Miniature β-Hairpin Mimetic by Intramolecular Hydrogen Bond and C–H···π Interactions

[Image: see text] Canonically, protein β-hairpin motifs are stabilized by intramolecular hydrogen bonds. Here, we attempt to develop a rational design recipe for a miniature hairpin structure stabilized by hydrogen bonding as well as C–H···π interaction and try to understand how such a stabilization effect varies with different functional groups at each terminus. Database analysis shows that the α-amino acids with an aromatic side chain will not favor that kind of C–H···π stabilized hairpin structure. However, hybrid tripeptides with an N-terminal Boc-Trp-Aib corner residue and C-terminal aromatic ω-amino acids fold into the hairpin conformation with a central β-turn/open-turn that is reinforced by a C–H···π interaction. The CCDC database analysis further confirms that this C–H···π stabilized hairpin motif is general for Boc-protected tripeptides containing Aib in the middle and aromatic functionality at the C-terminus. The different α-amino acids like Leu/Ala/Phe/Pro/Ser at the N-terminus have a minor influence on the C–H···π interaction and stabilities of the folded structures in solid-state. However, the hybrid peptides exhibit different degrees of conformational heterogeneity both in the solid and solution phase, which is common for this kind of flexible small molecule. Conformational heterogeneity in the solution phase including the C–H···π stabilized β-hairpin structures are characterized by the molecular dynamics (MD) simulations explaining their plausible origin at an atomistic level.