Peptide design. Helix-helix motifs in synthetic sequences

Abstract

Two centrally positioned α-aminoisobutyryl (Aib) residues have been used to stabilize distinct heptapeptide helical segments in the 15-residue synthetic sequence Boc-Met-Ala-Leu-Aib-Val-Ala-Leu- Acp-Val-Ala-Leu-Aib-Val-Ala-Phe-OMe. The helices are connected by the flexible linker å-aminocaproic acid (Acp). NMR studies in CDCl₃ establish helical conformations for both independent segments as evidenced by NH–NH nuclear Overhauser effects (NOEs). The peptide strongly aggregates in CDCl₃ with the NH groups of Met(1) and Ala(2) participating in intermolecular hydrogen bonds. In (CD₃)₂SO two solvated helical segments are supported by NMR results. Solvent dependent breakdown of aggregates on addition of (CD₃)₂SO to CDCl₃ solutions is suggested by analysis of chemical shifts and temperature coefficients of NH protons. The observation of several interhelical NOEs in CDCl₃, relatively few NOEs in 10% (CD₃)₂SO–CDCl₃ and their absence in (CD₃)₂SO provides a means of inferring helix orientations. While an antiparallel arrangement resulting in closed aggregate formation is suggested in CDCl₃, a parallel solvated arrangement is favoured in (CD₃)₂SO.