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.