Conformational Analysis of Two Cyclic Analogs of Angiotensin: Implications for the Biologically Active Conformation

Conformations of two cyclic analogs of angiotensin (Asp¹-Arg²-Val³-Tyr⁴-Val/Ile⁵-His⁶-Pro⁷- Phe⁸, AT), cyclo[Sar¹, Cys³, Mpt⁵]-AT and cyclo[Sar¹, HCys³, Mpt⁵]-AT, were studied, independently employing two complementary techniques, energy calculations and NMR measurements in DMSO solution. NMR data were indicative of well-defined solution conformations for the cyclic moieties of cyclo [Sar¹, Cys³, Mpt⁵]-AT and cyclo[Sar¹, HCys³, Mpt⁵]-AT, including the ϕ values for the Cys³/HCys³ and Tyr⁴ residues, as well as the χ1 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 cyclic moieties of cyclo [Sar¹, Cys³, Mpt⁵]-AT and cyclo[Sar¹, HCys³, Mpt⁵]-AT among low-energy conformers for both peptides. Moreover, the same conformations are compatible with the model of AT receptor-bound conformation (Nikiforovich & Marshall, 1993), which assumes the particular spatial arrangement of aromatic moieties of Tyr⁴, His⁶, and Phe⁸ residues and the C-terminal carboxyl. These conformers of cyclo [Sar¹, Cys³, Mpt⁵]-AT and cyclo[Sar¹, HCys³, Mpt⁵]-AT contain “an open turn” in the backbone of the Tyr⁴-Val⁵ residues, instead of the earlier proposed β-like reversal, thus confirming the suggestion that the conformation(s) ensuring binding of AT analogs with specific receptors should not be described in terms of a unique backbone conformer.