, alcohol not only reduces the pore radius of the ion channel within the TMD but also decreases accessibility of glutamate to the ligand binding sites by altering the structure of the ligand binding domain and significantly widening the receptor in that area