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

Abstract

Preferential lipid solvation of the G-protein coupled A2A adenosine receptor (A2AR) is evaluated from 35 μsec of all-atom molecular dynamics simulation. A coarse-grained transition matrix algorithm is developed to overcome slow equilibration of the first solvation shell, obtaining statistically robust 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 GPCR activity is proposed in which the chemical potential of lipids in the bulk membrane modulates receptor activity. The enthalpy and entropy associated with moving saturated vs. unsaturated lipids from bulk to A2AR's first solvation shell are compared. In the simulated mixture, saturated chains are disordered (i.e., obtain a favorable entropic contribution) when partitioning to the receptor surface, but this is outweighed by a favorable enthalpic contribution for unsaturated chains to occupy the first solvation shell.

Toward a Suite of Coarse-Grained Models for Molecular Simulation of Monoclonal Antibodies and Therapeutic Proteins

“…At a minimum, this would include repulsive steric interactions, (screened) electrostatic repulsions and attractions, and short-ranged nonelectrostatic attractions. Additional features might also include contributions from explicit cosolutes, − local hydration layers, − and amphiphilic molecules such as lipids and surfactants. ,− The sequence and/or structure are key inputs to any model as they provide guidance for bead positions and types (e.g., different atoms, united-atom chemical moieties, amino acids, or domains). Protein structure can come from homology modeling or experimental X-ray crystallography, NMR spectroscopy, or electron microscopy …”