Stereochemical Requirements for β-Hairpin Formation: Model Studies with Four-Residue Peptides and Depsipeptides

Spectroscopic and crystallographic data are presented
for a series of tetrapeptides and analogous
depsipeptides that can form a minimal β-hairpin (two intramolecular
hydrogen bonds). These model compounds
have been used to test the hypothesis that “mirror image” β-turns
promote β-hairpin formation. This hypothesis was
inspired by a statistical survey of β-hairpins in globular proteins
(Sibanda, B. L.; Thornton, J. M. Nature 1985,
316,
170), which showed that mirror image β-turns (type I‘ and type II‘),
although rare in general, are very commonly
associated with β-hairpins containing a two-residue loop between the
strand segments. Each of our four-residue
molecules contains proline at the second position, to promote a central
β-turn. The β-turn is induced to be either
“common” or “mirror-image”, relative to the outer residues, by
choice of residue configuration (l vs d).
In methylene
chloride, end-capped tetrapeptide
Ac−l-Val-d-Pro-d-Ala-l-Leu-NMe2
folds largely into the β-hairpin conformation,
while the diastereomer
Ac-l-Val-l-Pro-l-Ala-l-Leu-NMe2
displays little or no β-hairpin folding. For each
diastereomer, the hydrogen-bonded driving force for β-hairpin folding
is identical, and the dramatic difference in
folding behavior therefore reflects a variation in the intrinsic
conformational properties of the diastereomeric backbones.
Similar behavior is seen for the diastereomeric peptide pair
Ac-l-Val-d-Pro-Gly-l-Leu-NMe2
vs Ac-l-Val-l-Pro-Gly-l-Leu-NMe2, and for the analogous
depsipeptides with a lactic acid or glycolic acid residue at the third
position.
Thus, our results show not only that mirror-image Pro-X turns
strongly promote β-hairpin folding, but also that
common β-turns strongly discourage formation of a β-hairpin with a
two-residue loop.