Effect of trifluoroethanol on the solution structure and flexibility of desmopressin: a two-dimensional NMR study

The solution structures of desmopressin, a nine-residue peptide with specific antidiuretic and antibleeding activities, have been studied in aqueous and TFE-containing solutions by two-dimensional NMR and molecular modeling techniques. It is found that TFE induces a conformational change of the peptide. The structure(s) in water are flexible, and may show multiple conformations, with a significant population of a conformation that contains two fused beta-turns. TFE diminishes the peptide conformational flexibility to form more well defined structure(s). The TFE structure(s) were generated by using molecular modeling based on NOE-derived distance restraints and hydrogen-bond restraints obtained from amide proton exchange rates and chemical shift temperature coefficients. While the structure in TFE is more rigid, two different orientations were found for the last two residues in the three residue tail. The conformation of the first seven residues of the peptide is well defined and consists of a short distorted antiparallel beta-sheet with residue Tyr2 and Phe3 in one strand and residue Cys6 and Pro7 in the other strand. A type I beta-turn, centered in residues Gln4 and Asn5, connects the two strands. A distorted type II beta-turn is found in the three-residue tail involving residues Cys6-Pro7-D-Arg8-Gly9 in both families of TFE structures.