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a-Aminoisobutyric acid (Aib)

Di-n-ethylgiycint (Deg)

1 -A mi nocycloh exane-I -carboxyiic acitl (Ac^c)

Fig. 5.3 Chemical structures of some representative a,a-dialkylglycines.

fungi; Trichoderma species being the most widely studied. The conformational properties of Aib were uncovered in early structural investigations of synthetic peptide fragments of antibiotics of fungal origin [16], which have later been termed as peptaibols or peptaibiotics [17]. The related chiral residue isovaline (a-methyl-a-ethyl glycine) is also a constituent of these natural products, occurring almost exclusively as S-isovaline [18]. A large number of chiral and achiral dialkyl glycines have been synthetically produced (see Fig. 5.3 for representative structures). The presence of a tetrasubstituted C a-atom in the backbone of polypeptide chains results in a dramatic reduction in 'allowed'conformational space'.

The sterically accessible regions of space for Aib may be readily derived by examining the regions of overlap of the Ramachandran map for l-Ala and d-Ala, which are related by inversion about the origin (Fig. 5.4). The two distinct areas of overlap are small and restricted to the right- (aR) and left- (aL) handed helical regions, leading to the simple conclusion that Aib and related Ca a-dialkyl amino acids may be expected to be strongly helix stabilizing. This expectation has been borne out by a large body of investigations on peptide containing Aib and related residues. Indeed, the largest body of crystal structures of oligopeptides available to date is on sequences containing Aib residues [19-23]. Helical folding in host amino acid sequences containing very few guest Aib residues has been repeatedly demonstrated, suggesting that helix nucleation and stabilization may be readily achieved by strategic incorporation of these conformationally constrained amino acids. Figure 5.5 shows three examples of helices constructed in stable sequences. Both 310 and a-helices may be generated. Mixed helical structures are relatively

Fig. 5.4 Overlapped Ramachandran maps for N-acetyl-L-Ala-N'-methylamide and N-acetyl-D-Ala-N'-methylamide. The shaded regions are stereochemically allowed for both L- and D-Ala and these correspond to the "allowed" regions for N-acety-Aib-N'-methylamide.

31(r helix 3l(/a-helix a-helix

Fig. 5.5 Molecular conformations observed in the crystals of synthetic peptides (a) pBrBz-(Aib)10-OtBu [22b]; (b) Boc-Aib-(Ala-Leu-Aib)3-OMe [23]. (c) Boc-Leu-Aib-Val-Ala-Leu-Aib-Val-Ala-Leu-Aib-OMe [21b].

31(r helix 3l(/a-helix a-helix

Fig. 5.5 Molecular conformations observed in the crystals of synthetic peptides (a) pBrBz-(Aib)10-OtBu [22b]; (b) Boc-Aib-(Ala-Leu-Aib)3-OMe [23]. (c) Boc-Leu-Aib-Val-Ala-Leu-Aib-Val-Ala-Leu-Aib-OMe [21b].

common. In solution, the barriers to helix interconversions, within the limited region of space defined for 310 and a-helices, are likely to be small.

The introduction of a few Aib residues is sufficient to stabilize helices in sequences of length upto 20 residues. The structure of a 19-residue peptide containing as many as three internally positioned d-residues provides an example of helix promotion by a guest Aib residue [24]. The crystal structures of normally occurring peptaibols have also established that helical folding is maintained even when several internal proline residues are present. Solid-state conformations of zervamicin and antiamoebin (Fig. 5.6) are examples when an Aib-Pro/Hyp C-terminus segment adopts the b-bend ribbon structure, in which all residues adopt values in the helical region of space [18b, d].

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