title: Conformation and Dynamics of Human Urotensin II and Urotensin Related Peptide in Aqueous Solution.
abstract: Conformation and dynamics of the vasoconstrictive peptides human urotensin II (UII) and urotensin related peptide (URP) have been investigated by both unrestrained and enhanced-sampling molecular-dynamics (MD) simulations and NMR spectroscopy. These peptides are natural ligands of the G-protein coupled urotensin II receptor (UTR) and have been linked to mammalian pathophysiology. UII and URP cannot be characterized by a single structure but exist as an equilibrium of two main classes of ring conformations, open and folded, with rapidly interchanging subtypes. The open states are characterized by turns of various types centered at K8Y9or F6W7predominantly with no or only sparsely populated transannular hydrogen bonds. The folded conformations show multiple turns stabilized by highly populated transannular hydrogen bonds comprising centers F6W7K8or W7K8Y9. Some of these conformations have not been characterized previously. The equilibrium populations that are experimentally difficult to access were estimated by replica-exchange MD simulations and validated by comparison of experimental NMR data with chemical shifts calculated with density-functional theory. UII exhibits approximately 72% open:28% folded conformations in aqueous solution. URP shows very similar ring conformations as UII but differs in an open:folded equilibrium shifted further toward open conformations (86:14) possibly arising from the absence of folded N-terminal tail-ring interaction. The results suggest that the different biological effects of UII and URP are not caused by differences in ring conformations but rather by different interactions with UTR.
authors.forename: Elke
authors.initials: E
authors.lastname: Haensele
authors.affiliation: School of Chemistry, University of Southampton , Highfield, Southampton SO17 1BJ, United Kingdom.
authors.forename: Nawel
authors.initials: N
authors.lastname: Mele
authors.affiliation: School of Chemistry, University of Southampton , Highfield, Southampton SO17 1BJ, United Kingdom.
authors.forename: Marija
authors.initials: M
authors.lastname: Miljak
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Read
authors.forename: David C
authors.initials: DC
authors.lastname: Whitley
authors.forename: Lee
authors.initials: L
authors.lastname: Banting
authors.affiliation: Normandie Université, CS 14032 Caen Cedex 5, France, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN, EA 4258, FR CNRS 3038 INC3M SF 4206 ICORE), UFR des Sciences Pharmaceutiques, Université de Caen Basse-Normandie (UNICAEN) , F-14032 Caen, France.
authors.forename: Carla
authors.initials: C
authors.lastname: Delépée
authors.affiliation: Normandie Université, CS 14032 Caen Cedex 5, France, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN, EA 4258, FR CNRS 3038 INC3M SF 4206 ICORE), UFR des Sciences Pharmaceutiques, Université de Caen Basse-Normandie (UNICAEN) , F-14032 Caen, France.
authors.forename: Jana
authors.initials: J
authors.lastname: Sopkova-de Oliveira Santos
authors.affiliation: Normandie Université, CS 14032 Caen Cedex 5, France, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN, EA 4258, FR CNRS 3038 INC3M SF 4206 ICORE), UFR des Sciences Pharmaceutiques, Université de Caen Basse-Normandie (UNICAEN) , F-14032 Caen, France.
authors.forename: Alban
authors.identifier: 0000-0003-0202-1588
authors.initials: A
authors.lastname: Lepailleur
authors.affiliation: Normandie Université, CS 14032 Caen Cedex 5, France, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN, EA 4258, FR CNRS 3038 INC3M SF 4206 ICORE), UFR des Sciences Pharmaceutiques, Université de Caen Basse-Normandie (UNICAEN) , F-14032 Caen, France.
authors.forename: Ronan
authors.initials: R
authors.lastname: Bureau
authors.affiliation: School of Chemistry, University of Southampton , Highfield, Southampton SO17 1BJ, United Kingdom.
authors.forename: Jonathan W
authors.identifier: 0000-0003-2639-2746
authors.initials: JW
authors.lastname: Essex
authors.affiliation: Computer-Chemie-Centrum and Interdisciplinary Center for Molecular Materials, Friedrich-Alexander-Universität Erlangen-Nürnberg , Nägelsbachstraße 25, 91052 Erlangen, Germany.
authors.forename: Timothy
authors.identifier: 0000-0001-7931-4659
authors.initials: T
authors.lastname: Clark
mesh_terms: D006801:Humans; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D012996:Solutions; D014579:Urotensins / Q000737:chemistry* / Q000378:metabolism*; D014867:Water / Q000737:chemistry*
chemical_list: D010455:Peptides; D012996:Solutions; D014579:Urotensins; D014867:Water; C029677:urotensin II