The solution conformations of two potent bicyclic antagonists
[dPen1,
cyclo(Glu4,Lys8)]OT were
studied
by a combined use of 1H and 13C NMR
spectroscopy in DMSO and molecular dynamics (MD) simulations.
NMR
data have suggested a model for the three-dimensional (3D) structure of
the bicyclic analogues of OT (OT-BC) with
a β-turn at the Tyr2 and Ile3 residues, and
with a cis amide bond between Cys6 and
Pro7. A 3D structure containing
a type III β-turn at Tyr2-Ile3 has been shown
to be consistent with NMR data. This structure was proposed as
a
model of the solution conformation of OT-BC and extensively tested by
MD simulations with the AMBER force
field. MD simulations at 300 K with NMR derived distance and φ
torsion angle constraints demonstrated the
consistency of this model with NMR data, and its stability was further
demonstrated by non-constrained MD
simulations. Dynamic properties of the 3D structure were explored
by high-temperature MD at 500 K. Conformational
transitions induced by a constrained rotation around the S−S bond
revealed relatively low potential energy barriers
(30 to 50 kJ/mol) between equilibrium left-handed and right-handed
conformers of the disulfide bridge in OT-BC.
A dynamic model of the solution structure of OT-BC with the
relatively stable backbone conformation and a fast
conformational equilibrium in the disulfide bridge and lactam bridge
moieties was proposed as a result of the extensive
MD simulations. The solution structure of OT-BC is consistent with
structure−activity relations of peptide and
non-peptide antagonists of OT. In particular, a β-turn at
Tyr2-Ile3 seems to be the common feature
responsible for
antagonist interaction with the uterine receptor of OT. On the
other hand, the 3D structure of OT-BC differs
considerably from the crystal and solution structures of OT analogues
with agonist activity. Therefore, this study
supports the hypothesis of different modes of receptor binding for
agonists and antagonists of OT. The model of 3D
structure of OT-BC proposed in this study may be used as a template for
the rational design of peptide and non-peptide antagonists of oxytocin.
The synthesis of an 11 membered ring bis-lactam, a system which is designed as a conformationally restricted mimetic of type I and type II beta-turns is described. Computer assisted molecular modeling was used to compare the predicted low energy conformers of the turn mimetic with idealized type I and type II turn structures. Initial computational analysis indicates that the basic ring structure will provide an excellent foundation for the development of a varieity of beta-turn mimetics.
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