The G-protein coupled receptors (GPCRs) are an enormous superfamily of transmembrane signaling proteins, comprising some 800 members. GPCRs are found in every imaginable physiological context, from vision, to immune response, to taste and smell, to the nervous system. It is estimated that the GPCRs account for the targets of nearly half of the drugs presently on the market, making them perhaps the most pharmacologically interesting protein family.

We use high-performance computing resources and molecular simulation to study signaling by the A2A adenosine receptor, a member of the GPCR family of interest in the treatment of Parkinson’s disease. A2A is also one of the major targets of caffeine—the most widely consumed psychoactive substance in the world. Our aims are to (1) Rationalize differences in specificity and efficacy among different synthetic ligands, and (2) Understand the role of the membrane in modulating signaling by A2A.