NMR AND COMPUTATIONAL EVIDENCE THAT HIGH-AFFINITY BRADYKININ RECEPTORANTAGONISTS ADOPT C-TERMINAL BETA-TURNS

Three tetrapeptides were prepared, each corresponding to the four C-te rminal amino acid residues of highly potent, second-generation bradyki nin receptor antagonists. The tetrapeptides are (IA) Ser-D-Phe-Oic-Arg , (IIA) Ser-D-Tic-Oic-Arg, and (IIIA) Ser-D-Hype(trans-propyl)-Oic-Arg . Solution conformations for each were determined by incorporating int erproton distance restraints, determined by 2D NMR experiments perform ed in water at neutral pH, into a series of distance geometry/simulate d annealing model building calculations. Similarly, systematic conform ational analyses were performed for each using molecular mechanics cal culations. Both the NMR-derived structures, as well as the calculated structures, are shown to adopt a beta-turn as the primary conformation . Excellent agreement between the predicted structures and the NMR-der ived structures is demonstrated. Aside from being the first examples o f linear tetrapeptides reported to be ordered in aqueous solvent, the results presented support the hypothesis that high-affinity bradykinin receptor antagonists must adopt C-terminal beta-turn conformations.