Conformational Studies of Aib-Rich Peptides Containing Lactam-bridged Side-Chains. Evidence of 3-10-Helix Formation

Aib-rich side-chain lactam-bridged oligomers Ac–(Glu–Aib–Aib–Lys)n–Ala–OH with n = 1,2,3 were designed and synthesized as putative models of the 310-helix. The lactam bridge between the side chains of L-Glu and L-Lys in (i) - (i + 3) positions was introduced in order to enhance the structural preference toward the right-handed 310-helix. The conformational properties of the three peptides were studied in trifluoroethanol (TFE) solution by CD, NMR, and computer simulations. The structural information was derived mainly from the analysis of nuclear Overhauser effect spectroscopy spectra. The presence of aH(i)—HN(i + 2) and of aH(i)—HN(i + 3) connectivities and the absence of aH(i)—HN(i + 4) connectivities indicate that these peptides fold into a 310-helix rather than into an _-helix. Based on these conformational features, stereospecific assignment of the Aib methyl groups was possible. The results of such experiments and of the subsequent distance geometry and restrained molecular dynamics simulations reveal a marked preference of these peptides for 310-helix. The CD spectra of these peptides indicate that the helix content increases upon chain elongation. The CD spectrum of the trimer is characterized by a negative band at 200 nm and by a weak positive band around 220 nm. The CD spectrum in TFE is different from that observed in aqueous solution in the presence of SDS micelles, reported in our previous work, and from those reported by a different research group for 310-helical peptides. A possible reason for these differences could rest in the presence of different equilibria of the conformer populations of the various peptides in different solvent systems.