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

Structure. 2019 Feb 5;27(2):392-403.e3. doi: 10.1016/j.str.2018.10.024. Epub 2018 Dec 20.


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.

Keywords: GM3; GPCR; PIP(2); adenosine A2a receptor; cholesterol; lipid bilayer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Binding Sites
  • Cholesterol / metabolism
  • Gangliosides / metabolism
  • Humans
  • Lipid Bilayers / metabolism*
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Receptor, Adenosine A2A / chemistry*
  • Receptor, Adenosine A2A / metabolism*


  • ADORA2A protein, human
  • Gangliosides
  • Lipid Bilayers
  • Phosphatidylinositol 4,5-Diphosphate
  • Receptor, Adenosine A2A
  • sialogangliosides
  • Cholesterol