CONTRASTING SOLUTION CONFORMATIONS OF PEPTIDES CONTAINING ALPHA,ALPHA-DIALKYLATED RESIDUES WITH LINEAR AND CYCLIC SIDE-CHAINS

The conformational properties of alpha,alpha-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(n)c) 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), AC(6)C (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)(2)SO and by paramagnetic radical induced line broadening in peptide III. In the Dxg peptides the order of solvent exposure of NH groups is Ala(1) > Ala(3) > Dxg(2), whereas in the Ac(n)c peptides the order of solvent exposure of NH groups is Ala(1) > Ac(n)c(2) > Ala(3). The nmr results suggest that Ac(n)c peptides adopt folded beta-turn conformations with Ala(1) and Ac(n)c(2) occupying i + 1 and i + 2 positions. In contrast, the Dxg peptidesfavor extended C-5 conformations. The conformational differences in the two series are clearly borne out in CD studies. The solution conformations of peptides I-III ale distinctly different from the beta-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 beta-turn or incipient 3(10)-helix in solution. (C) 1995 John Wiley & Sons, Inc.