Conformation of the central sequence of angiotensin II and analogs

We describe the synthesis and the conformational analysis by ir, CD, and proton‐nmr spectroscopy of four model peptides of the type N ‐Ac‐Tyr‐X‐His‐NH 2 with X = Val, Leu, Ala, Gly. These peptides represent the central sequence of the hormone angiotensin II and its position‐5 analogs. We studied their conformational behavior in aqueous solution during pH titration and in organic solvents. For specific purposes of spectral analysis (ir band assignment, proton‐nmr signal assignment, heteronuclear vicinal coupling constants), we synthesized three isotopically enriched homologs of the mother sequence, i.e., N ‐Ac‐( 15 N‐Tyr)‐Val‐His‐NH 2 , N ‐Ac‐( 13 C, 2 H, Tyr)‐Val‐His‐NH 2 , and N ‐Ac‐Tyr‐( 13 C, 2 H, Val)‐His‐NH 2 . Results are summarized as follows: the tyrosine and the histidine side chains influence each other through space; this mutual influence is modulated by the nature of the side chain in position X and decreases in going from XVal to XGly as a consequence of two simultaneous events, changes in the side‐chain rotamer distribution and changes in the φ and ψ angles of residue X. The decrease in the bulkiness of the side‐chain X (Val → Gly) leads to increased flexibility of the peptide backbone at this site, which is also reflected in the apparent ratio of C 5 , C 7 , and intermediate conformations present in equilibrium. The three spectroscopic techniques, in addition to the results of chymotryptic degradation experiments, show a high level of agreement, and all reflect the dynamic conformation of these peptides in a different manner.