Structural Characterization of Lipopeptide Agonists for the Bradykinin B2 Receptor.

The conformational features of Pam–Lys0–Arg1–Pro2–Pro3–Gly4–Phe5–Ser6–Pro7–Phe8– Arg9–OH (PKD) and Pam–Gly21–Lys0–Arg1–Pro2–Pro3–Gly4–Phe5–Ser6–Pro7–Phe8–Arg9–OH (PGKD), the Pam–Lys and Pam–Gly–Lys analogues of bradykinin, have been determined by highresolution NMR in a zwitterionic lipoid environment. Radical-induced relaxation of the 1HNMR signals was used to probe the topological orientation of the peptides with respect to the zwitterionic lipid interface. The radical-induced relaxation and molecular dynamics (MD) data indicated that the palmitic acid and N-terminal amino acid residues embed into the micelles, while the rest of the polypeptide chain is closely associated with the water-micelle interface. Throughout the entire nuclear Overhauser effect restrained MD simulation, a nonideal type I b-turn was observed in the C-terminus of PKD between residues 6 and 9, and a g-turn was observed in the C-terminus of PGKD between residues 6 and 7. Therefore, the additional glycine has a dramatic effect on the structural preferences of the biologically important C-terminus, an effect brought about by the interaction with the lipid environment. These structural features are correlated to the biological activity at the bradykinin B2 receptor.