Conformational properties of a cyclic peptide bradykinin B2 receptor antagonist using experimental and theoretical methods

Abstract: The solution conformation of the cyclic peptide J324 (cyclo^0,6‐Lys⁰,Glu⁶,d ‐Phe⁷]BK), an antagonist targeted at the bradykinin (BK) B₂ receptor, has been investigated using experimental and theoretical methods. In order to gain insight into the structural requirements essential for BK antagonism, we carried out molecular dynamics (MD) simulations using simulated annealing as the sampling protocol. Following a free MD simulation we performed simulations using nuclear Overhauser enhancement (NOE) distance constraints determined by NMR experiments. The low‐energy structures obtained were compared with each other, grouped into families and analyzed with respect to the presence of secondary structural elements in their backbone. We also introduced new ways of plotting structural data for a more comprehensive analysis of large conformational sets. Finally, the relationship between characteristic backbone conformations and the spatial arrangement of specific pharmacophore centers was investigated.