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

Yulong Zhong,Zhong-Lin Lu,Quan Tang,Bing Gong,Rui Liu,Eva Zurek,Daniel P Miller

doi:10.3389/fchem.2020.530083

Abstract

Factors responsible for the persistent adoption of hairpin conformations by hybrid oligopeptides, each having a central β/α dipeptide segment flanked by aromatic γ-amino acid (γAr) residues, are probed. Our recent studies revealed that tetrapeptide 1 and 2, having central dipeptide segments consisting of β-alanine (β-Ala) and glycine (Gly), and L-β-homophenylalanine (L-β-homoPhe) and Gly residues, respectively, that are flanked by γAr residues, fold into well-defined, expanded β-turns with doubly H-bonded γAr residues. Replacing the γAr residues of 1 and 2 with L-Val and L-Leu residues results in tetrapetides 1′ and 2′ that fail to fold into defined conformations, which confirms the decisive role played by the H-bonded γAr residues in the promoting folding of 1 and 2. Attaching L-Val and L-Leu residues to the termini of 1 affords hexapeptide 1a. With an additional H-bond between its L-Val and L-Leu residues, peptide 1a folds into a hairpin with higher stability than that of 1, indicating that the expanded β-turn can nucleate and stabilize β-hairpin with longer β-strands. Attaching L-Val and L-Leu residues to the termini of 2 affords hexapeptide 2a. Substituting the L-β-homoPhe residue of 2a with a D-β-homoPhe residue gives hexapeptide 2b. Surprisingly, hexapeptide 2a fold into a hairpin showing the similar stability as those of tetrapeptides 1 and 2. Hexapeptide 2b, with its combination of a D-β-homoPhe residue and the L-Val/L-Leu pair, fold into a hairpin that is significantly more stable than the other hybrid peptides, demonstrating that a combination of hetero-chirality between the β-amino acid residue of the dipeptide loop and the α-amino acid residues of the β-strands enhances the stability of the resultant β-hairpin.

Highlights

As a major class of protein secondary structure, reverse turns provide sites of chain reversal, which results in the globular character of a protein (Smith and Pease, 1980; Milner-White and Poet, 1987)
The models for 2a and 2b were optimized with the revPBE-D3 (Zhang and Yang, 1998; Grimme et al, 2010) functional and dispersion correction using the Amsterdam Density Functional (ADF) (Fonseca Guerra et al, 1998; te Velde et al, 2001)1 software package
The triple-zeta with polarization functions (TZP) basis set was used while keeping the core 1s electrons fixed in the oxygen, nitrogen, and carbon atoms

Summary

Introduction

As a major class of protein secondary structure, reverse turns provide sites of chain reversal, which results in the globular character of a protein (Smith and Pease, 1980; Milner-White and Poet, 1987). 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). The combinations of chirality between the β-amino acid residue in the dipeptide loop and the terminal α-amino acid residues are examined for its influence on the folding of the corresponding hybrid peptides

Methods

Results

Conclusion