Dataset Information

Comparative Hydrophobic Core Dynamics Between Wild-Type Amyloid-β Fibrils, Glutamate-3 Truncation, and Serine-8 Phosphorylation.

ABSTRACT: Post-translational modifications (PTMs) of amyloid-β (Aβ) species are implicated in the modulation of overall toxicities and aggregation propensities. We investigated the internal dynamics in the hydrophobic core of the truncated ΔE3 mutant fibrils of Aβ_1-40 and compared them with prior and new data for wild-type fibrils as well as with phosphorylated S8 fibrils. Deuteron static solid-state NMR techniques, spanning line-shape analysis, longitudinal relaxation, and chemical exchange saturation transfer methods, were employed to assess the rotameric jumps of several methyl-bearing and aromatic groups in the core of the fibrils. Taken together, the results indicate the rather significant influence of the PTMs on the hydrophobic core dynamics, which propagates far beyond the local site of the chemical modification. The phosphorylated S8 fibrils display an overall rigidifying of the core based on the higher activation barriers of motions than the wild-type fibrils, whereas the ΔE3 fibrils induce a broader variety of changes, some of which are thermodynamic in nature rather than the kinetic ones.

SUBMITTER: Vugmeyster L

PROVIDER: S-EPMC9484291 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Publications

Comparative Hydrophobic Core Dynamics Between Wild-Type Amyloid-β Fibrils, Glutamate-3 Truncation, and Serine-8 Phosphorylation.

Vugmeyster Liliya L Fai Au Dan D Smith Matthew C MC Ostrovsky Dmitry D

Chemphyschem : a European journal of chemical physics and physical chemistry 20211213 3

Post-translational modifications (PTMs) of amyloid-β (Aβ) species are implicated in the modulation of overall toxicities and aggregation propensities. We investigated the internal dynamics in the hydrophobic core of the truncated ΔE3 mutant fibrils of Aβ<sub>1-40</sub> and compared them with prior and new data for wild-type fibrils as well as with phosphorylated S8 fibrils. Deuteron static solid-state NMR techniques, spanning line-shape analysis, longitudinal relaxation, and chemical exchange sa ...[more]

PMID: 34837296

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Project description:Functional amyloids are abundant in living organisms from prokaryotes to eukaryotes playing diverse biological roles. In contrast to the irreversible aggregation of most known pathological amyloids, we postulate that naturally-occurring functional amyloids are reversible under evolutionary pressure to be able to modulate the fibrillization process, reuse the composite peptides, or perform their biological functions. β-Endorphin, an endogenous opioid peptide hormone, forms such kinds of reversible amyloid fibrils in secretory granules for efficient storage and returns to the functional state of monomers upon release into the blood. The environmental change between low pH in secretory granules and neutral pH in extracellular spaces is believed to drive the reversible fibrillization of β-endorphin. Here, we investigate the critical role of a buried glutamate, Glu8, in the pH-responsive disassembly of β-endorphin fibrils using all-atom molecular dynamics simulations along with structure-based pKa prediction. The fibril was stable at pH 5.5 or lower with all the buried Glu8 residues protonated and neutrally charged. After switching to neutral pH, the Glu8 residues of peptides at the outer layers of the ordered fibrils became deprotonated due to partial solvent exposure, causing sheet-to-coil conformational changes and subsequent exposure of adjacent Glu8 residues in the inner chains. Via iterative deprotonation of Glu8 and induced structural disruption, all Glu8 residues would be progressively deprotonated. Electrostatic repulsion between deprotonated Glu8 residues along with their high solvation tendency disrupted the hydrogen bonding between the β1 strands and increased the solvent exposure of those otherwise buried residues in the cross-β core. Overall, our computational study reveals that the strategic positioning of ionizable residues into the cross-β core is a potential approach for designing reversible amyloid fibrils as pH-responsive smart bio-nanomaterials.

Dataset Information

Comparative Hydrophobic Core Dynamics Between Wild-Type Amyloid-β Fibrils, Glutamate-3 Truncation, and Serine-8 Phosphorylation.

Publications

Comparative Hydrophobic Core Dynamics Between Wild-Type Amyloid-β Fibrils, Glutamate-3 Truncation, and Serine-8 Phosphorylation.

Similar Datasets

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