Intercellular communication is essential for many facets of multicellular life. To accomplish this communication, the human genome contains over 800 G protein-coupled receptors (GPCRs), which have evolved to bind thousands of different chemicals and evoke varied cellular responses. Like all embedded proteins, the location and orientation of GPCRs are influenced by the lipidic component of biological membranes, which can also impact protein function via the formation of specific lipid-protein interactions. The beta 2 adrenergic receptor (B2AR) is a well-studied GPCR that mediates the fight-or-flight response and is the target of sixteen approved drugs. However, the stepwise mechanism by which extracellular ligand binding leads the B2AR to activate an intracellular G protein remains unclear. Moreover, molecular dynamics (MD) simulations indicate that, in the absence of an intracellular binding partner, activated forms of the receptor are unstable and undergo deactivation on the microsecond timescale. To understand the source of this instability, we conduct extensive (0.2 millisecond) MD simulations of two forms of the active state of the B2AR and define conditions that are sufficient to prolong receptor activity. The influence of lipid composition on receptor activity identified in these simulations is corroborated by comparison to experiment.<br/>This research was supported by NSF MCB-1050966.

Specific protein-lipid interactions stabilize an active state of the beta 2 adrenergic receptor

249th National Meeting (2015)

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