N-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors that play a crucial role in signal transmission, memory, and learning in the brain. NMDA receptor dysfunction leads to a number of disorders including schizophrenia, epilepsy and autism. However, the atomistic details of how NMDA receptors function have not been fully understood. Further, while there are many compounds known to alter NMDA receptor function, many lack the selective and nuanced modulation that is needed in a central nervous system drug. Using molecular dynamics simulations and Markov state modeling, we predict the mechanisms through which recently discovered positive (e.g. GNE-6901) and negative allosteric modulators (e.g. TCN-201) may affect channel dynamics at an atomistic level. Specifically, these ligands bind to GluN1 or GluN2A ligand binding domains of NMDA receptors and initiate a cascade of allosteric interactions between the aforementioned domains, as well as other domains of NMDA receptors, most importantly the transmembrane domain. Eventually, this modulation leads to an increased or decreased ion flow through NMDA receptors, respectively. We further discuss how even endogenous modification to NMDA receptors, namely glycosylation, plays a role in intramolecular potentiation. Better understanding of these dynamic mechanisms of NMDA receptor activation and modulation may lead to improved rational therapeutic approaches that intervene into the brain activity in a more delicate manner, evading the side effects of the currently available therapies.

Fine-tuned allosteric regulation of neuronal NMDA receptors with potential therapeutic importance

253rd National Meeting (2017)

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