New classes of alpha/gamma- and beta/gamma-hybrid peptides have been synthesized with novel 12/10- and 11/13-mixed helical patterns, respectively. The alpha/gamma-peptides were derived from the dipeptide repeats with alternating arrays of l-Ala and gamma-Caa((l)) (C-linked carbo-gamma-amino acid from d-mannose), which generated a new 12/10-mixed helix, for the first time, without a beta-amino acid. The beta/gamma-peptides made from an alternating arrangement of beta-Caa((x)) (C-linked carbo-beta-amino acid) and gamma-Caa((x)) (C-linked carbo-gamma-amino acid from d-xylose), on the other hand, resulted in an unprecedented 11/13-helix. The secondary structures in these peptides have been ascertained from detailed NMR studies, and CD spectroscopy and molecular dynamics investigations provided additional support for the structures derived.

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In a twist: Tethering of short peptides with robust 10/12‐mixed helices, derived from C‐linked carbo‐β‐amino acids, to the turn‐inducing motif, β‐hGly‐D‐Pro‐Gly‐β‐hGly, permitted a de novo design of the helix–turn–helix motif in the foldamer domain.

Peptides U 0400 12/10-and 11/13-Mixed Helices in α/γand β/γ-Hybrid Peptides Containing C-Linked Carbo-γ-amino Acids with Alternating αand β-Amino Acids. -(SHARMA*, G. V. M.; JADHAV, V. B.; RAMAKRISHNA, K. V. S.; JAYAPRAKASH, P.; NARSIMULU, K.; SUBASH, V.; KUNWAR, A. C.; J.

Hybrid peptides are prepared from a C-linked carbo-beta-amino acid ester (R-beta-Caa) and an alpha-aminoxy acid (R-Ama) derived from S-lactic acid. Extensive NMR (in CDCl 3 solution), CD, and MD studies on the tetra- and hexapeptides led to identification of robust 12/10-mixed helices. The dipeptide repeat having an R-beta-Caa and an R-Ama thus provides a "new motif" to realize a 12/10-mixed helix, for the first time, in oligomers containing R-Ama. To understand the impact of side chains in the mixed helix formation, R-beta-Caa/Ama (with no substitution in Ama) and S-beta-hAla/R-Ama oligomers were investigated. NMR studies revealed the existence of 12/10-helices in these hybrid peptides, and the side chains of monomers were found to have a profound influence on their stabilities. These observations imply that the propensity of beta-amino acid to prefer a mixed 12/10-helix governs the structural behavior in these peptides. The structural consequences of the lone-pair repulsion between nitrogen and oxygen atoms result in a new and interesting structural motif which behaves like "pseudo" beta (3),beta(2)-peptides in generating 12/10-mixed helices.