Propensities to form the β-turn and β-hairpin structures of d-Pro-Gly and Aib-d-Ala containing peptides: a computational study

Abstract

The preferences for peptides containing D-Pro-Gly or Aib-D-Ala segments to adopt β-turn and β-hairpin structures were explored using DFT methods and the implicit solvation model in CH₂Cl₂ and water. The populations of the preferred β-turn structures varied depending on the sequence and solvent polarity. The preferences of β-turn structures for Ac-D-Pro-Gly-NHMe were βI′ > βII′ in CH₂Cl₂ and βII′ > βI′ in water. The preferences for Ac-Aib-D-Ala-NHMe were βI′ in CH₂Cl₂ and water. β-Hairpin structures with βI′ turn motifs were the most preferred for heptapeptides containing Aib-D-Ala in CH₂Cl₂ and water. However, the β-hairpin structures of D-Pro-Gly-containing heptapeptides with strands composed of non-Ala residues exhibited preferences for the βII′(u) turn motif in CH₂Cl₂ and the βI′(u) or βII′(d) turn motif in water. Through the analysis of calculated thermodynamic properties, the sequence, strength of H-bonds, solvent polarity, and conformational flexibility appeared to interact in determining the preferred β-hairpin structure of each heptapeptide, although β-turn segments played a role in promoting the formation of β-hairpin structures and the β-hairpin propensities varied. In the heptapeptides containing D-Pro-Gly or Aib-D-Ala (hp_dPG-3 or hp_BdA-2, respectively), β-hairpin formation was enthalpically favored and entropically disfavored at 25 °C in water, which is consistent with experimental results for the oligopeptides with similar sequences around the β-turn segments. The propensity for β-hairpin formation was greater for hp_BdA-2, whereas the decrease in entropy due to β-hairpin formation was greater for hp_dPG-3. The structural preferences of β-turns and β-hairpins containing D-Pro-Gly or Aib-D-Ala segments obtained here may be useful for the design of bioactive macrocyclic peptides containing β-hairpin mimics and the design of binding epitopes for protein–protein and protein–nucleic acid recognitions.