Quantifying Water-Mediated Protein-Ligand Interactions in a Glutamate Receptor

Abstract

It is becoming increasingly clear that careful treatment of water molecules in ligand-protein interactions is required in many cases if the correct binding pose is to be identified in molecular docking. Water can form complex bridging networks and can play a critical role in dictating the binding mode of ligands. A particularly striking example of this can be found in the ionotropic glutamate receptors. Despite possessing similar chemical moieties, crystal structures of glutamate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) in complex with the ligand-binding core of the GluA2 ionotropic glutamate receptor revealed, contrary to all expectation, two distinct modes of binding. The difference appears to be related to the position of water molecules within the binding pocket. However, it is unclear exactly what governs the preference for water molecules to occupy a particular site in any one binding mode. In this work we use density functional theory (DFT) calculations to investigate the interaction energies and polarization effects of the various components of the binding pocket. Our results show i) that the ligand and its binding mode dictate the interaction energy of a key water molecule which can be thought of as part of the ligand rather than part of the protein ii) that polarization effects can be large and iii) that the interaction energy of a neighbouring water is particularly large (compared to the other waters in the binding pocket) and may offer a route to compounds with improved affinity if it can be displaced. We discuss the results within the broader context of drug-design.