CONFORMATIONAL-ANALYSIS OF 2 CYCLIC ANALOGS OF ANGIOTENSIN - IMPLICATIONS FOR THE BIOLOGICALLY-ACTIVE CONFORMATION

Conformations of two cyclic analogs of angiotensin (Asp1-Arg2-Val3-Tyr 4-Val/Ile5-His6-Pro7-Phe8, AT), cyclo[Sar1, Cys3, Mpt5]-AT and cyclo[S ar1, HCys3, Mpt5]-AT, were studied, independently employing two comple mentary techniques, energy calculations and NMR measurements in DMSO s olution. NMR data were indicative of well-defined solution conformatio ns for the cyclic moieties of cyclo[Sar1, Cys3, Mpt5]-AT and cyclo[Sar 1, HCVS3, Mpt5]-AT, including the phi values for the Cys3/HCys3 and Ty r4 residues, as well as the chi1 value for the Tyr4 residue. Solution conformations for the exocyclic linear parts of both molecules cannot be described by the NMR data with the same precision. At the same time , independent energy calculations revealed the same conformations of c yclic moieties of cyclo[Sar1, Cys3, Mpt5]-AT and cyclo[Sar1, HCys3, Mp t5]-AT among low-energy conformers for both peptides. Moreover, the sa me conformations are compatible with the model of AT receptor-bound co nformation (Nikiforovich & Marshall, 1993), which assumes the particul ar spatial arrangement of aromatic moieties of Tyr4, His6, and Phe8 re sidues and the C-terminal carboxyl. These conformers of cyclo[Sar1, Cy s3, Mpt5]-AT and cyclo[Sar1, HCys3, Mpt5]-AT contain ''an open turn'' in the backbone of the Tyr4-Val5 residues, instead of the earlier prop osed beta-like reversal, thus confirming the suggestion that the confo rmation(s) ensuring binding of AT analogs with specific receptors shou ld not be described in terms of a unique backbone conformer.