These reports sparked a flurry of activity on the conformational properties of β peptide oligomers. The unsubstituted β, and γ amino acid residues can be incorporated into oligopeptide helices, without disturbing the overall helical fold [1-4]. This study suggested that hybrid sequences with expanded hydrogen bonded, rings could indeed be constructed. A very large number of recent studies have greatly expanded our understanding of the conformational properties of substituted β and γ residues, when incorporated into α peptide host sequences [2-17]. One approach that has been investigated by Appavu et al. [18] is to examine the role of gem dialkyl substitution on the conformational properties of β, and γ residues [2,12,14]. The ready availability of the achiral β, β′-disubstituted γ amino acid, gabapentin (1-aminomethylcyclohexaneacetic acid, Gpn), has permitted detailed exploration of the structural chemistry of gabapentin peptides (Figure 1). The presence of gem dialkyl substituents at the central β carbon atom, limits the accessible conformations about the C^β-C^γ(θ₁), and C^β-C^α(θ₂) bonds. A large body of crystallographic evidence has been presented, which suggests that in the case of Gpn θ₁, and θ₂, are largely restricted to gauche conformations (θ₁ ± 60, θ₂ ± 60), a property that favors locally folded conformation at this residue. Consequently, a very large number of folded peptides have been characterized, in which diverse hydrogen bonded rings are facilitated by the gabapentin residue. Figure 2 provides a summary of the conformational characteristics for the gabapentin residue.

Figure 1: Chemical structure of Gabapentin (Gpn).

Figure 2: Nine combinations of the torsion angles θ1 and θ2 in gabapentin. (a) Gpn with chair conformation of the cyclohexane ring in which the aminomethyl group is equatorial and carboxymethyl group axial, (b) the inverted chair conformation of the cyclohexane ring with respect to (a), in which the aminomethyl group is axial and carboxymethyl group is equatorial. Sterically disallowed combinations are shaded dark. Numbers of Gpn residues crystallographically characterized are shown in circles in the respective cells. In the case of achiral structures both the combinations, (+60°, +60°) and (-60°, -60°) are indicated. (21achiral structures in (a) and 11 in (b)).

The success in generating folded structures in hybrid peptides containing, the gabapentin residue prompted an examination of the related β-amino acid residues 1-aminomethylcyclohexane carboxylic acid (β^2,2Ac₆c), and 1-aminocyclohexane acetic acid (β^3,3Ac₆c). Figure 3 shows the structures of the four related residues, all of which posses 1,1-disubstituted cyclohexane rings. The parent α amino acid residue 1-aminocyclohexane 1-carboxylic acid (Ac₆c) has been conformationally characterized in a number of synthetic peptides [6,12,14]. The Ac₆c residue strongly favors helical conformations,with φ ∼ 60 ± 30, and ψ ∼ 30 ± 20. Thus, both β-turn and 310/α-helical structures can readily accommodate the Ac₆c residue. Two β amino acid homologs may be considered viz β^2,2Ac₆c, and β^3,3Ac₆c. Earlier studies from Appavu et al., focused on the more readily synthetically accessible residue β^3,3Ac₆c [7,10-13]. X-ray crystallographic characterization of a number of small peptides containing the β^3,3Ac₆c residue revealed that internally hydrogen bonded conformations were rarely observed. The overwhelming majority of the β-amino acid residues (149) adopt gauche conformation (θ = ± 60°). Out of a total of 210 examples, 61 residues adopt the trans conformation (φ = -180°). Figure 4 provides a summary of the observed φ,ψ values for all β amino acid residues in which θ values of ∼ ± 60° have been obtained. Most β^3,3Ac₆c amino acid residue fall out outside the region, expected for intra molecularly hydrogen bonded structures, which have been characterized for other β amino acid residues. Only one example of a hydrogen bonded hybrid αβ C₁₁ turn has been observed in the peptide Piv-Pro-β^3,3Ac₆c-NHMe [7,12- 14]. These results suggest that the intrinsic conformational preferences of the β^3,3Ac₆c residue may not readily facilitate its incorporation into folded, intramolecular hydrogen bonded structures in short peptides. Therefore, an examination of the conformational properties of the isomeric β^2,2Ac₆c residue was undertaken. The characterization of folded structures in model peptides containing the β^2,2Ac₆c residue [2,10-14]. Advancing the fundamental structures of alpha amino acids to homologation would significantly impact the nanovaccine development for infectious and non-infectious diseases [17-20].

Figure 3: Definition of backbone torsion angles in α, β and γ amino acid residues.

Figure 4: Two - dimensional scatter plot in φ - ψ space (θ = ± 60°) for intramolecularly hydrogen bonded β-residues determined in several peptide crystal structures. Specific intramolecular hydrogen bond types and the space for non - hydrogen bonded β^3,3Ac₆c residue are marked. The arrow indicates the position of the N- and C- terminus residues of the ββ C₁₀ turn. Regions accommodating C₁₂ and C₁₄ helices (ββ) and C₁₁ helices (αβ) are shaded.

Thus far, relatively few structural reports are available for the β^2,2Ac₆c residue. Figure 5 shows a view of the structure of the tripeptide Boc-β^2,2Ac₆c-β^2,2Ac₆c-β^2,2Ac₆c-OMe which was already reported at the time these studies undertaken. In this structure the unusual ββ C₁₀ hydrogen bond with reverse directionality and a C₆ hydrogen bond were observed. The hydrogen bonded C₁₁ turns obtained in αβ hybrid sequences incorporating the β^2,2Ac₆c residue.

Figure 5: Molecular conformation of the tripeptide Boc-β^2,2Ac₆c-β^2,2Ac₆c- β^2,2Ac₆c-OMe, which has a C₆ hydrogen bond at β^2,2Ac₆c(1) and a non-helical ββ C10 hydrogen bond with reversed directionality, at the β^2,2Ac₆c(2)- β^2,2Ac₆c(3) segment. The backbone dihedral angles are marked [9-14].