ArticleProceedings of the National Academy of Sciences of the United States of America2005
Folding events in the 21-30 region of amyloid beta-protein (Abeta) studied in silico.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 115 citations in OpenAlex.
- Computational Study of AmyloidβInorganic chemistry · 2024Article
- β-amyloid model core peptides: Effects of hydrophobes and disulfides.Protein science : a publication of the Protein Society · 2020Article
- Activated Bone Marrow-Derived Macrophages Eradicate Alzheimer's-Related AβFrontiers in immunology · 2020Article
- 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
- Amino acid substitutions [K16A] and [K28A] distinctly affect amyloid β-protein oligomerization.Journal of biological physics · 2016Article
- The peculiar role of the A2V mutation in amyloid-β (Aβ) 1-42 molecular assembly.The Journal of biological chemistry · 2014Article
- Gly25-Ser26 amyloid β-protein structural isomorphs produce distinct Aβ42 conformational dynamics and assembly characteristics.Journal of molecular biology · 2014Article
- Minimal model of self-assembly: emergence of diversity and complexity.The journal of physical chemistry. B · 2014Article
- Structural diversity of Alzheimer's disease amyloid-β dimers and their role in oligomerization and fibril formation.Journal of Alzheimer's disease : JAD · 2014Article
- Disrupting self-assembly and toxicity of amyloidogenic protein oligomers by "molecular tweezers" - from the test tube to animal models.Current pharmaceutical design · 2014Review
- Aβ monomers transiently sample oligomer and fibril-like configurations: ensemble characterization using a combined MD/NMR approach.Journal of molecular biology · 2013Article
- The structures of the E22Δ mutant-type amyloid-β alloforms and the impact of E22Δ mutation on the structures of the wild-type amyloid-β alloforms.ACS chemical neuroscience · 2013Article
- Tracking the mechanism of fibril assembly by simulated two-dimensional ultraviolet spectroscopy.The journal of physical chemistry. A · 2013Article
- Molecular plasticity regulates oligomerization and cytotoxicity of the multipeptide-length amyloid-β peptide pool.The Journal of biological chemistry · 2012Article
- Response surface methodology for optimizing the bovine serum albumin fibrillation.The protein journal · 2012Article
- A key role for lysine residues in amyloid β-protein folding, assembly, and toxicity.ACS chemical neuroscience · 2012Article
- Dynamics of metastable β-hairpin structures in the folding nucleus of amyloid β-protein.The journal of physical chemistry. B · 2012Article
- Structural dynamics of the amyloid β-protein monomer folding nucleus.Biochemistry · 2012Article
- An azobenzene photoswitch sheds light on turn nucleation in amyloid-β self-assembly.ACS chemical neuroscience · 2012Article
- Investigating how peptide length and a pathogenic mutation modify the structural ensemble of amyloid beta monomer.Biophysical journal · 2012Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Oligomeric assemblies of the amyloid beta-protein (Abeta) have been implicated in the pathogenesis of Alzheimer's disease as a primary source of neurotoxicity. Recent in vitro studies have suggested that a 10-residue segment, Ala-21-Ala-30, forms a turn-like structure that nucleates the folding of the full-length Abeta. To gain a mechanistic insight, we simulated Abeta(21-30) folding by using a discrete molecular dynamics algorithm and a united-atom model incorporating implicit solvent and a variable electrostatic interaction strength (EIS). We found that Abeta(21-30) folds into a loop-like conformation driven by an effective hydrophobic attraction between Val-24 and the butyl portion of the Lys-28 side chain. At medium EIS [1.5 kcal/mol (1 cal = 4.18 J)], unfolded conformations almost disappear, in agreement with experimental observations. Under optimal conditions for folding, Glu-22 and Asp-23 form transient electrostatic interactions (EI) with Lys-28 that stabilize the loop conformations. Glu-22-Lys-28 is the most favored interaction. High EIS, as it occurs in the interior of proteins and aggregates, destabilizes the packing of Val-24 and Lys-28. Analysis of the unpacked structures reveals strong EI with predominance of the Asp-23-Lys-28 interaction, in agreement with studies of molecular modeling of full-length Abeta fibrils. The binary nature of the EI involving Lys-28 provides a mechanistic explanation for the linkage of amino acid substitutions at Glu-22 with Alzheimer's disease and cerebral amyloid angiopathy. Substitutions may alter the frequency of Glu-22 or Asp-23 involvement in contact formation and affect the stability of the folding nucleus formed in the Abeta(21-30) region.
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