Conformation and Dynamics of Human Urotensin II and Urotensin Related Peptide in Aqueous Solution

Haensele E, Mele N, Miljak M, Read CM, Whitley DC, Banting L, Delepee C, Santos JSDO, Lepailleur A, Bureau R, Essex JW, Clark T (2017)

Publication Status: Published

Publication Type: Journal article

Publication year: 2017

Journal

Journal of Chemical Information and Modeling American Chemical Society

Publisher: AMER CHEMICAL SOC

Book Volume: 57

Pages Range: 298-310

Journal Issue: 2

DOI: 10.1021/acs.jcim.6b00706

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. U11 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 (KY9)-Y-8 or (FW7)-W-6 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 (FWK8)-W-6-K-7 or (WKY9)-K-7-Y-8. 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 TM 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 Ull and URP are not caused by differences in ring conformations but rather by different interactions with UTR.

Authors with CRIS profile

Timothy Clark Computer-Chemie-Centrum

Involved external institutions

University of Portsmouth GB United Kingdom (GB) University of Southampton GB United Kingdom (GB) Université de Caen Basse-Normandie FR France (FR)

How to cite

APA:

Haensele, E., Mele, N., Miljak, M., Read, C.M., Whitley, D.C., Banting, L.,... Clark, T. (2017). Conformation and Dynamics of Human Urotensin II and Urotensin Related Peptide in Aqueous Solution. Journal of Chemical Information and Modeling, 57(2), 298-310. https://dx.doi.org/10.1021/acs.jcim.6b00706

MLA:

Haensele, Elke, et al. "Conformation and Dynamics of Human Urotensin II and Urotensin Related Peptide in Aqueous Solution." Journal of Chemical Information and Modeling 57.2 (2017): 298-310.

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