HYDROGEN-BOND-MEDIATED FOLDING IN DEPSIPEPTIDE MODELS OF BETA-TURNS AND ALPHA-HELICAL TURNS

The folding of several depsipeptides constructed from alpha-amino acids [L-proline (P) and L-alanine (A)] and alpha-hydroxy acids [L-lactic acid (L) and glycolic acid (G)] has been examined in methylene chloride 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 depsipeptides 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 depsipeptides can also form 10-membered-ring amide-to-ester hydrogen bonds, which would correspond to beta-trun formation for a peptide backbone. For PLL and PLG, distinct N-H stretch bands can be identified for three folding patterns: non-hydrogen-bonded, beta-turn, and alpha-helical turn. IR-based van't Hoff analyses for PLL indicate that the alpha-helical turn and the beta-turn are both modestly enthalpically favored relative to the non-hydrogen-bonded state, but neither turn is enthalpically preferred over the other. For PLG, in contrast, the alpha-helical turn appears to be enthalpically preferred over both of the alternative folding patterns. Comparison between PLL and ALL indicates that 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 favored by ca. 1.6 kcal/mol, but formation of this enthalpically stronger intramolecular hydrogen bond is more costly entropically. Extrapolation 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-turn folding has previously been widely studied in model peptides and depsipeptides; however, the present report appears to represent the first experimental effort to model formation of a single alpha-helical turn.