Structural Dimorphism of Achiral α,γ‐Hybrid Peptide Foldamers: Coexistence of 12‐ and 15/17‐Helices

Abstract

Here, novel 12-helices in α,γ-hybrid peptides composed of achiral α-aminoisobutyric acid (Aib) and 4-aminoisocaproic acid (Aic, doubly homologated Aib) monomers in 1:1 alternation are reported. The 12-helices were indicated by solution and crystal structural analyses of tetra- and heptapeptides. Surprisingly, single crystals of the longer nonapeptide displayed two different helix types: the novel 12-helix and an unprecedented 15/17-helix. Quantum chemical calculations on both helix types in a series of continuously lengthened Aib/Aic-hybrid peptides confirm that the 12-helix is more stable than the 15/17-helix in shorter peptides, whereas the 15/17-helix is more stable in longer sequences. Thus, the coexistence of both helix types can be expected within a definite range of sequence lengths. The novel 15/17- and 12-helices in α,γ-hybrid peptides with 5→1 and 4→1 hydrogen-bonding patterns, respectively, can be viewed as backbone-expanded analogues of native α- and 3 -helices.

Modulating the Structural Properties of α,γ‐Hybrid Peptides by α‐Amino Acid Residues: Uniform 12‐Helix Versus “Mixed” 12/10‐Helix

“…Its X‐ray structure is shown in Figure d. As expected for achiral molecules, the crystal structure of P6 reveals two molecules with opposite handedness in the asymmetric unit. In contrast to peptides P1 – P5 , peptide P6 adopts the same novel unidirectional 12‐helix in single crystals as was recently found, for the first time, in the Aib/Aic‐hybrid peptides . This 12‐helix is stabilized by eight 4→1 intramolecular hydrogen bonds (Figure b).…”

“…The structural data for peptides P1 – P5 show that the combination of various chiral natural amino acids with the achiral γ 4,4 ‐amino acid Aic in 1:1 alternation leads to 12/10‐helices with alternately changing hydrogen‐bond directionality (for an example, see the structure of P5 in Figure a) both in the solid state and in the solvent chloroform. This is completely different from the folding behavior of α,γ 4,4 ‐hybrid peptides composed of achiral α‐amino acid constituents, for example, Aib, and the γ‐amino acid constituent Aic in our former studies . As already mentioned, unidirectional hydrogen bonding in the form of 12‐ and 15/17‐helices is observed in these Aib/Aic‐hybrid peptides.…”

“…Along with our studies on stable 12‐helices in α,γ 4 ‐hybrid peptides without steric constraints,, we recently demonstrated the co‐existence of uniform 12‐ and 15/17‐helical conformations in achiral α,γ 4,4 ‐hybrid peptides composed of the sterically constrained α‐amino acid 2‐aminoisobutanoic acid (Aib) and its doubly backbone homologated amino acid 4‐aminoisocaproic acid (Aic, see Figure ) in 1:1 alternation . The serendipitous 15/17‐helix in achiral α,γ 4,4 ‐hybrid peptides motivated us to investigate the structural behavior of α,γ‐hybrid peptide sequences composed of chiral proteinogenic α‐amino acids in combination with Aic residues in 1:1 alternation.…”

“…Moreover, Gellman and co‐workers explored this strategy to design various biologically active α,β‐hybrid peptides . In the case of α,γ‐hybrid peptides the formation of stable uniform 12‐helical conformations was often found, in analogy to the 3 10 ‐helix in α‐peptides –,–,. A very interesting observation was that α,β‐– and α,γ‐hybrid peptides,,,, are able to form helices with alternately changing hydrogen‐bond directionality, as first found in β‐peptide sequences composed of alternating β 3 ‐and β 2 ‐amino acids by Seebach and co‐workers, and later by other authors –.…”

“…The torsion angles for the Aic residues are φ =−56±6°, θ 1 =−56±6°, θ 2 =143±16°, and ψ =−115±8°. These torsion angles also differ from those in the corresponding 12‐helix alternatives –,–,. The torsion angle θ 2 of the Aic residues corresponds to an extended conformation, whereas gauche conformations occur in the 12/10‐helix and the 12‐helix alternative.…”