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Extended Helices with Small H-bonded Rings Centered at a Single Residue

This section focuses on small (generally < 10 atoms) pseudocycles with 1 ^ 3 H-bond interaction as potent helix building blocks. The pseudocycle is centered at the (i + 1) residue, with an H-bond joining the C=O and NH groups at positions i and i + 2 respectively (Fig. 2.5A). This H-bonding scheme recurs in the b- and g-peptide lineage subject to the presence of strong pre-organization structural elements in monomeric units (e.g. ring, backbone or side chain heteroatoms).

2.3.2.1 a-Peptides: the g-Helix

In a-peptides, 1 ^ 3 H-bond interaction corresponds to a seven (C7) H-bonded ring, i.e. the g-turn (f @ +70°, c @ —70°) or the more stable inverse g-turn (f @ —70°, c @ +70°) according to the equatorial or axial orientation of the side chain [106]. They are quite common structuring elements of cyclic peptides, and can also be observed in crystallized proteins, although much less frequently than b-turns. A series of consecutive inverse g-turns generates a theoretical 2.27-helix called g-helix [107] (Fig. 2.5B), which has, however, not been detected in natural peptides or proteins so far. Recently, a first step was accomplished towards the construction of an artificial g-helix template. Jimenez et al. showed that the dipep-tide Ac-l-Pro-D-c3Dip-NHMe (8) adopts two consecutive g-turns, induced by the presence of the d-form of the cyclopropane amino acid (c3Dip) derivative (Fig. 2.5B) [108].

2.3.2.2 o-Peptides with Specific Conformation-stabilizing Elements b-Peptides: the 8-helix The world of b-peptides is mostly associated with the prominent 12- and 14-helical folds. Considering that their topology excludes the presence of axial substituents (see Fig. 2.2), b-peptides consisting of geminally disubstituted amino acids or of b2' 3-amino acids of unlike configuration (see

Fig. 2.5 (A) 1 ^ 3 H-bonding scheme in o-peptides and analogs. (B) The «-peptide g-helix and the two consecutive C7 turns observed experimentally for dipeptide 8 in the solid state [108]. (C-E) Expansion of the «-peptide C7 structure by the addition of one backbone atom: the C8 H-bonded conformations of b-peptides 9-11 consisting of specific conformation-stabilizing elements: (C) (2R,3S)-a-hydroxylated b23-amino acid [109], (D) 1-aminomethylcyclopropane-carboxylic acid [50], and (E) trans-oxabornene-b-amino acid residues (B3LYP/6-311++G** minimum energy conformation) [110].

Fig. 2.5 (A) 1 ^ 3 H-bonding scheme in o-peptides and analogs. (B) The «-peptide g-helix and the two consecutive C7 turns observed experimentally for dipeptide 8 in the solid state [108]. (C-E) Expansion of the «-peptide C7 structure by the addition of one backbone atom: the C8 H-bonded conformations of b-peptides 9-11 consisting of specific conformation-stabilizing elements: (C) (2R,3S)-a-hydroxylated b23-amino acid [109], (D) 1-aminomethylcyclopropane-carboxylic acid [50], and (E) trans-oxabornene-b-amino acid residues (B3LYP/6-311++G** minimum energy conformation) [110].

also Section 2.5) cannot fit in any of the two folds. Seebach and collaborators found that b-peptides consisting of (2R,3S)-a-hydroxylated b2'3-amino acid residues (e.g. 9) exist in polar solvent as a helical conformation based on repetitive 8-membered H-bonded rings resulting from 1 ^ 3 H-bond interactions (C=O;---H-N;+2) [109]. The structure is probably further stabilized by an additional interaction between C=O;■■■H-O; (Fig. 2.5C). A remarkably similar C8-based conformation was reported for b2' 2-substituted oligomers consisting of 1-aminomethylcyclopropanecarboxylic acid residues (Fig. 2.5D) [50]. X-ray diffraction studies of short chain oligomers revealed that orbital hyperconjugation between the s-bonding orbitals (HOMO) of the cyclopropane ring and the p* non-bonding orbital (LUMO) of the carbonyl constrained c values close to 0° (bisected conformation), thus favoring a C8 H-bonding pattern. A ribbon-like secondary structure was extrapolated from these data.

