State-dependent Lipid Interactions with the A2a Receptor Revealed by MD Simulations Using In Vivo-Mimetic Membranes

Membranes are known to have modulatory effects on G protein-coupled receptors (GPCRs) via specific lipid interactions. However, the mechanisms of such modulations in physiological conditions and how they influence GPCR functions remain unclear. Here we report coarse-grained molecular dynamics simulations on the Adenosine A2a receptor in different conformational states embedded in an in vivo-mimetic membrane model. Nine lipid interaction sites were revealed. The strength of lipid interactions with these sites showed a degree of dependence on the conformational states of the receptor, suggesting that these lipids may regulate the conformational dynamics of the receptor. In particular, we revealed a dual role of PIP₂ on A2aR activation that involves both stabilization of the characteristic outward tilt of TM6 and enhancement of A2aR-mini-Gs association. Our results demonstrated that the bound lipids allosterically regulate the functional properties of GPCRs. These protein-lipid interactions provide a springboard for design of allosteric modulators of GPCRs.