Open AccessDeciphering conformational selectivity in the A2A adenosine G protein-coupled receptor by free energy simulations
Author(s) -
Willem Jespers,
Laura H. Heitman,
Adriaan P. IJzerman,
Eddy Sotelo,
Gerard J. P. van Westen,
Johan Åqvist,
Hugo GutiérrezdeTerán
Publication year - 2021
Publication title -
plos computational biology/plos computational biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.628
H-Index - 182
eISSN - 1553-7358
pISSN - 1553-734X
DOI - 10.1371/journal.pcbi.1009152
Subject(s) - g protein coupled receptor , receptor , biophysics , ligand (biochemistry) , adenosine a2a receptor , adenosine receptor , chemistry , conformational change , extracellular , signal transduction , protein structure , biochemistry , biology , agonist
Transmembranal G Protein-Coupled Receptors (GPCRs) transduce extracellular chemical signals to the cell, via conformational change from a resting (inactive) to an active (canonically bound to a G-protein) conformation. Receptor activation is normally modulated by extracellular ligand binding, but mutations in the receptor can also shift this equilibrium by stabilizing different conformational states. In this work, we built structure-energetic relationships of receptor activation based on original thermodynamic cycles that represent the conformational equilibrium of the prototypical A 2A adenosine receptor (AR). These cycles were solved with efficient free energy perturbation (FEP) protocols, allowing to distinguish the pharmacological profile of different series of A 2A AR agonists with different efficacies. The modulatory effects of point mutations on the basal activity of the receptor or on ligand efficacies could also be detected. This methodology can guide GPCR ligand design with tailored pharmacological properties, or allow the identification of mutations that modulate receptor activation with potential clinical implications.