Structural and Energetic Effects of A2A Adenosine Receptor Mutations on Agonist and Antagonist Binding

摘要: To predict structural and energetic effects of point mutations on ligand binding is considerable interest in biochemistry pharmacology. This not only useful connection with site-directed mutagenesis experiments, but could also allow interpretation prediction individual responses to drug treatment. For G-protein coupled receptors systematic has provided the major part functional data as information until recently been very limited. pharmacologically important A2A adenosine receptor, extensive agonist antagonist available crystal structures both types complexes have determined. Here, we employ a computational strategy, based molecular dynamics free energy simulations, rationalize interpret alanine-scanning experiments for this receptor. These computer simulations show excellent agreement experimental and, most importantly, reveal details behind observed which are often immediately evident from structures. The work further provides distinct validation strategy used assess point-mutations binding. It highlights importance considering protein-ligand interactions those mediated by solvent water molecules, design projects.