Design of helical peptides: solution conformation of Boc-Gly-Δ^ZPhe-Leu-Δ^ZPhe-Ala-NHMe and Boc-Val-Δ^ZPhe-Phe-Ala-Leu-Ala-Δ^ZPhe-Leu-OMe

Abstract

Two model peptides have been synthesized, a pentapeptide 1 (Boc-Gly-Δ^ZPhe-Leu-Δ^ZPhe-Ala-NHMe) and an octapeptide 2 (Boc-Val-Δ^ZPhe-Phe-Ala-Δ^ZPhe-Phe-Ala-Leu-Ala-gD^ZPhe-Leu-OMe). The conformations have been investigated in chloroform and dimethylsulfoxide by one and two dimensional NMR techniques. Assignments of amide protons' resonances have been made and intramolecularly hydrogen bonded NH resonances have been identified using solvent and temperature dependence of NH chemical shifts. The results in CDCl₃ have implicated that in the pentapeptide out of five NH groups first two NH groups belonging to Gly (1) and Δ^ZPhe (2) residues are solvent exposed while rest are solvent shielded suggesting a 4:1 intramolecular hydrogen bonding pattern. However, in the octapeptide first three NH groups corresponding to Val(1),gD^ZPhe(2)and Phe(3) are solvent exposed while rest are shielded suggesting a 5:1 hydrogen bonding pattern. Presence of consecutive N_i H < > N_i+1H nuclear Overhauser effects (NOEs), diagnostic of helical conformation has been confirmed by difference NOE in CDCI₃ and NOESY techniques. Consistent with the data, a 3₁₀ helical conformation for the pentapeptide and an a-helical for the octapeptide in CDCl₃ have been proposed. In (CD₃)₂SO, although the major conformation in solution is a 3₁₀ helix for the pentapeptide and an a-helix for the octapeptide, a few evidences like presence of some isolated C_iH < > N_i+1H NOEs are obtained that point out towards some conformational heterogenity. These results suggest that in highly polar solvent the folded conformations are not very stable.