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Updated: Jul 31, 2025

Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
Published on: August 16, 2018
General Metadynamics Protocol To Simulate Activation/Deactivation of Class A GPCRs: Proof of Principle for the
Jacqueline C Calderón1, Passainte Ibrahim2, Dorothea Gobbo3,4
1Computer-Chemistry-Center, Department of Chemistry and Pharmacy, Friedrich-Alexander-University Erlangen-Nuernberg, Naegelsbachstr. 25, 91052 Erlangen, Germany.
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.
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