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Oligomerization Alters Binding Affinity Between Amyloid Beta and a Modulator of Peptide Aggregation.

ABSTRACT: The soluble oligomeric form of the amyloid beta (A?) peptide is the major causative agent in the molecular pathogenesis of Alzheimer's disease (AD). We have previously developed a pyrroline-nitroxyl fluorene compound (SLF) that blocks the toxicity of A?. Here we introduce the multi-parametric surface plasmon resonance (MP-SPR) approach to quantify SLF binding and effect on the self-association of the peptide via a label-free, real-time approach. Kinetic analysis of SLF binding to A? and measurements of layer thickness alterations inform on the mechanism underlying the ability of SLF to inhibit A? toxicity and its progression towards larger oligomeric assemblies. Depending on the oligomeric state of A?, distinct binding affinities for SLF are revealed. The A? monomer and dimer uniquely possess sub-nanomolar affinity for SLF via a non-specific mode of binding. SLF binding is weaker in oligomeric A?, which displays an affinity for SLF on the order of 100 ?M. To complement these experiments we carried out molecular docking and molecular dynamics simulations to explore how SLF interacts with the A? peptide. The MP-SPR results together with in silico modeling provide affinity data for the SLF-A? interaction and allow us to develop a new general method for examining protein aggregation.

SUBMITTER: Hilt S

PROVIDER: S-EPMC6130836 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Oligomerization Alters Binding Affinity Between Amyloid Beta and a Modulator of Peptide Aggregation.

Hilt Silvia S Rojalin Tatu T Viitala Tapani T Koivuniemi Artturi A Bunker Alex A Hogiu Sebastian Wachsmann SW Kálai Tamás T Hideg Kálmán K Yliperttula Marjo M Voss John C JC

The journal of physical chemistry. C, Nanomaterials and interfaces 20171010 43

The soluble oligomeric form of the amyloid beta (Aβ) peptide is the major causative agent in the molecular pathogenesis of Alzheimer's disease (AD). We have previously developed a pyrroline-nitroxyl fluorene compound (SLF) that blocks the toxicity of Aβ. Here we introduce the multi-parametric surface plasmon resonance (MP-SPR) approach to quantify SLF binding and effect on the self-association of the peptide via a label-free, real-time approach. Kinetic analysis of SLF binding to Aβ and measurem ...[more]

PMID: 30214656

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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.

Dataset Information

Oligomerization Alters Binding Affinity Between Amyloid Beta and a Modulator of Peptide Aggregation.

Publications

Oligomerization Alters Binding Affinity Between Amyloid Beta and a Modulator of Peptide Aggregation.

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