Ea. Gallo et Sh. Gellman, HYDROGEN-BOND-MEDIATED FOLDING IN DEPSIPEPTIDE MODELS OF BETA-TURNS AND ALPHA-HELICAL TURNS, Journal of the American Chemical Society, 115(21), 1993, pp. 9774-9788
The folding of several depsipeptides constructed from alpha-amino acid
s [L-proline (P) and L-alanine (A)] and alpha-hydroxy acids [L-lactic
acid (L) and glycolic acid (G)] has been examined in methylene chlorid
e solution by variable-temperature IR spectroscopy. Additional studies
have been conducted in some cases, involving variable-temperature H-1
NMR spectroscopy and molecular mechanics calculations. The depsipepti
des include three-residue molecules (PLL, ALL, and PLG) that can form
a 13-membered-ring amide-to-amide hydrogen bond, which, for a peptide
backbone, would correspond to a single turn of an alpha-helix. These d
epsipeptides can also form 10-membered-ring amide-to-ester hydrogen bo
nds, which would correspond to beta-trun formation for a peptide backb
one. For PLL and PLG, distinct N-H stretch bands can be identified for
three folding patterns: non-hydrogen-bonded, beta-turn, and alpha-hel
ical turn. IR-based van't Hoff analyses for PLL indicate that the alph
a-helical turn and the beta-turn are both modestly enthalpically favor
ed relative to the non-hydrogen-bonded state, but neither turn is enth
alpically preferred over the other. For PLG, in contrast, the alpha-he
lical turn appears to be enthalpically preferred over both of the alte
rnative folding patterns. Comparison between PLL and ALL indicates tha
t the N-terminal proline residue favors alpha-helical turn formation.
The strengths of amide-to-amide and amide-to-ester hydrogen bonds have
been compared in the context of a beta-turn geometry by analyzing LG
and AG in CH2Cl2. The amide-to-amide hydrogen bond is enthalpically fa
vored by ca. 1.6 kcal/mol, but formation of this enthalpically stronge
r intramolecular hydrogen bond is more costly entropically. Extrapolat
ion from the behavior of these depsipeptides leads us to predict that
for tripeptides in a nonpolar environment, a beta-turn will generally
be enthalpically preferred over an isolated alpha-helical turn. Beta-t
urn folding has previously been widely studied in model peptides and d
epsipeptides; however, the present report appears to represent the fir
st experimental effort to model formation of a single alpha-helical tu
rn.