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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\n                    <jats:sub>2A<\/jats:sub>\n                    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\n                    <jats:sub>2A<\/jats:sub>\n                    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.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1009152","type":"journal-article","created":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T13:35:13Z","timestamp":1637760913000},"page":"e1009152","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Deciphering conformational selectivity in the A2A adenosine G protein-coupled receptor by free energy simulations"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4951-9220","authenticated-orcid":true,"given":"Willem","family":"Jespers","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1381-8464","authenticated-orcid":true,"given":"Laura H.","family":"Heitman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriaan P.","family":"IJzerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eddy","family":"Sotelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard J. 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