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

Abstract

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.

Short Peptide-Based Smart Thixotropic Hydrogels

“…The interaction differs from the conventional supramolecular noncovalent forces such as H-bonding, hydrophobic interactions, and π-π stacking. In addition to the CT interaction, cation–π interaction is another critical noncovalent interaction recognized in biological systems to stabilize the tertiary or quaternary structures in proteins [ 5 , 163 ]. Taking together an unorthodox combination of the above-mentioned interactions, in 2019, our group explored the co-assembly of pyrene-capped tripeptides (Py-PhePheLys:T 3 P3 (Py = 1 pyrene butyric acid) and T 3 P20 (Py = 1 pyrene carboxylic acid); Figure 15 A,B), which undergo self-assembly with cationic naphthalene diimide (NDI) through CT interactions between the donor (pyrene) and acceptor (NDI) molecules ( Figure 15 A,B), cation-π interaction between pyrene and quaternary ammonium group from NDI, and β -sheet arrangement of the PhePheLys unit to form a self-supporting thixotropic hydrogel [ 5 ] ( Figure 15 A, Table 6 ).…”