Collateral Existence of Folded and Extended Conformations of the β-Ala Moiety in a Model Peptide

Abstract

The single-crystal X-ray diffraction analysis of a nonchiral β-Ala-containing model peptide, Boc-β-Ala-Aib-OCH3 1 (β-Ala, 3-aminopropionic acid; Aib, α-aminoisobutyric acid), establishes the coexistence of distinctly different backbone conformations in two crystallographically independent molecules, A and B, in the asymmetric unit. Interestingly, the central μ torsion angle around the -Cβ–Cα- bond of the conformationally flexible β-Ala residue appears to be critical in dictating the overall distinct structural features, i.e., in molecule A it adopts a folded gauche conformation: μ = −71.0°, whereas it favors an extended trans conformation, μ = 161.2°, in molecule B. As expected, the stereochemically constrained Aib residue preferred an energetically favorable folded backbone conformation, the torsion angles being φ = 46.2° and ψ = 48.3° for molecule A and φ = −43.6° and ψ = −45.5° for molecule B, lying in the left-handed and right-handed helical regions of the Ramachandran map, respectively. Considering the signs as well as the magnitudes of the backbone torsional angles, molecule A typically folds into a pseudo type III′ β-turn-like structure while molecule B prefers an overall extended conformation. Entrapping the two dramatically distinct conformational characteristics in the crystalline state clearly suggests that the gauche and the trans effects of the β-Ala moieties are indeed energetically accessible to a short linear peptide and receive strong experimental support. The analyses permitted us to emphasize that in addition to conformational constraints of the neighboring residue, the chemical nature of the side-chain acyclic substituents and the “local environments” collectively seem to influence the stabilization of the folding–unfolding behavior of the two methylene units (-CONH-CH2-CH2-CONH-) in 1.