Thermodynamics of the NMDA Receptor Amino-Terminal Domain

Abstract

The N-methyl-D-aspartate receptor (NMDAR) is a ligand-gated ion channel found in post-synaptic neurons that is critically important in learning and memory. This tetrameric membrane protein has two extracellular domains, a ligand-binding domain (LBD) and an amino-terminal domain (ATD), that control the movement of ions through the channel. Specifically, conformational changes in the ATD layer have been linked to the allosteric regulation of channel gating. Previous structural studies of the GluN1/GluN2B NMDAR have identified a ∼20° opening of the GluN2B ATD and a ∼15° rotation of the GluN1 and GluN2B ATD subunits with respect to the dimer interface in the presence of allosteric modulators. In this investigation, we constructed models of both GluN1 and GluN2B ATD monomers and the GluN1/GluN2B dimer with and without allosteric modulators. We then selected order parameters that capture the range of conformational motion adopted by these domains. By performing free energy molecular dynamics simulations, we gain insight into the thermodynamics that drive these observed structural changes.