Solution conformations of potent bicyclic antagonists of oxytocin by nuclear magnetic resonance spectroscopy and molecular dynamics simulations

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 rotati...