Conformation of desmopressin, an analogue of the peptide hormone vasopressin, in aqueous solution as determined by NMR spectroscopy

Desmopressin (1‐desamino‐[ D Arg8]vasopressin, is a synthetic analogue of the neurohypophyseal peptide hormone vasopressin which has high antidiuretic and antibleeding potency. The structure of desmopressin has been determined in aqueous solution by two‐dimensional NMR techniques and molecular dynamics simulations. Both standard and time‐averaged distance restraints were used in structure calculations because of the inherent flexibility in small peptides. 21 models calculated with standard restraints were compared with structures refined with time‐averaged distance restraints and were found to be good representatives of the conformational ensemble of desmopressin. The macrocyclic ring forms an inverse γ‐turn centered around Gln4. Residues 1 and 2, the disulphide bridge and the three‐residue acyclic tail were found to be flexible in solution. Residues 4−6 in the ensemble of calculated structures contain essentially the same backbone conformation as in the crystal structure of pressinoic acid, the cyclic moiety of vasopressin, whereas residues 2−6 superimpose on the NMR‐derived conformation of oxytocin bound to neurophysin. The results presented in this work suggest that, in addition to the differences in sequence between desmopressin and vasopressin, differences in conformational and dynamic properties between the two compounds explain their pharmacological differences.