Project Summary/Abstract. With over 800 members, the largest family of human membrane proteins is the G-
protein coupled receptors (GPCRs, also called seven transmembrane receptors), which account for somewhere
between 30 and 40% of pharmaceutical targets. The significance of the family has fueled a flurry of structure
determination work with an explosion of new structures reported in just the last few years. Over the same period,
a lipidomic revolution has changed our view of the membrane environment of GPCRs — it is remarkably complex
and tightly regulated, with distinct lipid compositions in different tissues and in different cellular compartments.
There is abundant evidence that lipids regulate GPCRs. But how does the membrane regulate GPCR
function? For example, the fully active state of a GPCR (the A2A adenosine receptor) is favored by negatively
charged lipids. But, how do we quantify “favors activation?” Answering this very basic question would advance
work that focuses on understanding mechanism in specific targets (like the A2A receptor), or other GPCRs, or
indeed any IMP for which conformational changes couple to the lipids. It would also allow surveying such
mechanisms across entire families (like the GPCRs), to understand lipid regulation across very different
membranes and physiological contexts. And, it would provide a path to quantitatively compare results from well-
controlled model systems and more physiological membrane environments — most GPCRs traffic to the plasma
membrane, which has a complex and asymmetric lipid composition. We propose to pursue this question through
a campaign of simulations and experimental measurements, tightly coordinated and organized by a
thermodynamic model for lipid regulation. By comparing across different GPCRs, membrane environments, and
between different receptor states, we will learn what aspects of functional lipid interactions are conserved, and
also how they vary.