title: On the modularity of the intrinsic flexibility of the µ opioid receptor: a computational study.
abstract: The µ opioid receptor (µOR), the principal target to control pain, belongs to the G protein-coupled receptors (GPCRs) family, one of the most highlighted protein families due to their importance as therapeutic targets. The conformational flexibility of GPCRs is one of their essential characteristics as they take part in ligand recognition and subsequent activation or inactivation mechanisms. It is assessed that the intrinsic mechanical properties of the µOR, more specifically its particular flexibility behavior, would facilitate the accomplishment of specific biological functions, at least in their first steps, even in the absence of a ligand or any chemical species usually present in its biological environment. The study of the mechanical properties of the µOR would thus bring some indications regarding the highly efficient ability of the µOR to transduce cellular message. We therefore investigate the intrinsic flexibility of the µOR in its apo-form using all-atom Molecular Dynamics simulations at the sub-microsecond time scale. We particularly consider the µOR embedded in a simplified membrane model without specific ions, particular lipids, such as cholesterol moieties, or any other chemical species that could affect the flexibility of the µOR. Our analyses highlighted an important local effect due to the various bendability of the helices resulting in a diversity of shape and volume sizes adopted by the µOR binding site. Such property explains why the µOR can interact with ligands presenting highly diverse structural geometry. By investigating the topology of the µOR binding site, a conformational global effect is depicted: the correlation between the motional modes of the extra- and intracellular parts of µOR on one hand, along with a clear rigidity of the central µOR domain on the other hand. Our results show how the modularity of the µOR flexibility is related to its pre-ability to activate and to present a basal activity.
authors.affiliation: Laboratoire de Physico-Chimie Informatique, Unité de Chimie Physique Théorique et Structurale, University of Namur (UNamur), Namur, Belgium; Arrhenius Laboratory, Division of Physical Chemistry, Stockholm University, Stockholm, Sweden; Namur Medicine and Drug Innovation Center (NAMEDIC), University of Namur (UNamur), Namur, Belgium.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Fossépré
authors.affiliation: Laboratoire de Physico-Chimie Informatique, Unité de Chimie Physique Théorique et Structurale, University of Namur (UNamur), Namur, Belgium; Namur Medicine and Drug Innovation Center (NAMEDIC), University of Namur (UNamur), Namur, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Leherte
authors.affiliation: Arrhenius Laboratory, Division of Physical Chemistry, Stockholm University, Stockholm, Sweden; Stellenbosch Institute of Advanced Study (STIAS), Wallenberg Research Centre at Stellenbosch University, Stellenbosch, South Africa.
authors.forename: Aatto
authors.initials: A
authors.lastname: Laaksonen
authors.affiliation: Laboratoire de Physico-Chimie Informatique, Unité de Chimie Physique Théorique et Structurale, University of Namur (UNamur), Namur, Belgium; Namur Medicine and Drug Innovation Center (NAMEDIC), University of Namur (UNamur), Namur, Belgium.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Vercauteren
mesh_terms: D001665:Binding Sites; D019295:Computational Biology; D003198:Computer Simulation; D056004:Molecular Dynamics Simulation; D017434:Protein Structure, Tertiary; D017450:Receptors, Opioid, mu / Q000737:chemistry* / Q000502:physiology*; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D017450:Receptors, Opioid, mu