Conformational analysis of kainate in aqueous solution in relation to its binding to AMPA and kainic acid receptors

Conformational analyses for kainate in aqueous solution have been performed by using the MM3*, AMBER* and MMFF94 force fields in conjunction with the Generalized Born Solvent Accessible Surface (GB/SA) hydration model. A comparison of calculated results with experimentally determined conformational data indicates that MM3*-GB/SA strongly overestimates the stability of a hydrogen bonded ion-pair in aqueous solution in comparison with the separated and solvated ions. This results in an incorrect prediction by MM3* of the most stable conformer of kainate in aqueous solution, whereas AMBER* and MMFF94 correctly predict the lowest energy conformer. Calculated conformational energy penalties for binding of kainate to the AMPA iGluR2 receptor indicate that the lower affinity of kainate for AMPA receptors compared to its affinity for kainic acid (KA) receptors is not due to a higher energy bioactive conformation of kainate at AMPA receptors. This conclusion is strongly supported by an analysis of a recently reported nonselective AMPA/KA ligand and a comparison of the conformational and structural properties of this ligand with iGluR2-bound kainate. This comparison strongly suggests that kainate binds to AMPA and KA receptors in closely the same conformation.