Solvent-Directed Switch of a Left-Handed 10/12-Helix into a Right-Handed 12/10-Helix in Mixed ß-Peptides.

Present study describes the synthesis and conformational analysis of ß-peptides from C-linked carbo-ß-amino acids [ß-Caa(l)] with a d-lyxo furanoside side chain and ß-hGly in 1:1 alternation. NMR and CD investigations on peptides with an (S)-ß-Caa(l) monomer at the N-terminus revealed a right-handed 10/12-mixed helix. An unprecedented solvent-directed "switch" both in helical pattern and handedness was observed when the sequence begins with a ß-hGly residue instead of a (S)-ß-Caa(l) constituent. NMR studies on these peptides in chloroform indicated a left-handed 10/12-helix, while the CD spectrum in methanol inferred a right-handed secondary structure. The NMR data for these peptides in CD3OH showed the presence of a right-handed 12/10-helix. NMR investigations in acetonitrile indicated the coexistence of both helix types. Quantum chemical studies predicted a small energy difference of 0.3 kcal/mol between the two helix types, which may explain the possibility of solvent influence. Examples for a solvent-directed switch of both the H-bonding pattern and the handedness of foldamer helices are rare so far. A comparable solvent effect was not found in the corresponding peptides with (R)-ß-Caa(l) residues, where right-handed 12/10-helices are predominating.

Design and synthesis of peptides with hybrid helix-turn-helix (HTH) motif and their conformational study.

The present study is aimed at the design and synthesis of peptides with hybrid helix-turn-helix (HTH) motif and their conformational analysis (NMR, MD, and CD studies). The requisite peptides with heterogeneous backbones were prepared from ß-, γ-, and δ-amino acids with carbohydrate side chains and α-amino acid, L-Ala. The α/ß-peptides were prepared from (S)-ß-Caa(l) (C-linked carbo-ß-amino acid with D-lyxo furanoside side chain) and L-Ala with a 1:1 alternation. The α/ß-peptides with "helix-turn" motif displayed a 11/9-helix nucleating a 13-atom H-bonding turn. The α/ß-octapeptides showed the presence of HTH structures with bifurcated 11/15-H-bonded turn. Further, the α/ß-hexapeptide with HT motif, independently on coupling with γ/α/γ/α- and δ/α/δ/α-tetrapeptides at the C-terminus provided access to the decapeptides with "hybrid HTH" motifs. The decapeptide ("α-ß-α-ß-α-ß-γ-α-γ-α") showed a hybrid HTH with "11/9/11/9/11/16/9/12/10" H-bonding, while the decapeptide ("α-ß-α-ß-α-ß-δ-α-δ-α") revealed the presence of a "11/9/11/9/11/17/9/13/11" helical pattern. The above peptides thus have shown compatibility between different types of helices and serendipitous bifurcated 11/16- and 11/17-turns. The present study thus provided the first opportunity for the design and study of "hybrid HTH" motifs with more than one kind of helical structures in them.

Three-residue turn in ß-peptides nucleated by a 12/10 helix.

A new three-residue turn in ß peptides nucleated by a 12/10-mixed helix is presented. In this design, ß peptides were derived from the 1:1 alternation of C-linked carbo-ß-amino acid ester [BocNH-(R)-ß-Caa(r)-OMe] (Boc=tert-butyloxycarbonyl), which consisted of a D-ribo furanoside side chain, and ß-hGly residues. The hexapeptide with (R)-ß-Caa(r) at the N terminus showed the 'turn' stabilized by a 14-membered NH(4)⋅⋅⋅CO(6) hydrogen bond at the C terminus nucleated by a robust 12/10-mixed helix, thus providing a 'helix-turn' (HT) motif. The turn and the helix were additionally stabilized by intraresidue electrostatic interaction between the furan oxygen in the carbohydrate side chain and NH in the backbone. However, the hexapeptide with a ß-hGly residue at the N terminus demonstrated the presence of a 10/12 helix through its entire length, which again showed the intraresidue interaction between NH and furan oxygen. The intraresidue NH⋅⋅⋅O-Me electrostatic interactions observed in the monomer, however, were absent in the peptides.