Ionotropic glutamate receptors (iGluRs) mediate neurotransmission at the majority of excitatory synapses in the brain. Little is known, however, about how the neurotransmitter glutamate reaches the recessed binding pocket in iGluR ligand-binding domains (LBDs). Here we report the process of glutamate binding to a prototypical iGluR, GluA2, in atomistic detail using both enhanced sampling and unbiased molecular dynamics simulations. Charged residues on the LBD surface are found to form pathways that facilitate glutamate binding by effectively reducing a three-dimensional diffusion process to a spatially-constrained two-dimensional one. Free energy calculations identify residues that metastably interact with glutamate and help guide it into the binding pocket. These simulations also reveal that glutamate can bind in an inverted conformation and also reorient while in its pocket. Electrophysiological recordings demonstrate that eliminating these transient binding sites slows activation and deactivation, consistent with slower glutamate binding and unbinding. These results suggest that binding pathways have evolved to optimize rapid responses of GluA-type iGluRs at synapses.

Binding to glutamate receptors: Follow the yellow brick road

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.