Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate the majority of excitatory synaptic transmission in the central nervous system. The free energy of neurotransmitter-binding to the ligand-binding domains (LBDs) of iGluRs is converted into useful work to drive receptor activation. Here, the principal thermodynamic contributions from ligand-docking and ligand-induced LBD closure are computed for nine ligands of GluA2 using all-atom molecular dynamics free energy simulations. The results are validated by a comparison with experimentally measured apparent affinities to the isolated LBD. Features in the free energy landscapes governing LBD closure are critical determinants of binding free energies. An analysis of accessible LBD conformations transposed into the context of an intact GluA2 receptor reveals that the relative displacement of specific diagonal subunits in the tetrameric structure may be key to the action of partial agonists.