Ionotropic glutamate receptors (iGluRs) mediate excitatory neurotransmission and are central to synaptic plasticity as well as a variety of neurological conditions, including epilepsy, schizophrenia, depression, and anxiety. Although high-resolution cryo-EM structures have clarified overall receptor architecture, the dynamic processes of gating, auxiliary subunit modulation, and pore blocker interactions remain incompletely understood. Using extensive fully atomistic molecular dynamics simulations guided by structural data, we investigate the conformational landscapes of distinct iGluR subtypes to elucidate key mechanisms governing receptor activation, desensitization, and inhibition. Our work systematically explores how ligand binding, subunit composition, and regulatory proteins influence conformational transitions of the channel, providing detailed insights into the molecular determinants of gating dynamics and conductance levels in AMPA receptors. We further assess how small-molecule channel blockers interact within the pore to modulate ion conductance in GluK2 kainate receptors. By characterizing receptor conformational ensembles and pinpointing molecular determinants of gating, our study provides a dynamic framework for understanding iGluR function at the molecular level. These findings expand our knowledge of iGluR molecular mechanisms and inform strategies to design targeted therapeutic modulators for neurological disorders.
Aktolun et al. (Sun,) studied this question.