A Comparative Molecular Dynamics Simulation Study of the Amino Terminal Domain of Ionotropic Glutamate Receptors

Abstract

Glutamate receptors account for the vast majority of excitatory neurotransmission in the vertebrate nervous system. The modular architecture of these membrane receptors consists of an extracellular amino terminal domain (ATD) and ligand binding domain (LBD) as well as a transmembrane ion channel. While numerous water soluble constructs of the LBD have been crystallised, high resolution structures of the ATD have been unavailable till very recently. Multiple long (3 x 50 ns) molecular dynamics simulations of five ATD dimer structures - two GluA2 (AMPA) and three GluK2 (kainate) - were performed to evaluate the stability of the structure and the rigidity of the dimer interface. The dimers remained intact throughout the course of all simulations. Overall, these structures appear to undergo very little motion. It is yet unknown whether the ATD is capable of binding a ligand. Simulations of these ligand-free structures suggest two possible regions with increased flexibility that may lead to a potential binding site. Several water molecules are also conserved across the structures as well as the two families. Electrostatic calculations indicate that the bottom of the ATD and the top of the LBD exposes complementary charge surfaces, which could explain how the two modular regions may interact in the full-length receptor.