Helix Formation and Folding in γ‐Peptides and Their Vinylogues

Abstract

A complete overview of all possible periodic structures with characteristic H‐bonding patterns is provided for oligomers composed of γ‐amino acids (γ‐peptides) and their vinylogues by a systematic conformational search on hexamer model compounds employing ab initio MO theory at various levels of approximation (HF/6‐31G*, DFT/B3LYP/6‐31G*, SCRF/HF/6‐31G*, PCM//HF/6‐31G*). A wide variety of structures with definite backbone conformations and H‐bonds formed in forward and backward directions along the sequence was found in this class of foldamers. All formally conceivable H‐bonded pseudocycles between 7‐ and 24‐membered rings are predicted in the periodic hexamer structures, which are mostly helices. The backbone elongation in comparison to α‐ and β‐peptides allows several possibilities to realize identical H‐bonding patterns. In good agreement with experimental data, helical structures with 14‐ and 9‐membered pseudocycles are most stable. It is shown that the introduction of an (E)‐double bond into the backbone of the γ‐amino acid constituents, which leads to vinylogous γ‐amino acids, supports the folding into helices with larger H‐bonded pseudocycles in the resulting vinylogous γ‐peptides. Due to the considerable potential for secondary‐structure formation, γ‐peptides and their vinylogues might be useful tools in peptide and protein design and even in material sciences.

A Left‐Handed 9‐Helix in γ‐Peptides: Synthesis and Conformational Studies of Oligomers with Dipeptide Repeats of C‐Linked Carbo‐γ4‐amino Acids and γ‐Aminobutyric Acid

“…These helices have about 2.3 residues per turn and a height-per-residue value of about 3.3 . The helices reported by Balaram and co-workers [6] have values of f = 1098, q 1 = À638, q 2 = À778, and y = 888, 2.7 residues per turn, and a height-per-residue value of 3.4 , while the dihedral angle values predicted theoretically [7] are f = 978, q 1 = À708, q 2 = À758, and y = 978.…”

“…Recently, Farrera-Sinfreu et al [5] reported 9-membered sheets in g-peptides from cyclic g-amino acids, while Balaram and co-workers [6] reported 9-helices and ribbons in g-peptides from constrained acyclic gamino acids. Theoretical predictions by Hofmann and coworkers [7] for g-peptides revealed that structures with 14-and 9-helices are most stable. Herein, we report a left-handed 9-helix in a novel class of mixed g-peptides, derived from dipeptide repeats with alternating C-linked carbo-g 4 -amino acids (g-Caas) and g-aminobutyric acid (GABA), in CDCl 3 .…”

“…Based on the predictions by Hofmann and coworkers [7] and the NOEs mentioned above, the minor structure was presumed to be a 14-helix, although careful scrutiny of the NMR evidence ruled out the presence of any other helix type.…”

C9 Helices and Ribbons in γ‐Peptides: Crystal Structures of Gabapentin Oligomers

“…These studies suggest that helical structures with hydrogen bonds enclosing 14-and 9-membered rings are most stable. [10] An isolated C 9 hydrogen bond has been described in the crystal structure of a gdipeptide.…”

Conformational choices for the stereochemically constrained γ‐amino acid residue gabapentin: Theoretical studies and correlation with experimental results

“…Several theoretical studies have examined the energetics of regular helical structures in both homo oligomeric and hybrid sequences containing b and c amino acids. [5][6][7][8] The generation of well defined structures in homo oligomers of b and c amino acids and in hybrid a, b, c sequences is facilitated by the use of residues in which rotation about individual bonds are restricted. The use of the b…”