En route towards the peptide γ‐helix: X‐ray diffraction analyses and conformational energy calculations of Adm‐rich short peptides

Abstract

We performed the solution-phase synthesis of a set of model peptides, including homo-oligomers, based on the 2-aminoadamantane-2-carboxylic acid (Adm) residue, an extremely bulky, highly lipophilic, tricyclic, achiral, C -tetrasubstituted α-amino acid. In particular, for the difficult peptide coupling reaction between two Adm residues, we took advantage of the Meldal's α-azidoacyl chloride approach. Most of the synthesized Adm peptides were characterized by single-crystal X-ray diffraction analyses. The results indicate a significant propensity for the Adm residue to adopt γ-turn and γ-turn-like conformations. Interestingly, we found that a -CO-(Adm) -NH- sequence is folded in the crystal state into a regular, incipient γ-helix, at variance with the behavior of all of the homo-dipeptides from C -tetrasubstituted α-amino acids already investigated, which tend to adopt either the β-turn or the fully extended conformation. Our density functional theory conformational energy calculations on the terminally blocked homo-peptides (n = 2-8) fully confirmed the crystal-state data, strongly supporting the view that this rigid C -tetrasubstituted α-amino acid residue is largely the most effective building block for γ-helix induction, although to a limited length (anti-cooperative effect). Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

Metal‐Helix Frameworks from Short Hybrid Peptide Foldamers

“…The helical structures are stabilized by two successive intramolecular 12‐membered hydrogen bonds between the residues i and i +3. Similarly, the helical structures stabilized by the two consecutive H‐bonds have been observed in the α‐tripeptides of sterically constrained α‐amino acids . The two amide NH protons at the N ‐terminus and two carbonyl groups at the C ‐terminus of P1 and P2 are involved in the head‐to‐tail intermolecular H‐bonding with other helices in the crystal packing.…”

Influence of the C‐terminal substituent on the crystal‐state conformation of Adm peptides

“…Previously, conformational energy calculations using density functional theory [performed using the B3LYP functional combined with the 6‐31 + G(d,p) basis set] had predicted that after the most stable consecutive γ‐turn conformer, Ac‐(Adm) 2 ‐NHMe could adopt a distorted type‐II (II′) β‐turn with backbone torsion angles differing less than 10° from those found for tripeptide 4d . This nonhelical type of turn had however not been previously reported experimentally for N‐acyl Adm dipeptide amide sequences.…”

“…The diamondoid 2‐aminoadamantane‐2‐carboxylic acid (Adm) residue has shown intriguing potential for adopting the relatively uncommon γ‐turn conformation in X‐ray diffraction studies of short Adm‐rich peptides and homo‐peptides . In solution, Adm derivatives and dipeptides, such as Ac‐Adm‐NHMe (Ac, acetyl; NHMe, methylamino) and Ac‐Adm‐Gly‐NHMe, have been suggested to fold in γ‐turn conformations based on NMR and IR absorption spectroscopic studies.…”

“…In solution, Adm derivatives and dipeptides, such as Ac‐Adm‐NHMe (Ac, acetyl; NHMe, methylamino) and Ac‐Adm‐Gly‐NHMe, have been suggested to fold in γ‐turn conformations based on NMR and IR absorption spectroscopic studies. Moreover, certain Adm homo‐peptides have been observed by X‐ray diffraction to exhibit two consecutive, regular γ‐turns, indicating the possibility to form the still uncharacterized γ‐helix…”

Heterochiral Ala/(αMe)Aze sequential oligopeptides: Synthesis and conformational study

“…We wished in particular to discover and investigate in detail noncoded α‐amino acids with a high propensity to fold into single turns, and possibly offering a good chance to create new, longer ordered secondary structures. To this end, we especially considered two C α ‐tetrasubstituted α‐amino acids as potentially very promising building blocks, the chiral (αMe)Aze (Figure ) and the achiral 2‐aminoadamantane‐2‐carboxylic acid . In particular, by examining a series of repeating, homochiral , sequential ‐( S )‐(αMe)Aze‐( S )‐Ala‐ dipeptides, we found a novel stable peptide conformation, the γ‐bend ribbon structure, characterized by only half of the CO … HN intramolecular H‐bonds typical of the γ‐helix because the strong γ‐bend inducer (αMe)Aze, which forms Xxx‐(αMe)Aze tertiary amides, lacks the NH donor function.…”