Browsing by Author "Eurasto, Felix"

G protein-coupled receptors (GPCRs) constitute the largest family of receptors in humans. They are involved in the regulation of major biological processes including sight, taste, and mood. Due to their prevalence in the human body and involvement in such a wide range of tasks, GPCRs are medically extremely important. GPCRs are cell-surface receptors, responsible for conveying biological messages from the extracel- lular domain to the cytoplasmic region. As such, GPCRs are constantly interacting with the lipids of the cell membrane. These interactions are thought to mediate the activation behaviour of the GPCRs, although the exact nature of these effects is often unknown. The beta-2 adrenergic receptor (β2AR) is a class-A GPCR, whose native ligand is adrenaline. It plays a crucial role in the inactivation of the sympathetic nervous system to trigger the fight-or-flight response. Many GPCRs exhibit basal activity. That is, these receptors can activate even in the absence of an activating ligand. β2AR is one of these GPCRs. The specific cause and mechanism of basal activity are often unknown and, as of the start of the project presented in this thesis, were undetermined for β2AR. We used high-throughput fully atomistic molecular dynamics (MD) simulations coupled with ma- chine learning (ML) methods to ascertain specific interactions between a highly conserved aspartate residue of β2AR and phosphatidylcholine (PC) lipids that stabilize the active state of β2AR. We also found that cholesterol plays a role in mediating these interactions. These results shed light on the effect of the lipid composition of one’s cell membranes, and by extension one’s lipid diet, on the activation behaviour of β2AR, a medically extremely relevant receptor.