title: Structural heterogeneity of the μ-opioid receptor's conformational ensemble in the apo state.
abstract: G-protein coupled receptors (GPCRs) are the largest and most pharmaceutically relevant family of membrane proteins. Here, fully unbiased, enhanced sampling simulations of a constitutively active mutant (CAM) of a class A GPCR, the μ-opioid receptor (μOR), demonstrates repeated transitions between the inactive (IS) and active-like (AS-L) states. The interconversion features typical activation/inactivation patterns involving established conformational rearrangements of conserved residues. By contrast, wild-type μOR remains in IS during the same course of simulation, consistent with the low basal activity of the protein. The simulations point to an important role of residue W2936.48at the "toggle switch" in the mutation-induced constitutive activation. Such role has been already observed for other CAMs of class A GPCRs. We also find a significantly populated intermediate state, rather similar to IS. Based on the remarkable accord between simulations and experiments, we suggest here that this state, which has escaped so far experimental characterization, might constitute an early step in the activation process of the apo μOR CAM.
authors.affiliation: Laboratory of Computational Biophysics, German Research School for Simulation Sciences GmbH, Joint venture of RWTH Aachen University and Forschungszentrum Jülich, 52425 Jülich, Germany.|Computational Biomedicine section, Institute of Advanced Simulation (IAS-5), Institute of Neuroscience and Medicine (INM-9), Forschungszentrum Jülich, 52425 Jülich, Germany.|Departamento de Química Biológica, Universidade Regional do Cariri, Av Cel Antonio Luis 1161, 63100-000, Crato, Brazil.
authors.forename: Diniz M
authors.initials: DM
authors.lastname: Sena
authors.affiliation: Laboratory of Computational Biophysics, German Research School for Simulation Sciences GmbH, Joint venture of RWTH Aachen University and Forschungszentrum Jülich, 52425 Jülich, Germany.|Computational Biomedicine section, Institute of Advanced Simulation (IAS-5), Institute of Neuroscience and Medicine (INM-9), Forschungszentrum Jülich, 52425 Jülich, Germany.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Cong
authors.affiliation: Computational Biomedicine section, Institute of Advanced Simulation (IAS-5), Institute of Neuroscience and Medicine (INM-9), Forschungszentrum Jülich, 52425 Jülich, Germany.|Department of Biotechnology, University of Verona, Ca' Vignal 1, Strada Le Grazie 15, I-37134 Verona, Italy.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Giorgetti
authors.affiliation: Grünenthal Innovation, Grünenthal GmbH, 52078 Aachen, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Kless
authors.affiliation: Laboratory of Computational Biophysics, German Research School for Simulation Sciences GmbH, Joint venture of RWTH Aachen University and Forschungszentrum Jülich, 52425 Jülich, Germany.|Computational Biomedicine section, Institute of Advanced Simulation (IAS-5), Institute of Neuroscience and Medicine (INM-9), Forschungszentrum Jülich, 52425 Jülich, Germany.
authors.forename: Paolo
authors.initials: P
authors.lastname: Carloni
mesh_terms: D001059:Apoproteins / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D017450:Receptors, Opioid, mu / Q000737:chemistry* / Q000235:genetics
chemical_list: D001059:Apoproteins; D017450:Receptors, Opioid, mu