β²‐ and β³‐Peptides with Proteinaceous Side Chains: Synthesis and solution structures of constitutional isomers, a novel helical secondary structure and the influence of solvation and hydrophobic interactions on folding

Abstract

Enantiomerically pure a-amino-acid derivatives with the side chains of A h , Val, and Leu in the 2-or 3-position (8'-and P3-amino acids, resp.), as well as with substituents in both the 2-and 3-positions (Pz.3-amino acids, of like-configuration) have been prepared (compounds 8-17) and incorporated (by stepwise synthesis and fragment coupling, intermediates 24-34) into P-hexa-, P-hepta-, and j-dodecapeptides (1 -17). The new and some of the previously prepared P-peptides (35-39) showed NHiND exchange rates (in MeOH at room temperature) with T~,~ values of up to 60 days, unrivalled by short chain a-peptides. All P-peptides 1-7 were designed to be able to attain the previously described 3,-helical structure (Figs. I and 2). C D Measurements (Fig. 4), indicating a new secondary structure of certain P-peptides constructed of P'-and p3-arnino acids, were confirmed by detailed NMR solution-structure analyses: a P*-heptapeptide (2c) and a Pz.3-hexapeptide (7c) have the 3,-helical structure (Figs. 6 and 7), while to a P2/P3-hexapeptide (4) with alternating substitution pattern H-(P2-Xaa-P3-Xaa),-OH a novel, unusual helical structure (in (DJpyridine, Fig. 8; and in CD30H, Figs. 9 and f0) was assigned, with a central ten-membered and two terminal twelve-membered H-bonded rings, and with C=O and N-H bonds pointing alternatively up and down along the axis of the helix (Fig. 11). Thus, for the first time, two types of fi-peptide turns have been identified in solution. Hydrophobic interactions ofand hindrance to solvent accessibility by the aliphatic side chains are discussed as possible factors influencing the relative stability of the two types of helices.

A Theoretical Study of <i>β</i>-Amino Acid Conformational Energies and Solvent Effect

“…The biggest breakthrough in the synthesis β-peptides of defined sequence that allowed crystallographic and high-resolution NMR data to be obtained was achieved by the research groups of Gellman [10]- [15] and Seebach [16]- [19]. Gellman and co-workers have synthesized and characterized the oligomers of trans-2-aminocyclo-pentanecarboxylic acid (ACPC) [12], trans-2-aminocyclohexanecarboxylic acid (ACHC) [11] and trans-3-aminopyrrolidine-4-carboxylic acid (ACP) [15].…”

“…The Oligomers containing both ACPC and ACP residues were also shown to form 12-helical conformations in aqueous solution [15]. Seebach and co-workers showed that β-peptides composed of acyclic residues with side chains derived from α-amino acids also formed 14-helical conformations in organic solvent [16].…”

Towards mimicking short linear peptide motifs: identification of new mixed α,β-peptidomimetic ligands for SLAM-Associated Protein (SAP) by confocal on-bead screening

“…Since the introduction of beta peptides by Seebach et al [21], their propensity to fold into stable secondary structures has been successfully used to mimic secondary structures, such as helices [6,7,9,20,22], sheets [19] or turns [23]. Furthermore, beta peptides show a remarkable metabolic stability making them attractive candidates for peptidomimetic design.…”

Sculpting the β-peptide foldamer H12 helix via a designed side-chain shape

“…7 The cyclic side-chain of the latter lends extra stability to the secondary structure through the restricted conformational space and the i-(i+3) hydrophobic stacking interactions between the cyclohexane rings. 8 Recent results led to the successful synthesis of monoterpene-derived b-amino acids with an apopinane skeleton (2-amino-6,6-dimethyl-bicyclo[3.1.1]heptane-3-carboxylic acid; ABHC). 9 The apopinane moiety is a dimethyl-substituted, methylene-bridged analog of ACHC and, as such, further enhances the conformational preorganization of the cyclohexane ring, but the bulky substituent certainly disfavors the i-(i+3) hydrophobic stacking interactions in H14 (Fig.…”