Folding of peptides characterized by c3Val, a highly constrained analogue of valine

Using a combined chemical/chiral chromatographic approach we synthesized an N-protected derivative of (R)–c3Val, a severely conformationally restricted Cα-tetrasubstituted α-amino acid characterized by a Cβ,β-dimethylated cyclopropane system. A set of terminally protected derivatives and model peptides (to the heptamer level), containing one or two (R)–c3Val residues in combination with either Aib or Gly residues, was prepared by solution methods. A detailed solution and crystal-state conformational investigation, based on Fourier transform infrared (FTIR) absorption, 1H-NMR, and x-ray diffraction techniques, performed in comparison with a similar study on related derivatives and peptides rich in (αMe)Val, the prototype of Cα-tetrasubstituted α-amino acids of this subfamily, allowed us to conclude the following: (a) c3Val is a good β-bend and helix former, although less efficient than (αMe)Val. (b) The relationship between α-carbon chirality and screw sense of the folded structure formed is the same as that of (αMe)Val, i.e., the (R)-enantiomer has a strong left-handed bias. (c) c3Val seems more prone than (αMe)Val to fold into a γ-bend conformation. The conformational propensities of Cβ,β-disubstituted Ac3c residues are also discussed in comparison with those of the parent cyclopropane residue.Contract grant sponsors: Ministry of University and Research (MIUR) of Italy, National Research Council (CNR) of Italy, and Spanish Ministry of Science and Technology (SMST) Contract grant number: PPQ 2001-1834 (SMST)Peer reviewe