The IR absorption and NMR analysis of the preferred conformation of monodisperse Z-(Aib)"-OtBu (Z = (benzyloxy)carbonyl, OtBu = tert-butoxy, Aib = -aminoisobutyric acid; = 1-12) strongly indicates the formation of fully developed stable 310-helices for the higher (n = 8-12) homooligomers (pleionomers). This experimental study was performed in the solid state as well as in deuteriochloroform solution, in the latter case as a function of concentration, temperature, and addition of dimethyl sulfoxide and the free radical Tempo. A picture of the mode of self-association of the helical structures has also been obtained. A detailed theoretical study of Aib IV-acetyl-lV'-methyl amide by conformational energy computations indicates that the fully extended structure is less stable than the helical structures, irrespective of the actual value of the N-C"-C' valence angle.

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SynopsisThe conformational preferences of linear peptides containing a,a-disubstituted a-amino acids, derived from the crystal structures of 28 compounds, are reviewed. In particular, the sensitivity of peptide conformation to the geometry of these unusual amino acids is underlined. We also consider possible future directions of research, which, we hope, will result in a complete understanding of the structures adopted by peptaibol antibiotics.

Terminally blocked, isotactic molecular and crystal structures of the Z-trimer is folded in a type I11 /?-turn conhomopeptides from the sterically de-protected trimer, hexamer, heptamer and formation, the longest homopeptides manding a-methylvaline of general for-octamer have been determined by X-ray form well-developed, regular, rightIn the crystal state. while the ed 3,,-helices. The screw sense in the helix Bz, Ac; n = 2-8) have been prepared of the pBrBz-blocked octamer has been step-by-step in solution and fully characconfirmed to be right-handed by solidterized. The conformations preferred in state and solution CD spectroscopy. The possible exploitation of these peptide helices as rigid and precise molecular rulers solution (B-turn and right-handed 3,,-heis discussed.lix) have been assessed by FT-IR, 'HNMR and CD spectroscopy. The

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AESThACT ISolution conformations of the protected 2-9 segment of the peptaibol antibiotics emerimicins m and IV [a-aminoisobutyric acid (Aib)]3r-Val-Gly-L.Lkeu(b)2 and the related short _se s b oxy(Ab)Val-OMe and benzwoxy4Ab)jAal.GlyOMe have been investigated bycirculardichroism studies. For.the latter two cpounds the-structural preferences in the solid state have been assayed byx-ray diffraction analyses. The exerimental data described here, along with these previously reported, support the view that the shortest Aib-containing segments (from -tri-through pentapeptides) adopt the 31r-helical structure both in solution and In the solid state. In contrast, the octapeptide appears to adopt the a-helical-structure in solution. The role ofpeptide chain length and specific amino acid-sequences in stabilizing either of the two helicalstrucres and hence their possible implications on the nature of the channel.formed by peptibol antibiotics in the membrane are-also briefly-outline!4 -Peptaibol antibiotics alter the ionic permeability ofmembranes by forming channels (1, 2). They have in common:. (i) a high content (as much as 50%) of the unusual, achiral a-amino acid a-aminoisobutyric acid (Aib) dimethylated at the a carbon, and (ii) an-amino alcohol at the COOH-terminus. Our interest in the stereochemistry of peptides containing a-amino acid residues dialkylated at the a carbon was stimulated by the fiaet that they possess significant constraints on their conformational freedom (3-5). In particular, the 4, ipangles ofan Aib residue in apeptide ain are restricted th values near those associated with rightor left-handed 31 or a (3.6l3) helices.In this paper we present the results of a confdrmational CD investigation,. in solution, of the protected 2-9 segment of emerimicins III and IV (6)two components of the ffamily of peptaibol antibiotics produced by-Emericelop&i microspora (7)-and the related short sequences Z-(Aib)r-xVal-OMe (Z, benzyloxycarbonyl; OMe, methoxy) and Z-(Aib)3-L-Val-GlyOMe. For the latter two compounds, the solid state conformations, as determined by x-ray diffraction analyses, will be discussed. The results of this crystallographic study are complementaryto results on the other shorter sequences t-Boc-Aib-OH (t-Boc, tert-butyloxycarbonyl), Z-(Aib)rOH, and Z-(Aib)3-OtBu (OtBu, tert-butoxy) previously reported (8,9).Selection ofthe emerimicin family for this investigation was based on the fact that, among all the known peptaibol antibiotics, emerimicins IIH and IV each incorporate an octapeptide segment (residues 2-9) which contains the longest sequence (a triplet) of-a-amino acid residues monoalkylated at the a carbon. It was expected that this would provide some information relating the effect ofmain-chain length.-and specific amino acid sequences on the type of-helical structure that is assumed by natural antibiotics ning a high proportion of residues dialkylated at the a carbon. Abbreviations: Aib; a-ahinnoisobutyric aid (ammethyalaine);Iva, isovaline (a-ethylalailne); PheoL-, -plienylal ninol (ph...

Conformational energy computations on a derivative and a homo‐dipeptide of Cα,α‐diethylglycine were performed. In both cases the N‐ and C‐terminal groups are blocked as acetamido and methylamido moieties, respectively. It was found that the Cα,α‐diethylglycine residues are conformationally restricted and that the minimum energy conformation corresponds to the fully extended C5 structure when the NCαC′ bond angle is smaller than 108° (as experimentally observed). The results of the theoretical analysis are in agreement with the crystal‐state structural propensity of the complete series of N‐trifluoroacetylated homo‐peptides of this Cα,α‐dialkylated residue from monomer to pentamer, determined by x‐ray diffraction and also described in this work. Interestingly, for the first time, a crystallographically planar peptide backbone was observed (in the protected tripeptide). A comparison with peptides of Cα,α‐dimethylglycine, Cα‐methyl, Cα‐ethylglycine, and Cα,α‐di‐n‐propylglycine indicates that the fully extended conformation becomes more stable than the helical structures when both amino acid side‐chain Cβ atoms are substituted.