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A method for constraining short peptides (<20 residues) of arbitrary sequence to an α-helical conformation (∼100% helical in H 2 O at 25 °C) is presented. Glutamine residues at positions i and i + 7 of the peptides were tethered with an alkanediyl chain between the side chain nitrogen atoms. Peptides containing this tether were readily synthesized on the solid phase by amide formation between an α,ω-diaminoalkane and the side chain carboxylates of glutamate residues. The resulting cyclic peptides were studied by NMR and CD and were found to adopt an α-helical conformation in aqueous solution. The α-helix was thermally stable to ≥40 °C. Corresponding untethered control peptides with N -methylglutamine at the i and i + 7 positions lacked helicity under the same conditions. Analogous peptides were also prepared for comparison using the thiolysine cross-linking method described previously Jackson, D. Y.; King, D. S.; Chmielewski, J.; Singh, S.; Schultz, P. G. J. Am. Chem. Soc. 1991, 113, 9391−9392.
Phelan et al. (Wed,) studied this question.