C(alpha,alpha)-disubstituted amino acids (alphaalphaAAs) are widely used to conformationally constrain peptides. A series of pentapeptides containing dipropylglycine (Dpg) at alternating positions and their alpha-amino acid counterpart L-norvaline (Nva) analogues were synthesized to fully investigate the impact of Dpg on peptide backbone structure in aqueous solution. CD, VCD, and NMR spectral analysis suggest that Dpg containing peptides adopt more ordered structures relative to their Nva containing analogues. The central residues (Ala, Thr, Tyr, Val) and the charged side-chains of Glu and Lys play important roles in the degree of peptide folding. Hydrophobic and branched residues (Val, Tyr) at the central position of the peptide produce greater folding as judged by CD and NMR. Variation of the chemical shift with temperature (Deltadelta/DeltaT NH) of Ac-Glu-Dpg-Tyr-Dpg-Lys-NH(2) suggests a series of i --> i + 3 hydrogen bonds between the N-terminal acetyl carbonyl and the Tyr(3) NH, and the Glu(1) carbonyl and the Dpg(4) NH. The solution conformation of Ac-Glu-Dpg-Tyr-Dpg-Lys-NH(2) calculated from NMR-derived constraints shows a 3(10)-helical structure (two repetitive type-III beta-turns) at residues 1-4, which is supported by 2D NMR, CD, and VCD spectra. Analysis of NMR-derived models of these peptides suggest that there is a strong hydrophobic interaction of the pro-S propyl side chain of Dpg(2) and the Tyr(3) side-chain that may be a strong stabilizing force of the peptide folding in water.
(c) 2009 Wiley Periodicals, Inc.