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

  • Jacqueline C. Calderón
    Jacqueline C. Calderón
    Computer-Chemistry-Center, Department of Chemistry and Pharmacy, Friedrich-Alexander-University Erlangen-Nuernberg, Naegelsbachstr. 25, 91052 Erlangen, Germany
  • Passainte Ibrahim
    Passainte Ibrahim
    Institute of Medical Physics and Biophysics, Faculty of Medicine, University of Leipzig, Leipzig 04107, Germany
  • Dorothea Gobbo
    Dorothea Gobbo
    Pharmaceutical Sciences, University of Geneva, CH1206 Geneva, Switzerland
    Institute of Pharmaceutical Sciences of Western Switzerland, CH1206 Geneva, Switzerland
  • Francesco Luigi Gervasio*
    Francesco Luigi Gervasio
    Pharmaceutical Sciences, University of Geneva, CH1206 Geneva, Switzerland
    Institute of Pharmaceutical Sciences of Western Switzerland, CH1206 Geneva, Switzerland
    Chemistry Department, University College London, WC1H 0AJ London, U.K.
    *Email: [email protected]
  • , and 
  • Timothy Clark*
    Timothy Clark
    Computer-Chemistry-Center, Department of Chemistry and Pharmacy, Friedrich-Alexander-University Erlangen-Nuernberg, Naegelsbachstr. 25, 91052 Erlangen, Germany
    *Email: [email protected]
Cite this: J. Chem. Inf. Model. 2023, 63, 10, 3105–3117
Publication Date (Web):May 9, 2023
https://doi.org/10.1021/acs.jcim.3c00208
Copyright © 2023 American Chemical Society

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    Abstract

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    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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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jcim.3c00208.

    • 5-HT1A systems preparation protocol; microswitches definition; time-series plots for (i) A100, (ii) TM3–TM6 distance, (iii) YY distance, (iv) NPxxY RMSD, and (v) PIF RMSD; dispersion plots showing A100 as a function of (i) TM3–TM6 distance, (ii) YY distance, (iii) NPxxY RMSD, and (iv) PIF RMSD; steered MD simulation protocol and results; correlation plot between the mean A100-value from MD runs and the deepest minimum identified in the A100 free-energy profiles; A100 free-energy profiles reconstructed at increasing metadynamics sampling times; time evolution of the Gaussian hill height during the metadynamics simulations; comparison of the orthosteric pocket in 5-HT1A binary and ternary complexes; representation of A6.55 outward displacement; comparison of 5-HT1A ternary complexes in terms of (i) polar interaction network in the binding pocket and (ii) hydrogen bond occupancy (PDF)

    • SMILES of compounds carvedilol, serotonin, and aripiprazole (TXT)

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 4 publications.

    1. Jacqueline C. Calderón, Passainte Ibrahim, Dorothea Gobbo, Francesco Luigi Gervasio, Timothy Clark. Determinants of Neutral Antagonism and Inverse Agonism in the β2-Adrenergic Receptor. Journal of Chemical Information and Modeling 2024, 64 (6) , 2045-2057. https://doi.org/10.1021/acs.jcim.3c01763
    2. Jacqueline C. Calderón, Eva Plut, Max Keller, Chiara Cabrele, Oliver Reiser, Francesco L. Gervasio, Timothy Clark. Extended Metadynamics Protocol for Binding/Unbinding Free Energies of Peptide Ligands to Class A G-Protein-Coupled Receptors. Journal of Chemical Information and Modeling 2024, 64 (1) , 205-218. https://doi.org/10.1021/acs.jcim.3c01574
    3. Martin Vögele, Bin W. Zhang, Jonas Kaindl, Lingle Wang. Is the Functional Response of a Receptor Determined by the Thermodynamics of Ligand Binding?. Journal of Chemical Theory and Computation 2023, 19 (22) , 8414-8422. https://doi.org/10.1021/acs.jctc.3c00899
    4. Jacqueline C. Calderón, Passainte Ibrahim, Dorothea Gobbo, Francesco Luigi Gervasio, Timothy Clark. Activation/Deactivation Free-Energy Profiles for the β2-Adrenergic Receptor: Ligand Modes of Action. Journal of Chemical Information and Modeling 2023, 63 (20) , 6332-6343. https://doi.org/10.1021/acs.jcim.3c00805

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