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The Effects of Charged Amino Acid Side-Chain Length on Diagonal Cross-Strand Interactions between Carboxylate- and Ammonium-Containing Residues in a β-Hairpin.

ABSTRACT: The β-sheet is one of the common protein secondary structures, and the aberrant aggregation of β-sheets is implicated in various neurodegenerative diseases. Cross-strand interactions are an important determinant of β-sheet stability. Accordingly, both diagonal and lateral cross-strand interactions have been studied. Surprisingly, diagonal cross-strand ion-pairing interactions have yet to be investigated. Herein, we present a systematic study on the effects of charged amino acid side-chain length on a diagonal ion-pairing interaction between carboxylate- and ammonium-containing residues in a β-hairpin. To this end, 2D-NMR was used to investigate the conformation of the peptides. The fraction folded population and the folding free energy were derived from the chemical shift data. The fraction folded population for these peptides with potential diagonal ion pairs was mostly lower compared to the corresponding peptide with a potential lateral ion pair. The diagonal ion-pairing interaction energy was derived using double mutant cycle analysis. The Asp2-Dab9 (Asp: one methylene; Dab: two methylenes) interaction was the most stabilizing (-0.79 ± 0.14 kcal/mol), most likely representing an optimal balance between the entropic penalty to enable the ion-pairing interaction and the number of side-chain conformations that can accommodate the interaction. These results should be useful for designing β-sheet containing molecular entities for various applications.

SUBMITTER: Chang JY

PROVIDER: S-EPMC9268152 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Swapping the Positions in a Cross-Strand Lateral Ion-Pairing Interaction between Ammonium- and Carboxylate-Containing Residues in a β-Hairpin.

Project description:Cross-strand lateral ion-pairing interactions are important for antiparallel β-sheet stability. Statistical studies suggested that swapping the position of cross-strand lateral residues should not significantly affect the interaction. Herein, we swapped the position of ammonium- and carboxylate-containing residues with different side-chain lengths in a cross-strand lateral ion-pairing interaction in a β-hairpin. The peptides were analyzed by 2D-NMR. The fraction folded population and folding free energy were derived from the chemical shift data. The ion-pairing interaction energy was derived using double mutant cycle analysis. The general trends for the fraction folded population and interaction energetics remained similar upon swapping the position of the interacting charged residues. The most stabilizing cross-strand interactions were between short residues, similar to the unswapped study. However, the fraction folded populations for most of the swapped peptides were higher compared to the corresponding unswapped peptides. Furthermore, subtle differences in the ion-pairing interaction energy upon swapping were observed, most likely due to the "unleveled" relative positioning of the interacting residues created by the inherent right-handed twist of the structure. These results should be useful for developing functional peptides that rely on lateral ion-pairing interactions across antiparallel β-strands.

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Like-charged residues at the ends of oligoalanine sequences might induce a chain reversal.

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A study of the influence of charged residues on β-hairpin formation by nuclear magnetic resonance and molecular dynamics.

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