Aib-rich peptides containing lactam-bridged side chains as models of the 3(10)-helix

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 3(10)-helix. These peptides were conformationally characterized in aqueous solution containing SDS micelles by CD, NMR, and computer simulations. The lactam bridge between the side chains of L-Glu and L-Lys in (i) and (i+3) p ositions was introduced in order to enhance the conformational preference t oward the right-handed 3(10)-helix. The NMR results clearly indicate that t here is an increase of 3(10)-helix formation upon chain elongation. In the dimer and trimer (n = 2 and n = 3, respectively, in the structure reported above) the observed NOE connectivities are compatible with the 3(10)-helica l arrangement, confirmed by the temperature coefficients of the amide proto n resonances which suggest the presence of a hydrogen-bonded structure. The phi and psi dihedral angles of the structures obtained by molecular dynami cs calculations are also compatible with the 3(10)-helix. Identification of the hydrogen-bond pattern indicate that C=O(i)- - -HN(i+3) hydrogen bonds, typical of the 3(10)-helical conformation, are highly probable in all low- energy structures. The CD spectra of these Aib-rich lactam-bridged oligopep tides, obtained in the same solvent system used for NMR experiments, provid e important insight into the spectroscopic characteristics of the 3(10)-hel ix.