ArticleBiophysical journal2015
Alzheimer's protective A2T mutation changes the conformational landscape of the Aβ₁₋₄₂ monomer differently than does the A2V mutation.
Article in Biophysical journal, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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24 citing papers in PubMed, 52 citations in OpenAlex.
- Missense variants in TUBA4A cause myo-tubulinopathies.Brain : a journal of neurology · 2026Article
- Survey of the Aβ-peptide structural diversity: molecular dynamics approaches.Biophysical reviews · 2024Review
- A turn for the worse: Aβ β-hairpins in Alzheimer's disease.Bioorganic & medicinal chemistry · 2024Review
- Resolution exchange with tunneling for enhanced sampling of protein landscapes.Physical review. E · 2022Article
- Anatomy and formation mechanisms of early amyloid-β oligomers with lateral branching: graph network analysis on large-scale simulations.Chemical science · 2022Article
- Characterization of Amyloidogenic Peptide Aggregability in Helical Subspace.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Alzheimer's protection effect of A673T mutation may be driven by lower Aβ oligomer binding affinity.Journal of neurochemistry · 2021Article
- Acetylation of AβACS chemical neuroscience · 2020Article
- Recent Advances in Computational Protocols Addressing Intrinsically Disordered Proteins.Biomolecules · 2019Review
- Cu and Zn coordination to amyloid peptides: From fascinating chemistry to debated pathological relevance.Coordination chemistry reviews · 2018Article
- Femtosecond Hydration Map of Intrinsically Disordered α-Synuclein.Biophysical journal · 2018Article
- Looking at the Disordered Proteins through the Computational Microscope.ACS central science · 2018Review
- Insights into the Molecular Mechanisms of Alzheimer's and Parkinson's Diseases with Molecular Simulations: Understanding the Roles of Artificial and Pathological Missense Mutations in Intrinsically Disordered Proteins Related to Pathology.International journal of molecular sciences · 2018Review
- Emergence of Alternative Structures in Amyloid Beta 1-42 Monomeric Landscape by N-terminal Hexapeptide Amyloid Inhibitors.Scientific reports · 2017Article
- High-Resolution Structures of the Amyloid-β 1-42 Dimers from the Comparison of Four Atomistic Force Fields.The journal of physical chemistry. B · 2017Article
- Pyroglutamate-Modified Amyloid-β(3-42) Shows α-Helical Intermediates before Amyloid Formation.Biophysical journal · 2017Article
- Conformational Ensembles of the Wild-Type and S8C Aβ1-42 Dimers.The journal of physical chemistry. B · 2017Article
- Comparison of force fields for Alzheimer's A β42: A case study for intrinsically disordered proteins.Protein science : a publication of the Protein Society · 2017Article
- How accurate are your simulations? Effects of confined aqueous volume and AMBER FF99SB and CHARMM22/CMAP force field parameters on structural ensembles of intrinsically disordered proteins: Amyloid-βIntrinsically disordered proteins · 2017Article
- Alzheimer's amyloid-β A2T variant and its N-terminal peptides inhibit amyloid-β fibrillization and rescue the induced cytotoxicity.PloS one · 2017Article
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The aggregation of amyloid-β (Aβ) peptides plays a crucial role in the etiology of Alzheimer's disease (AD). Recently, it has been reported that an A2T mutation in Aβ can protect against AD. Interestingly, a nonpolar A2V mutation also has been found to offer protection against AD in the heterozygous state, although it causes early-onset AD in homozygous carriers. Since the conformational landscape of the Aβ monomer is known to directly contribute to the early-stage aggregation mechanism, it is important to characterize the effects of the A2T and A2V mutations on Aβ₁₋₄₂ monomer structure. Here, we have performed extensive atomistic replica-exchange molecular dynamics simulations of the solvated wild-type (WT), A2V, and A2T Aβ₁₋₄₂ monomers. Our simulations reveal that although all three variants remain as collapsed coils in solution, there exist significant structural differences among them at shorter timescales. A2V exhibits an enhanced double-hairpin population in comparison to the WT, similar to those reported in toxic WT Aβ₁₋₄₂ oligomers. Such double-hairpin formation is caused by hydrophobic clustering between the N-terminus and the central and C-terminal hydrophobic patches. In contrast, the A2T mutation causes the N-terminus to engage in unusual electrostatic interactions with distant residues, such as K16 and E22, resulting in a unique population comprising only the C-terminal hairpin. These findings imply that a single A2X (where X = V or T) mutation in the primarily disordered N-terminus of the Aβ₁₋₄₂ monomer can dramatically alter the β-hairpin population and switch the equilibrium toward alternative structures. The atomistically detailed, comparative view of the structural landscapes of A2V and A2T variant monomers obtained in this study can enhance our understanding of the mechanistic differences in their early-stage aggregation.
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