Identification of ligand-specific G-protein coupled receptor states and prediction of downstream efficacy via data-driven modeling

  1. Oliver Fleetwood
  2. Jens Carlsson
  3. Lucie Delemotte  Is a corresponding author
  1. KTH Royal Institute of Technology, Sweden
  2. Uppsala University, Sweden


Ligand binding stabilizes different G protein-coupled receptor states via a complex allosteric process that is not completely understood. Here, we have derived free energy landscapes describing activation of the β2 adrenergic receptor bound to ligands with different efficacy profiles using enhanced sampling molecular dynamics (MD) simulations. These reveal shifts towards active-like states at the G protein binding site for receptors bound to partial and full agonists and that the ligands modulate the conformational ensemble of the receptor by tuning protein microswitches. We indeed find an excellent correlation between the conformation of the microswitches close to the ligand binding site and in the transmembrane region and experimentally reported cAMP signaling responses. Dimensionality reduction further reveals the similarity between the unique conformational states induced by different ligands and examining the output of classifiers highlights two distant hotspots governing agonism on transmembrane helices 5 and 7.

Data availability

The data necessary to reproduce the findings presented in this paper can be found on OSF (DOI 10.17605/OSF.IO/B5RAV). The code used to run and analyze simulations has been deposited on GitHub (, and

The following previously published data sets were used

Article and author information

Author details

  1. Oliver Fleetwood

    Applied Physics, KTH Royal Institute of Technology, Solna, Sweden
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4277-2661
  2. Jens Carlsson

    Uppsala University, Uppsala, Sweden
    Competing interests
    No competing interests declared.
  3. Lucie Delemotte

    Science for Life Laboratory, Department of Applied Physics, KTH Royal Institute of Technology, Stockholm, Sweden
    For correspondence
    Competing interests
    Lucie Delemotte, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0828-3899


Göran Gustafssons Stiftelse

  • Jens Carlsson
  • Lucie Delemotte

Science for Life Laboratory

  • Jens Carlsson
  • Lucie Delemotte

Vetenskapsrådet (2017-4676)

  • Jens Carlsson

Swedish strategic research program eSSENCE

  • Jens Carlsson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Toby W Allen, RMIT University, Australia

Publication history

  1. Received: July 3, 2020
  2. Accepted: January 27, 2021
  3. Accepted Manuscript published: January 28, 2021 (version 1)
  4. Version of Record published: February 16, 2021 (version 2)
  5. Version of Record updated: November 24, 2022 (version 3)


© 2021, Fleetwood et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.


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  1. Oliver Fleetwood
  2. Jens Carlsson
  3. Lucie Delemotte
Identification of ligand-specific G-protein coupled receptor states and prediction of downstream efficacy via data-driven modeling
eLife 10:e60715.

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