Miniature -Hairpin Mimetic by Intramolecular Hydrogen Bond and C-H??? Interactions

Canonically, protein beta-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 center dot center dot center dot pi interaction and try to understand how such a stabilization effect varies with different functional groups at each terminus. Database analysis shows that the alpha-amino acids with an aromatic side chain will not favor that kind of C-H center dot center dot center dot pi stabilized hairpin structure. However, hybrid tripeptides with an N-terminal Boc-Trp-Aib corner residue and C-terminal aromatic omega-amino acids fold into the hairpin conformation with a central beta-turn/open-turn that is reinforced by a C-H center dot center dot center dot pi interaction. The CCDC database analysis further confirms that this C-H center dot center dot center dot pi stabilized hairpin motif is general for Boc-protected tripeptides containing Aib in the middle and aromatic functionality at the C-terminus. The different alpha-amino acids like Leu/Ala/Phe/Pro/Ser at the N-terminus have a minor influence on the C-H center dot center dot center dot pi 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 center dot center dot center dot pi stabilized beta-hairpin structures are characterized by the molecular dynamics (MD) simulations explaining their plausible origin at an atomistic level.