Activation of G-protein-coupled receptors is thermodynamically linked to lipid solvation

Preferential lipid solvation of the G-protein-coupled A(2A) adenosine receptor (A(2A)R) is evaluated from 35 ms of all-atom molecular dynamics simulation. A coarse-grained transition matrix algorithm is developed to overcome slow equilibration of the first solvation shell, obtaining estimates of the free energy of solvation by different lipids for the receptor in different activation states. Results indicate preference for solvation by unsaturated chains, which favors the active receptor. A model for lipid-dependent G-protein-coupled receptor activity is proposed in which the chemical potential of lipids in the bulk membrane modulates receptor activity. The entropies associated with moving saturated and unsaturated lipids from bulk to A(2A)R's first solvation shell are evaluated. Overall, the acyl chains are more disordered (i.e., obtain a favorable entropic contribution) when partitioning to the receptor surface, and this effect is augmented for the saturated chains, which are relatively more ordered in bulk.

Automated summary

The study shows a preference of the A(2A) adenosine receptor for unsaturated lipid solvation, favoring active receptor states. A model for lipid-dependent G-protein-coupled receptor activity is proposed, suggesting that the chemical potential of lipids in the membrane modulates receptor activity. The acyl chains become more disordered when moving from bulk membrane to the receptor surface, with a more pronounced effect observed for saturated chains.