Independently, using JH NMR and density functional theory computations, Klein and co-workers concluded that the b-peptide consisiting of trans-oxabornene-b-aminoacid (e.g. 11, Fig. 2.5E) also adopts a C8-based helix conformation [110]. These results show that cyclohexyl ring bridging and unsaturation impose angular constraints that translate the robust 314-helix sustained by trans-ACHC-b2'3 amino acid units (see Section 2.3.1.2) [1, 56, 57], into a new folding pattern. Additional H-bond contacts between amide NHs and the ring oxygens were also hypothesized. Altogether, these results do not question the proposal formulated by Gellman [41] that 1 ^ 3 H-bonding between nearest-neighbor amide groups in b-peptides is not favored, but rather suggest that extra-interaction or specific angular constraints can overcome this general feature.

g-Peptides According to model studies [41], /-peptides have higher propensities than b-peptides to populate conformations stabilized by H-bonding between nearest neighbor amide groups. Several examples of secondary structures stabilized by 1 ^ 3 H bonds have been identified in designed /-peptides incorporating various levels of backbone pre-organization [74-76, 111]. In the case of gabapentin (Gpn), a g3; 3-geminally disubstituted amino acid, both C(a)-C(b) and C(b)-C(g) bonds are locked in a gauche conformation with 91 @ d2 @ +60° [75]. In the solid state, Gpn oligomers populate C9 H-bonded conformations. Because the molecules are achiral, two sets of dihedral angles (+) and (—) of opposite values can be associated with the C9-pseudocycle. The structure of the dimer shows a (+, +) arrangement, which can be extrapolated to a 2.7-helix, whereas the structure of the tetramer corresponds to a heterochiral sequence (+, —, +, —) leading to a ribbon structure (Fig. 2.6A). In all cases, the secondary structures rely on consecutive C9 H-bonded rings [75].

A related C9-ribbon type structure has been postulated on the basis of NMR spectroscopy data in H2O for /-peptide oligomers of cis-g-amino-l-proline (Fig. 2.6B) [76]. In the proposed secondary structure of 12, the two amide bonds connected to a- and g-positions of each proline residue are in the same plane, perpendicular to the average plane of the proline rings. The solid phase synthesis approach which authorizes facile incorporation of a variety of acyl and alkyl side chains at the g-amino position is highly modular.

The carbofuranosyl group was used by Sharma and Kunvar as a conformation-stabilizing side chain to enforce the backbone of b- and g-peptides into well-defined folded conformations (see also peptides 16 and 22 in Sections 2.4.2.2 and 2.4.3). A left-handed 9-helix with 1 ^ 3 H-bonding pattern (Fig. 2.6C) was identified from NMR studies in CDCl3 solution and molecular dynamics calculations for a hybrid g-hexapeptide (13) with alternating carbofuranosyl-g4-aminoacid and g-aminobutyric acid (GABA or g-Gly). It is worth mentioning that the corresponding b-peptides made of alternating (3S)-carbofuranosyl-b3-amino acid and b-HGly residues adopt a mixed helical structure with (M)-helicity. (see Section 2.4.2.2).

Fig. 2.6 C9 H-bonded conformations of g-peptides. (A) Gabapentin oligomers. Structure of dimer and tetramer in the solid state [75]. (B) Oligomers of cis-g-amino-L-proline [76]. (C) g-Hexapeptide 13 with alternating carbofuranosyl-g4-aminoacid and g-Gly residues [111].

2.3.2.3 Stabilizing Local Backbone Conformation by Inverse-Bifurcation Involving an Additional Heteroatom

Oligo a- and b- and g-aminoxyacids As already mentioned in Section 2.3.1.2 for N,N'-oligoureas (g-peptide lineage), replacing carbon atoms in an «-peptide backbone with heteroatoms represents a promising opportunity to design new foldamers. a-Aminoxypeptides formerly obtained by substitution of oxygen for the b-carbon atoms within the b-peptide backbone (Fig. 2.7A) have been investigated in depth by ab initio quantum-mechanical calculations and molecular dynamics simulation. This theoretical work predicted that a C8 H-bonded ring (N-O turn, Fig. 2.7A) should stabilize a !.88-helix conformation in homochiral segments [112, 113] (Fig. 2.7B), at least in aprotic solvents [114]. Spectroscopic studies on a series of oligomers supported these predictions and established that such an helical conformation occurs in oligomers as short as a trimer [115]. The high stability of the helix was interpreted as the result of the replacement of the amide bonds by ''amidoxy'' bonds in which the strong withdrawing effect of the oxygen atom considerably enhances the acidity of the NHs and the strength of the H

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