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Conformation and dynamics of human urotensin II and urotensin related peptide in aqueous solution

Conformation and dynamics of human urotensin II and urotensin related peptide in aqueous solution
Conformation and dynamics of human urotensin II and urotensin related peptide in aqueous solution
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 K8Y9 or F6W7 predominantly with no or only sparsely populated transannular hydrogen bonds. The folded conformations show multiple turns stabilized by highly populated transannular hydrogen bonds comprising centers F6W7K8 or 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.
1549-9596
1-13
Haensele, Elke
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Mele, Nawel
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Miljak, Marija
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Read, Christopher M.
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Whitley, David C.
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Banting, Lee
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Delépée, Carla
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Sopkova-de Oliveira Santos, Jana
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Lepailleur, Alban
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Bureau, Ronan
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Essex, Jonathan
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Clark, Timothy
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Haensele, Elke
40647a17-8951-4c64-9776-c9a7eab98533
Mele, Nawel
40cc6e86-abd6-43c7-b16c-900bda7e70fa
Miljak, Marija
053049b1-fc46-43ab-a6c6-75722d5d51d6
Read, Christopher M.
f74e4dfc-a87d-455f-8ee8-36084513a2ff
Whitley, David C.
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Banting, Lee
d71b4dc3-3ac5-440d-b1cf-aa7797e968ab
Delépée, Carla
2b02c75c-50ae-4afd-bb7b-42f9294f7b8f
Sopkova-de Oliveira Santos, Jana
6c0d9fed-2f08-47db-a29d-ac767193b72c
Lepailleur, Alban
4312b801-cef4-46d9-afbe-c334765a22dc
Bureau, Ronan
cf5e82a5-5f08-4be6-ac5f-7073c82b2905
Essex, Jonathan
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Clark, Timothy
6221bc5b-2c6f-46bb-9eb8-191ca1c83b5d

Haensele, Elke, Mele, Nawel, Miljak, Marija, Read, Christopher M., Whitley, David C., Banting, Lee, Delépée, Carla, Sopkova-de Oliveira Santos, Jana, Lepailleur, Alban, Bureau, Ronan, Essex, Jonathan and Clark, Timothy (2017) Conformation and dynamics of human urotensin II and urotensin related peptide in aqueous solution. Journal of Chemical Information and Modeling, 1-13. (doi:10.1021/acs.jcim.6b00706).

Record type: Article

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 K8Y9 or F6W7 predominantly with no or only sparsely populated transannular hydrogen bonds. The folded conformations show multiple turns stabilized by highly populated transannular hydrogen bonds comprising centers F6W7K8 or 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.

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UII_05 01 2017_postprint.pdf - Accepted Manuscript
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Accepted/In Press date: 5 January 2017
e-pub ahead of print date: 5 January 2017
Organisations: Faculty of Natural and Environmental Sciences

Identifiers

Local EPrints ID: 405240
URI: http://eprints.soton.ac.uk/id/eprint/405240
ISSN: 1549-9596
PURE UUID: 696c2a51-bc00-4ce5-8767-29d137ba108e
ORCID for Jonathan Essex: ORCID iD orcid.org/0000-0003-2639-2746

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Date deposited: 31 Jan 2017 14:30
Last modified: 16 Mar 2024 02:45

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Contributors

Author: Elke Haensele
Author: Nawel Mele
Author: Marija Miljak
Author: Christopher M. Read
Author: David C. Whitley
Author: Lee Banting
Author: Carla Delépée
Author: Jana Sopkova-de Oliveira Santos
Author: Alban Lepailleur
Author: Ronan Bureau
Author: Jonathan Essex ORCID iD
Author: Timothy Clark

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