Propensities of peptides containing the Asn‐Gly segment to form β‐turn and β‐hairpin structures

Abstract

The propensities of peptides that contain the Asn-Gly segment to form β-turn and β-hairpin structures were explored using the density functional methods and the implicit solvation model in CH2 Cl2 and water. The populations of preferred β-turn structures varied depending on the sequence and solvent polarity. In solution, β-hairpin structures with βI' turn motifs were most preferred for the heptapeptides containing the Asn-Gly segment regardless of the sequence of the strands. These preferences in solution are consistent with the corresponding X-ray structures. The sequence, H-bond strengths, solvent polarity, and conformational flexibility appeared to interact to determine the preferred β-hairpin structure of each heptapeptide, although the β-turn segments played a role in promoting the formation of β-hairpin structures and the β-hairpin propensity varied. In the heptapeptides containing the Asn-Gly segment, the β-hairpin formation was enthalpically favored and entropically disfavored at 25°C in water. The calculated results for β-turns and β-hairpins containing the Asn-Gly segment imply that these structural preferences 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. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 653-664, 2016.

Self‐assembly of β‐turn motif‐connected tandem repeats of Aβ16‐22 and its aromatic analogs

“…We investigated the self-assembly of Aβ [16][17][18][19][20][21][22] , its aromatic analogs, and their tandem analogs wherein β-turn-inducing motifs have been incorporated between two peptide repeats. In order to understand how β-turn can modulate peptide assembly, we investigated 12 peptides containing β-turn-inducing motifs between the two peptide repeats of AβFF, AβFY, AβYY, and AβWW (Table 1).…”

“…[9,10] The basic propagating unit of β-amyloid fibers is a dimer wherein the peptide molecules take hairpin-like structures albeit with strands rotated by 90 , that is, the two strands of the monomeric unit belong to two different sheets that are stacked through side-chain interdigitation. [11] Aβ [16][17][18][19][20][21][22] , an amyloidogenic fragment from β-amyloid peptide, selfassembles into amyloid-like aggregates with an antiparallel organization of β-strands. [12] The peptide has a "Phe-Phe" cassette which is believed to be important in its self-assembly.…”

“…[13,14] Self-assembly of the tandem Aβ [16][17][18][19][20][21][22] repeats connected through a type I 0 turn nucleating sequence Asn-Gly has recently been investigated. [15] Pachahara and Nagaraj investigated the role of specific aromatic residues by substituting the Phe residues with Trp and Tyr and identified highly amyloidogenic Aβ [16][17][18][19][20][21][22] variants. [16] Tight turns in proteins cause reversal of the polypeptide backbone thereby playing critical role in protein folding.…”

“…[17] Aggregation of short amyloidogenic peptides could conceivably be facilitated by connecting the two strands through a tight turn. We investigated the aggregation of Aβ [16][17][18][19][20][21][22] , Ac-KLVFFAE-am (AβFF), and its aromatic analogs, Ac-KLVFYAE-am (AβFY), Ac-KLVYYAE-am (AβYY), and Ac-KLVWWAE-am (AβWW), connected in tandem through type I 0 and type II 0 β-turn inducing motifs. Asn-Gly and Aib-D Pro are chosen as the type I 0 β-turn-inducing motifs [18][19][20] while D Pro-Gly is chosen as the type II 0 turn-inducing motif.…”

“…We investigated the aggregation of Aβ [16][17][18][19][20][21][22] , Ac-KLVFFAE-am (AβFF), and its aromatic analogs, Ac-KLVFYAE-am (AβFY), Ac-KLVYYAE-am (AβYY), and Ac-KLVWWAE-am (AβWW), connected in tandem through type I 0 and type II 0 β-turn inducing motifs. Asn-Gly and Aib-D Pro are chosen as the type I 0 β-turn-inducing motifs [18][19][20] while D Pro-Gly is chosen as the type II 0 turn-inducing motif. [21,22] Introduction of the turn-inducing motifs rendered the peptides more amyloidogenic as indicated by thioflavin T (ThT) fluorescence spectroscopy and transmission electron microscopy (TEM).…”