Free Energy Simulations Resolve the Low Affinity Na+- High Affinity Aspartate Binding Paradox in Gltph (Biophysical Journal)

Glutamate transporters clear up excess extracellular glutamate by cotransporting three Na+ and one H+ with the countertransport of one K+. The archaeal homologs are selective to aspartate and only cotransport three Na+. The crystal structures of Gltph from archaea have been used in computational studies to understand the transport mechanism. While some progress have been made with regard to the ligand binding sites, a consistent picture of transport still eludes us. A major concern is the discrepancy between the computed binding free energies, which predict high affinity Na+- low affinity aspartate binding, and the experimental results where the opposite is observed.