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PH-controlled stacking direction of the ?-strands in peptide fibrils.

ABSTRACT: Peptides provide a framework for generating functional biopolymers. In this study, the pH-dependent structural changes in the 21-29 fragment peptide of ?₂-microglobulin (?₂m_21-29) during self-aggregation, i.e., the formation of an amyloid fibril, were discussed. The ?-sheet structures formed during parallel stacking under basic conditions (pH???7.7) adopted an anti-parallel stacking configuration under acidic conditions (pH???7.6). The parallel and anti-parallel ?-sheets existed separately at the intermediate pH (pH?=?7.6-7.7). These results were attributed to the rigidity of the ?-sheets in the fibrils, which prevented the stable hydrogen bonding interactions between the parallel and anti-parallel ?-sheet moieties. This observed pH dependence was ascribed to two phenomena: (i) the pH-dependent collapse of the ?₂m_21-29 fibrils, which consisted of 16?±?3 anti-parallel ?-sheets containing a total of 2000 ?-strands during the deprotonation of the NH₃⁺ group (pK_a?=?8.0) of the ?-strands that occurred within 0.7?±?0.2 strands of each other and (ii) the subsequent formation of the parallel ?-sheets. We propose a framework for a functional biopolymer that could alternate between the two ?-sheet structures in response to pH changes.

SUBMITTER: Tseng WH

PROVIDER: S-EPMC7747703 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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pH-controlled stacking direction of the β-strands in peptide fibrils.

Tseng Wei-Hsuan WH Chen Szu-Hua SH Hiramatsu Hirotsugu H

Scientific reports 20201217 1

Peptides provide a framework for generating functional biopolymers. In this study, the pH-dependent structural changes in the 21-29 fragment peptide of β2-microglobulin (β2m21-29) during self-aggregation, i.e., the formation of an amyloid fibril, were discussed. The β-sheet structures formed during parallel stacking under basic conditions (pH ≥ 7.7) adopted an anti-parallel stacking configuration under acidic conditions (pH ≤ 7.6). The parallel and anti-parallel ...[more]

PMID: 33335192

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Project description:The misfolding and aggregation of amyloid-β (Aβ) peptides into amyloid fibrils is regarded as one of the causative events in the pathogenesis of Alzheimer's disease (AD). Tanshinones extracted from Chinese herb Danshen (Salvia Miltiorrhiza Bunge) were traditionally used as anti-inflammation and cerebrovascular drugs due to their antioxidation and antiacetylcholinesterase effects. A number of studies have suggested that tanshinones could protect neuronal cells. In this work, we examine the inhibitory activity of tanshinone I (TS1) and tanshinone IIA (TS2), the two major components in the Danshen herb, on the aggregation and toxicity of Aβ1-42 using atomic force microscopy (AFM), thioflavin-T (ThT) fluorescence assay, cell viability assay, and molecular dynamics (MD) simulations. AFM and ThT results show that both TS1 and TS2 exhibit different inhibitory abilities to prevent unseeded amyloid fibril formation and to disaggregate preformed amyloid fibrils, in which TS1 shows better inhibitory potency than TS2. Live/dead assay further confirms that introduction of a very small amount of tanshinones enables protection of cultured SH-SY5Y cells against Aβ-induced cell toxicity. Comparative MD simulation results reveal a general tanshinone binding mode to prevent Aβ peptide association, showing that both TS1 and TS2 preferentially bind to a hydrophobic β-sheet groove formed by the C-terminal residues of I31-M35 and M35-V39 and several aromatic residues. Meanwhile, the differences in binding distribution, residues, sites, population, and affinity between TS1-Aβ and TS2-Aβ systems also interpret different inhibitory effects on Aβ aggregation as observed by in vitro experiments. More importantly, due to nonspecific binding mode of tanshinones, it is expected that tanshinones would have a general inhibitory efficacy of a wide range of amyloid peptides. These findings suggest that tanshinones, particularly TS1 compound, offer promising lead compounds with dual protective role in anti-inflammation and antiaggregation for further development of Aβ inhibitors to prevent and disaggregate amyloid formation.

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PH-controlled stacking direction of the ?-strands in peptide fibrils.

Publications

pH-controlled stacking direction of the β-strands in peptide fibrils.

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