General Metadynamics Protocol To Simulate Activation/Deactivation of Class A GPCRs: Proof of Principle for the Serotonin Receptor

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: 3105-3117

Journal Issue: 10

DOI: 10.1021/acs.jcim.3c00208

Abstract

We present a generally applicable metadynamics protocol for characterizing the activation free-energy profiles of class A G-protein coupled receptors and a proof-of-principle study for the 5HT1A-receptor. The almost universal A100 activation index, which depends on five inter-helix distances, is used as the single collective variable in well-tempered multiple-walker metadynamics simulations. Here, we show free-energy profiles for the serotonin receptor as binary (apo-receptor + G-protein-α-subunit and receptor + ligand) and ternary complexes with two prototypical orthosteric ligands: the full agonist serotonin and the partial agonist aripiprazole. Our results are not only compatible with previously reported experimental and computational data, but they also allow differences between active and inactive conformations to be determined in unprecedented atomic detail, and with respect to the so-called microswitches that have been suggested as determinants of activation, giving insight into their role in the activation mechanism.

Authors with CRIS profile

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

Involved external institutions

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

How to cite

APA:

Calderón Reyes, J., Ibrahim, P., Gobbo, D., Gervasio, F.L., & Clark, T. (2023). General Metadynamics Protocol To Simulate Activation/Deactivation of Class A GPCRs: Proof of Principle for the Serotonin Receptor. Journal of Chemical Information and Modeling, 63(10), 3105-3117. https://dx.doi.org/10.1021/acs.jcim.3c00208

MLA:

Calderón Reyes, Jacqueline, et al. "General Metadynamics Protocol To Simulate Activation/Deactivation of Class A GPCRs: Proof of Principle for the Serotonin Receptor." Journal of Chemical Information and Modeling 63.10 (2023): 3105-3117.

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