title: A Three-Site Mechanism for Agonist/Antagonist Selective Binding to Vasopressin Receptors.
abstract: Molecular-dynamics simulations with metadynamics enhanced sampling reveal three distinct binding sites for arginine vasopressin (AVP) within its V2 -receptor (V2 R). Two of these, the vestibule and intermediate sites, block (antagonize) the receptor, and the third is the orthosteric activation (agonist) site. The contacts found for the orthosteric site satisfy all the requirements deduced from mutagenesis experiments. Metadynamics simulations for V2 R and its V1a R-analog give an excellent correlation with experimental binding free energies by assuming that the most stable binding site in the simulations corresponds to the experimental binding free energy in each case. The resulting three-site mechanism separates agonists from antagonists and explains subtype selectivity.
authors.affiliation: Computer-Chemie-Centrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstrasse 25, 91052, Erlangen, Germany.
authors.forename: Noureldin
authors.identifier: 0000-0002-5116-2312
authors.initials: N
authors.lastname: Saleh
authors.affiliation: Department of Chemistry and Institute of Structural and Molecular Biology, University College London, London, WC1E 6BT, UK.
authors.forename: Giorgio
authors.identifier: 0000-0002-3234-5762
authors.initials: G
authors.lastname: Saladino
authors.affiliation: Department of Chemistry and Institute of Structural and Molecular Biology, University College London, London, WC1E 6BT, UK.
authors.forename: Francesco L
authors.identifier: 0000-0003-4831-5039
authors.initials: FL
authors.lastname: Gervasio
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, PO1 2DT, UK.
authors.forename: Elke
authors.initials: E
authors.lastname: Haensele
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, PO1 2DT, UK.
authors.forename: Lee
authors.identifier: 0000-0002-3623-3629
authors.initials: L
authors.lastname: Banting
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, PO1 2DT, UK.
authors.forename: David C
authors.identifier: 0000-0002-1647-1427
authors.initials: DC
authors.lastname: Whitley
authors.affiliation: UNICAEN, CERMN, UPRES EA 4258, FR CNRS 3038 INC3M -, Normandie Univ., Boulevard Becquerel, 14032, CAEN Cedex, France.
authors.forename: Jana
authors.initials: J
authors.lastname: Sopkova-de Oliveira Santos
authors.affiliation: UNICAEN, CERMN, UPRES EA 4258, FR CNRS 3038 INC3M -, Normandie Univ., Boulevard Becquerel, 14032, CAEN Cedex, France.
authors.forename: Ronan
authors.initials: R
authors.lastname: Bureau
authors.affiliation: Computer-Chemie-Centrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstrasse 25, 91052, Erlangen, Germany. Tim.Clark@fau.de.|School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, PO1 2DT, UK. Tim.Clark@fau.de.
authors.forename: Timothy
authors.identifier: 0000-0001-7931-4659
authors.initials: T
authors.lastname: Clark
mesh_terms: D065092:Antidiuretic Hormone Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D001127:Arginine Vasopressin / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D017483:Receptors, Vasopressin / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D008024:Ligands; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin
keywords: G-protein coupled receptors; hormones; metadynamics; molecular dynamics; receptors