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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
Authors:Jing-Yuan Chang  Yen-Jin Pan  Pei-Yu Huang  Yi-Ting Sun  Chen-Hsu Yu  Zhi-Jun Ning  Shou-Ling Huang  Shing-Jong Huang  Richard P. Cheng
Affiliation:1.Department of Chemistry, National Taiwan University, Taipei 10617, Taiwan; (J.-Y.C.); (Y.-J.P.); (P.-Y.H.); (Y.-T.S.); (C.-H.Y.); (Z.-J.N.);2.Instrumentation Center, National Taiwan University, Taipei 10617, Taiwan; (S.-L.H.); (S.-J.H.)
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.
Keywords:peptide, β  -hairpin, diagonal interaction, ion-pairing interaction, charged amino acid, side-chain length
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