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.