Contrasting solution conformations of peptides containing α,α-dialkylated residues with linear and cyclic side chains

Abstract

The conformational properties of α,α-dialkylated amino acid residues possessing acyclic (diethylglycine, Deg: di-n-propylglycine, Dpg; di-n-butylglycine, Dbg) and cyclic (1-amino-cycloalkane-1-carboxylic acid, Ac_nc) side chains have been compared in solution. The five peptides studied by nmr and CD spectroscopy are Boc-Ala-Xxx-Ala-OMe, where Xxx = Deg(I). Dpg (II), Dbg (III), Ac₆c (IV), and Ac₇c (V). Delineation of solvent-shielded NH groups have been achieved by solvent and temperature dependence of NH chemical shifts in CDCl₃ and (CD₃)₂SO and by paramagnetic radical induced line broadening in pepiide III. In the Dxg peptides the order of solvent exposure of NH groups is Ala(1) > Ala(3) > Dxg(2), whereas in the Acnc peptides the order of solvent exposure of NH groups is Ala(1) > Ac_nc(2) > Ala(3). The nmr results suggest that Ac_nc peptides adopt folded β-turn conformations with Ala(1) and Ac_nc(2) occupying i + 1 and i + 2 positions. In contrast, the Dxg peptides favor extended C₅ conformations. The conformational differences in the two series are clearly borne out in CD studies. The solution conformations of peptides I-III are distinctly different from the β-turn structure observed in crystals. Low temperature nmr spectra recorded immediately after dissolution of crystals of peptide II provide evidence for a structural transition. Introduction of an additional hydrogen-bonding function in Boc-Ala-Dpg-Ala-NHMe (VI) results in a stabilization of a consecutive β-turn or incipient 3₁₀-helix in solution.