SOLUTION CONFORMATION OF A POTENT BICYCLIC ANTAGONIST OF OXYTOCIN

Conformational studies of [Mpa1, cyclo(Glu4, Lys8)]oxytocin, a potent bicyclic antagonist of oxytocin, were carried out by combined use of N MR, molecular mechanics, and molecular dynamics simulations. Previous energy calculations with ECEPP/2 potentials resulted in three distinct models for the backbone structures, which differed both in the locati on of a reverse turn, and in the conformation of the Cys6-Pro7 peptide bond. One of the models containing a type III beta-turn at residues T yr2-Ile3 and a cis-peptide bond at Cys6-Pro7 was in excellent agreemen t with H-1- and C-13-NMR data. This model was refined by molecular dyn amics simulations using the AMBER force field. A dynamic model was pro posed for [Mpa1, cyclo(Glu4, Lys8)]oxytocin in DMSO, which assumes a s table backbone structure and an equilibrium between the left- and righ t-handed conformers of the disulfide bridge.