Homooligomeric β³(R)‐valine peptides: Transformation between C₁₄ and C₁₂ helical structures induced by a guest Aib residue

Abstract

Novel helical, structures unprecedented in the chemistry of α-polypeptides, may be found in polypeptides containing β and γ amino acids. The structural characterization of C and C -helices in oligo β-peptides was originally achieved using conformationally constrained cyclic β-residues. This study explores the conformational characteristics of proteinogenic β residues in homooligomeric sequences and addresses the issue of inducing a transition between C and C helices by the introduction of a guest α-residue. Folded C -helical structures are demonstrated for the nonapeptide Boc-[β (R)Val] -OMe by NMR methods in CDCl -DMSO mixtures, while the peptide was found to be aggregated in CDCl . The insertion of a guest Aib residue into an oligo-β-valine sequence in the octapeptide model Boc-[(β (R)Val) -Aib-(β (R)Val] -OMe results in well dispersed NH region in the NMR spectrum indicating folded structures in CDCl . Structure calculations for both the peptides using NOE distance constraints support a C helical structure in the homooligomer which transform into a C helix on introduction of the guest Aib residue.

Conformational properties and aggregation of homo‐oligomeric β3(R)‐valine peptides in organic solvents

“…While the population and nature of folded, intramolecularly hydrogen‐bonded conformations may differ under the two distinct solvent conditions, 20%, v/v DMSO:CDCl 3 and CD 3 OH, it is clear that the 12‐residue peptide upon disaggregation tends to fold, resulting in shielding from solvent of most of the backbone NH groups. In a previous study, we had demonstrated folding into a 14‐helical structure for the related 9‐residue peptide, based upon hydrogen bonding data together with nuclear Overhauser effects (NOEs) . It is thus reasonable to suggest that further extension of the β 3 (R)‐Val chain does indeed lead to extension of the helical structure.…”

“…In Boc‐protected peptides, the N‐terminus, NH resonance appears at higher field than the remaining backbone NH groups and is readily assigned. Assignment of the remaining resonances may be achieved by a combination of TOCSY and NOESY experiments as described in our earlier report for the 9‐residue peptide . However, in homo‐oligomeric sequences extensive resonance overlap of the backbone protons of the β‐residues can render unambiguous assignment difficult with increasing peptide chain length.…”

“…All peptides were synthesized by conventional solution phase procedures. Detailed procedures and characterization of the peptides Boc‐[β 3 (R)‐Val] n ‐OMe, n = 2, 3, 4, 6, and 9 have been previously reported …”

“…Backbone conformational flexibilities may be restricted by multiple substitutions or by the use of cyclization restricting backbone CC torsion angles . As part of a program to investigate the intrinsic conformational preferences of β‐ and γ‐ residues derived by backbone homologation of genetically coded α amino acids (proteinogenic residues), we have been examining the solution conformations of homo‐oligomeric sequences of monosubstituted β 3 and γ 4 amino acids . In a recent report we investigated the conformation of a 9‐residue β 3 ( R )Val homo‐oligomer.…”

“…While the peptide existed predominantly in an aggregated form in CDCl 3 solution, addition of small amounts of the polar, hydrogen bonding solvent DMSO resulted in disaggregation, permitting complete 1 H NMR assignments and establishment of a 14‐helical conformation at a solvent composition of 45% (v/v, DMSO:CDCl 3 ). Insertion of a single Aib residue in the center of the sequence resulted in transformation to a 12‐helical structure, which could be established in CDCl 3 solution …”