Omega amino acids in peptide design: incorporation into helices

Incorporation of easily available achiral omega-amino acid residues into an oligopeptide results in substitution of amide bonds by polymethylene units of an aliphatic chain, thereby providing a convenient strategy for constructing a peptidomimetic. The central Gly-Gly segment of the helical octapeptide Boc-Leu-Aib-Val-Gly-Gly-Leu-Aib-Val-OMe(1) has been replaced by delta-amino-valeric acid (delta-Ava) residue in the newly designed peptide Boc-Leu-Aib-Val-delta-Ava-Leu-Aib-Val-OMe(2). 1H-nmr results clearly suggest that in the apolar solvent CDCl3, the delta-Ava residue is accommodated into a folded helical conformation, stabilized by successive hydrogen bonds involving the NH groups of Val(3), delta-Ava(4), and Leu(5). The delta-Ava residue must adopt a gauche-gauche-trans-gauche-gauche conformation along the central polymethylene unit of the aliphatic segment, a feature seen in an energy-minimized model conformation based on nmr parameters. The absence of hydrogen bonding functionalities, however, limits the elongation of the helix. In fact, in CDCl3, the folded conformation consists of an N-terminal helix spanning residues 1-4, followed by a Type II beta-turn at residues 5 and 6, whereas in strongly solvating media like (CD3)2SO, the unfolding of the N-terminal helix results in beta-turn conformations at Leu(1)-Aib(2). The Type II beta-turn at the Leu(5)-Aib(6) segment remains intact even in (CD3)2SO.CD comparisons of peptides 1 and 2 reveal a "nonhelical" spectrum for 2 in 2,2,2-trifluoroethanol.