# \omega-Amino Acids in Peptide Design. Crystal Structures and Solution Conformations of Peptide Helices Containing a \beta-Alanyl-\gamma-Aminobutyryl Segment

Karle, IL and Pramanik, Animesh and Banerjee, Arindam and Bhattacharjya, Surajit and Balaram, P (1997) \omega-Amino Acids in Peptide Design. Crystal Structures and Solution Conformations of Peptide Helices Containing a \beta-Alanyl-\gamma-Aminobutyryl Segment. In: Journal of the American Chemical Society, 119 (39). pp. 9087-9095.

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## Abstract

Insertion of achiral \omega-amino acids into peptide sequences results in replacement of scissile peptide bonds by proteolytically stable C-C bonds. This provides a convenient means of creating peptidomimetics. The present study establishes the preservation of helical structures in octa- and undecapeptides with centrally located \beta- and \gamma-amino acids in the sequence. X-ray diffraction analyses of single crystals and NMR studies have been used to investigate the extent of perturbations of a regular $3_{10}$- or \alpha-helix by the introduction of $(-CH_2-)_n$ groups into the backbone by the use of the \beta-Ala-\gamma-Abu segment (\beta-Ala = \beta-alanine, \gamma-Abu ) \gamma-aminobutyric acid), which is formally homomorphous with a $(Gly)_3$ segment. In crystals, the octapeptide Boc-Leu-Aib-Val-\beta-Ala-\gamma-Abu-Leu-Aib-Val-OMe (1) and the undecapeptide Boc-Leu-Aib-Val-\beta-Ala-\gamma-Abu-Leu-Aib-Val-Ala-Leu-Aib-OMe (2) retain their helical motifs with minor bulges. Five new types of 4 \rightarrow 1, 5 \rightarrow 1, and 6 \rightarrow 1 hydrogen bond rings are formed with up to three extra $CH_2$ moieties. Cell parameters for peptide 1 are space group $P2_12_12_1$ with a =11.506 (1) \AA, b = 16.600 (1) \AA, c = 27.362(1) \AA, and R = 6.1% for 2696 data measured > 4\sigma(F); for the undecapeptide 2, the space group is $P2_1$ with a = 8.605 (3) \AA, b = 22.806 (4) \AA, c = 19.014 (3) \AA, \beta = 101.47(2)°, and R = 7.5% for 3797 data measured > 4\sigma(F). Helical conformations in solution are also maintained for peptide 2 as is evident from NMR studies in $CDCl_3$, which suggest that the centrally positioned, flexible \beta-Ala-\gamma-Abu segment can be comfortably accommodated into helical structures adopting gauche conformations about specific C-C bonds of the poly (methylene) units. Twenty structures for backbone conformations generated from MD simulations using NMR-derived contraints, superpose with a low RMSD value (0.78 \pm 0.05 \AA), further indicating that in these peptides the conformational flexibility of the \beta-Ala-\gamma-Abu segment is limited and confined to largely helical conformations.

Item Type: Journal Article Copyright for this article belongs to American Chemical Society. Division of Biological Sciences > Molecular Biophysics Unit M.K Anitha 20 Nov 2007 19 Sep 2010 04:16 http://eprints.iisc.ac.in/id/eprint/2189