Engineering the Structure of an N‑Terminal β‑Turn To Maximize Screw-Sense Preference in Achiral Helical Peptide Chains

Oligomers
of α-aminoisobutyric acid (Aib) are achiral peptides
that typically adopt 310 helical conformations in which
enantiomeric left- and right-handed conformers are, necessarily, equally
populated. Incorporating a single protected chiral residue at the
N-terminus of the peptide leads to induction of a screw-sense preference
in the helical chain, which may be quantified (in the form of “helical
excess”) by NMR spectroscopy. Variation of this residue and
its N-terminal protecting group leads to the conclusion that maximal
levels of screw-sense preference are induced by bulky chiral tertiary
amino acids carrying amide protecting groups or by chiral quaternary
amino acids carrying carbamate protecting groups. Tertiary l-amino acids at the N-terminus of the oligomer induce a left-handed
screw sense, while quaternary l-amino acids induce a right-handed
screw sense. A screw-sense preference may also be induced from the
second position of the chain, weakly by tertiary amino acids, and
much more powerfully by quaternary amino acids. In this position,
the l enantiomers of both families induce a right-handed
screw sense. Maximal, and essentially quantitative, control is induced
by an l-α-methylvaline residue at both positions 1
and 2 of the chain, carrying an N-terminal carbamate protecting group.