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

Abstract
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Abstract

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 (https://github.com/delemottelab/demystifying, https://github.com/delemottelab/gpcr-string-method-2019 and https://github.com/delemottelab/state-sampling).

The following previously published data sets were used

1. Foyzul Rahman Sabrina Javed Ian Apperly Peter Hansen Carol Holland Klaus Kessler Charlotte Hartwright
(2018) Sources of cognitive conflict and their relevance to Theory of Mind proficiency in healthy aging. A preregistered study
OSF, 10.17605/OSF.IO/9ZMX8.

https://osf.io/9zmx8/

Article and author information

Author details

Oliver Fleetwood

Applied Physics, KTH Royal Institute of Technology, Solna, Sweden

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-4277-2661
Jens Carlsson

Uppsala University, Uppsala, Sweden

Competing interests
No competing interests declared.
Lucie Delemotte

Science for Life Laboratory, Department of Applied Physics, KTH Royal Institute of Technology, Stockholm, Sweden

For correspondence
lucie.delemotte@scilifelab.se

Competing interests
Lucie Delemotte, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0002-0828-3899

Funding

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.

Copyright

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.