Reverse Turn Foldamers: An Expanded β-Turn Motif Reinforced by Double Hydrogen Bonds

Abstract

Hybrid tetrapeptides sharing a backbone with a central α/β-dipeptide segment flanked by aromatic γ-amino acid residues fold into the same hairpin conformation with an expanded β-turn. This hairpin/β-turn motif is general for accommodating different α- and β-amino acid residues. Replacing glycine with other α-amino acid residues has an insignificant influence on or slightly decreases the stabilities of the folded conformations; substituting β-alanine with other β-amino acid residues enhances the stabilities of the folded structures.

Major Factors for the Persistent Folding of Hybrid α, β, γ-Hybrid Peptides Into Hairpins

“…Results from our recent study indicate that hybrid tetrapeptides 1 and 2 , along with eight other homologous hybrid peptides (Tang et al, 2020 ), persistently fold into a doubly H-bonded hairpin conformation containing an expanded β-turn that is very resilient toward incorporating different α- and β-amino acid residues into the central β/α dipeptide loop. Such a turn motif is capable of accommodating a variety of β/α dipeptide sequences that otherwise could not be introduced into a β-turn.…”

“…The synthesis of tetrapetides 1 and 2 has been reported by us (Zhang et al, 2019 ; Tang et al, 2020 ). Peptides 1 ′ and 2 ′ were prepared based on standard amide/peptide coupling.…”

“…Table 1 shows the difference in the chemical shifts (Δδ NH ) of the amide protons of the four peptides at the two concentrations. In the folded conformations of 1 and 2 , protons a and d , like b and e , are intramolecularly H-bonded and exhibit either small upfield shifts or insignificant downfield shifts at high vs. low concentrations; while the signals of protons c , which are not intramolecularly H-bonded, shift noticeably downfield with increasing concentration (Tang et al, 2020 ). In contrast, all of the amide proton resonances of peptides 1 ′ and 2 ′ recorded at 25 mM show downfield shifts relative to those at 1 mM, with the signals of protons a, c , and d showing significant shifts, while those of protons b undergoing small shifts.…”

“…Hairpins and reverse turns including β-turns play crucial roles in initiating the folding of peptides and proteins (Jäger et al, 2001 ; Rotondi and Gierasch, 2003 ; Du et al, 2004 ; Marcelino and Gierasch, 2008 ), and also possess in important biological functions, for example, as epitopes in protein–protein (Ripoll, 1992 ; Wilson and Stanfield, 1994 ; DeLano et al, 2000 ; Tyndall et al, 2005 ; Shukla and Sasidhar, 2015 ) and protein–nucleic acid (Churchill and Suzuki, 1989 ; Erard et al, 1990 ; Maynard and Searle, 1997 ; Shi et al, 1998 ; Leon et al, 2008 ) interactions. Our recent studies (Zhang et al, 2019 ; Tang et al, 2020 ) led to the discovery of a series of expanded β-turns sharing a β/α loop, i.e., a central dipeptide segment consisting of a β and α amino acid residue that is flanked by doubly H-bonded aromatic γ-amino acid (γAr) residues. This expanded β-turn represents a surprisingly resilient turn motif that allows the incorporation of different α and β amino acid residues (Tang et al, 2020 ).…”

“…Our recent studies (Zhang et al, 2019 ; Tang et al, 2020 ) led to the discovery of a series of expanded β-turns sharing a β/α loop, i.e., a central dipeptide segment consisting of a β and α amino acid residue that is flanked by doubly H-bonded aromatic γ-amino acid (γAr) residues. This expanded β-turn represents a surprisingly resilient turn motif that allows the incorporation of different α and β amino acid residues (Tang et al, 2020 ). It was found that introducing various α amino acid residues into the β/α dipeptide loop results in β-hairpins with the same or slightly lower stabilities, while incorporating β amino acid residues enhances the stabilities of the resultant β-hairpins.…”