Activation/Deactivation Free-Energy Profiles for the β2-Adrenergic Receptor: Ligand Modes of Action

Calderón Reyes J, Ibrahim P, Gobbo D, Gervasio FL, Clark T (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Journal of Chemical Information and Modeling American Chemical Society

Book Volume: 63

Pages Range: 6332-6343

Journal Issue: 20

DOI: 10.1021/acs.jcim.3c00805

Abstract

We use enhanced-sampling simulations with an effective collective variable to study the activation of the β2-adrenergic receptor in the presence of ligands with different efficacy. The free-energy profiles are computed for the ligand-free (apo) receptor and binary (apo-receptor + G-protein α-subunit and receptor + ligand) and ternary complexes. The results are not only compatible with available experiments but also allow unprecedented structural insight into the nature of GPCR conformations along the activation pathway and their role in the activation mechanism. In particular, the simulations reveal an unexpected mode of action of partial agonists such as salmeterol and salbutamol that arises already in the binary complex without the G-protein. Specific differences in the polar interactions with residues in TM5, which are required to stabilize an optimal TM6 conformation that facilitates G-protein binding and receptor activation, play a major role in differentiating them from full agonists.

Authors with CRIS profile

Jacqueline Calderón Reyes Computer-Chemie-Centrum Timothy Clark Computer-Chemie-Centrum

Involved external institutions

University of Geneva / Université de Genève (UNIGE) CH Switzerland (CH) Universität Leipzig DE Germany (DE)

How to cite

APA:

Calderón Reyes, J., Ibrahim, P., Gobbo, D., Gervasio, F.L., & Clark, T. (2023). Activation/Deactivation Free-Energy Profiles for the β2-Adrenergic Receptor: Ligand Modes of Action. Journal of Chemical Information and Modeling, 63(20), 6332-6343. https://doi.org/10.1021/acs.jcim.3c00805

MLA:

Calderón Reyes, Jacqueline, et al. "Activation/Deactivation Free-Energy Profiles for the β2-Adrenergic Receptor: Ligand Modes of Action." Journal of Chemical Information and Modeling 63.20 (2023): 6332-6343.

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