Deciphering conformational selectivity in the A2A adenosine G protein-coupled receptor by free energy simulations

PLoS Computational Biology, vol. 17, pp. e1009152

Abstract

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 A2A adenosine receptor (AR). These cycles were solved with efficient free energy perturbation (FEP) protocols, allowing to distinguish the pharmacological profile of different series of A2AAR 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.

Authors 7

1. Willem Jespers corresponding Aachen Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University · Uppsala University

   Affiliation as printed

   Department of Cell and Molecular Biology, Uppsala University, Biomedical Center (BMC), Uppsala, Sweden

   Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden, The Netherlands

2. Laura H. Heitman Aachen Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University · Oncode Institute

   Affiliation as printed

   Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden, The Netherlands

   Oncode Institute, Leiden, Leiden

3. Adriaan P. IJzerman Aachen Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden, The Netherlands

4. Eddy Sotelo

   Universidade de Santiago de Compostela · Centro Singular de Investigación en Química Biológica y Materiales Moleculares

   Affiliation as printed

   Centro Singular de Investigación en Química Biolóxica y Materiais Moleculares (CIQUS), Santiago de Compostela, Spain

   Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, Santiago de Compostela, Spain

5. Gerard J. P. van Westen Aachen Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden, The Netherlands

6. Johan Åqvist

   Uppsala University

   Affiliation as printed

   Department of Cell and Molecular Biology, Uppsala University, Biomedical Center (BMC), Uppsala, Sweden

7. Hugo Gutiérrez‐de‐Terán corresponding

   Uppsala University

   Affiliation as printed

   Department of Cell and Molecular Biology, Uppsala University, Biomedical Center (BMC), Uppsala, Sweden

   Science for Life Laboratories, BMC, Uppsala, Sweden