Conformational Characterization of the 1-Aminocyclobutane-1-carboxylic Acid Residue in Model Peptides

• Published in: Journal of peptide science Vol. 3; no. 2; pp. 110 - 122
• Main Authors: Gatos, Maddalena, Formaggio, Fernando, Crisma, Marco, Toniolo, Claudio, Bonora, Gian Maria, Benedetti, Zettore, Di Blasio, Benedetto, Iacovino, Rosa, Santini, Antonello, Saviano, Michele, Kamphuis, Johan
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.03.1997
• Subjects: 310-helix; Amino Acids - chemistry; Amino Acids, Cyclic; Crystallization; cyclic amino acid; Magnetic Resonance Spectroscopy; Models, Molecular; peptide conformation; Peptides - chemical synthesis; Peptides - chemistry; Protein Conformation; Solutions; Spectroscopy, Fourier Transform Infrared; X-Ray Diffraction; β-bend
• ISSN: 1075-2617; 1099-1387
• DOI: 10.1002/(SICI)1099-1387(199703)3:2<110::AID-PSC88>3.0.CO;2-6

A series of N‐ and C‐protected, monodispersed homo‐oligopeptides (to the dodecamer level) from the small‐ring alicyclic Cα,α‐dialkylated glycine 1‐aminocyclobutane‐1‐carboxylic acid (Ac4c) and two Ala/Ac4c tripeptides were synthesized by solution methods and fully characterized. The conformational preferences of all the model peptides were determined in deuterochloroform solution by FT‐IR absorption and 1H‐NMR. The molecular structures of the amino acid derivatives Z‐Ac4c‐OH and Z2‐Ac4c‐OH, the tripeptides Z‐(Ac4c)3‐OtBu, Z‐Ac4c‐(L‐Ala)2‐OMe and Z‐L‐Ala‐Ac4c‐L‐Ala‐OMe, and the tetrapeptide Z‐(Ac4c)4‐OtBu were determined in the crystal state by X‐ray diffraction. The average geometry of the cyclobutyl moiety of the Ac4c residue was assessed and the τ(N–Cα–C′) bond angle was found to be significantly expanded from the regular tetrahedral value. The conformational data are strongly in favour of the conclusion that the Ac4c residue is an effective β‐turn and helix former. A comparison with the structural propensities of α‐aminoisobutyric acid, the prototype of Cα,α‐dialkylated glycines, and the other extensively investigated members of the family of 1‐aminocycloalkane‐1‐carboxylic acids (Acnc, with n=3, 5–8) is made and the implications for the use of the Ac4c residue in conformationally constrained peptide analogues are briefly examined. © 1997 European Peptide Society and John Wiley & Sons, Ltd