Peptide helices with pendant cycloalkane rings. Characterization of conformations of 1-aminocyclooctane-1-carboxylic acid (Ac8c) residues in peptides

• Published in: Journal of peptide science 2004-03, Vol.10 (3), p.160-172
• Main Authors: Datta, Saumen, Rathore, R. N. S., Vijayalakshmi, S., Vasudev, Prema G., Balaji Rao, R., Balaram, P., Shamala, N.
• Format: Article
• Language: English
• Subjects: 1-aminocyclooctane-1-carboxylic acid; Amino Acids, Cyclic - chemistry; Crystallography, X-Ray; cycloalkanes; Magnetic Resonance Spectroscopy; Oligopeptides - chemistry; peptide conformation; peptide helices; Protein Conformation
• ISSN: 1075-2617; 1099-1387
• DOI: 10.1002/psc.507

A pentapeptide, Boc‐Leu‐Ac8c‐Ala‐Leu‐Ac8c‐OMe 1, an octapeptide, Boc‐Leu‐Ac8c‐Ala‐Leu‐Ac8c‐Ala‐Leu‐Ac8c‐OMe 2 and a tripeptide, Boc‐Aib‐Ac8c‐Aib‐OMe 3 containing the 1‐aminocyclooctane‐1‐carboxylic acid residue (Ac8c) were synthesized and conformationally characterized by x‐ray diffraction studies in the crystal state. Peptides 1 and 2 were also studied by NMR in CDCl3 solution. Peptide 1 adopts a purely 310‐helical conformation in crystals, stabilized by three intramolecular 1 ← 4 hydrogen bonds. Peptide 2 in crystals is largely 310‐helical with distortion in the backbone at the N‐terminus by the insertion of a water molecule between Ac8c (2) CO and Ala (6) NH groups. Peptide 3 forms a C10‐ring structure, i.e. a type III (III′) β‐ turn conformation stabilized by an intramolecular 1 ← 4 hydrogen bond. Five cyclooctane rings assume boat–chair conformations, whereas the sixth [Ac8c(8) in 2] is appreciably distorted, resembling a chiral intermediate in the pseudorotational pathway from the boat–chair to the twisted boat–chair conformation. Internal bond angles of the cyclooctane rings are appreciably distorted from the tetrahedral value, a characteristic feature of the cyclooctane ring. Peptide 1 crystallized in the space group P212121 with a = 11.900(4) Å, b = 18.728(6) Å, c = 20.471(3) Å and Z = 4. The final R1 and wR2 values are 0.0753 and 0.2107, respectively, for 3901 observed reflections [Fo ≥ 3σ(Fo)]. Peptide 2 crystallized in space group P21 with a = 12.961(5) Å, b = 17.710(10) Å, c = 15.101(7) Å, β = 108.45(4)° and Z = 2. The final R1 and wR2 values are 0.0906 and 0.1832, respectively, for 2743 observed reflections [Fo ≥ 3σ(Fo)]. 1H‐NMR studies on both the peptides strongly suggest the persistence of 310‐helical conformations in solution. Peptide 3 crystallized in the space group P21/n, with a = 10.018(1) Å, b = 20.725(1) Å, c = 12.915(1) Å and Z = 4. The final R1 and wR2 values are 0.0411 and 0.1105, respectively, for 3634 observed reflections [Fo ≥ 4σ(Fo)]. Copyright © 2003 European Peptide Society and John Wiley & Sons, Ltd.