Proposed Conformations of Oxytocin and Selected Analogs in Dimethyl Sulfoxide as Deduced from Proton Magnetic Resonance Studies

The 220-MHz nmr spectra have been obtained and assigned for oxytocin, deamino-oxytocin, [4-glycine]oxytocin, [2-valine]oxytocin, [7-D-proline]oxytocin, and [1-β-mercaptopropionic acid, 7-D-proline]oxytocin. Several deuterated derivatives were used for making unambiguous assignments. Conformational calculations based on measured values of the vicinal amide to α-proton coupling were used for proposing conformations for the molecules in dimethyl sulfoxide solution. Three energetically favorable conformations of oxytocin are found, one of which has a single intramolecular hydrogen bond involving the asparagine-5 backbone NH and the glutamine-4 carboxamide carbonyl. The tripeptide side chain is proposed to possess a trans-cis' junction to the ring and is folded toward the ring. In dimethyl sulfoxide oxytocin appears to possess a nonrigid conformation. Deamino-oxytocin possess a conformation similar to oxytocin. The proposed conformation for [4-glycine]oxytocin has two transannular bonds: the asparagine-5 peptide NH and carbonyl to the tyrosine-2 carbonyl and peptide NH, respectively. The conformation of [2-valine]oxytocin appears to be quite different from that of any of the other peptide analogs examined, with no intramolecular hydrogen bond. Both D-proline-7 analogs differ from oxytocin and deamino-oxytocin in the orientation of the tripeptide side chain with respect to the ring. The influence of the amino acid substitutions on the conformation is discussed.