ArticleProceedings of the National Academy of Sciences of the United States of America2020
Differences in the free energies between the excited states of A
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed.
- Experimental and computational analysis of the basis for accelerated amyloid formation by a disease linked mutant of human islet amyloid polypeptide.Protein science : a publication of the Protein Society · 2025Article
- The multifaceted roles of apolipoprotein E4 in Alzheimer's disease pathology and potential therapeutic strategies.Cell death discovery · 2025Review
- Sizes, conformational fluctuations, and SAXS profiles for intrinsically disordered proteins.Protein science : a publication of the Protein Society · 2025Article
- The mechanism of amyloid fibril growth from Φ-value analysis.Nature chemistry · 2025Article
- Recent Advances in Co-Condensation and Co-Aggregation of Amyloid Proteins Linked to Neurodegenerative Diseases.Current protein & peptide science · 2025Review
- Helix-to-sheet transition of the Aβ42 peptide revealed using an enhanced sampling strategy and Markov state model.Computational and structural biotechnology journal · 2024Article
- Heterotypic Seeding Generates Mixed Amyloid Polymorphs.Small science · 2024Article
- Design of parallel 𝛽-sheet nanofibrils using Monte Carlo search, coarse-grained simulations, and experimental testing.Protein science : a publication of the Protein Society · 2024Article
- Article
- Exploring Structural Insights of Aβ42 and α-Synuclein Monomers and Heterodimer: A Comparative Study Using Implicit and Explicit Solvent Simulations.The journal of physical chemistry. B · 2024Article
- Can local heating and molecular crowders disintegrate amyloid aggregates?Chemical science · 2024Article
- Hairpin trimer transition state of amyloid fibril.Nature communications · 2024Article
- Conformational fluctuations and phases in fused in sarcoma (FUS) low-complexity domain.Biopolymers · 2024Review
- Recent Computational Advances Regarding Amyloid-β and Tau Membrane Interactions in Alzheimer's Disease.Molecules (Basel, Switzerland) · 2023Review
- Amyloid Aggregation and Liquid-Liquid Phase Separation from the Perspective of Phase Transitions.The journal of physical chemistry. B · 2023Review
- Comparative Performance of Computer Simulation Models of Intrinsically Disordered Proteins at Different Levels of Coarse-Graining.Journal of chemical information and modeling · 2023Article
- Odd-even disparity in the population of slipped hairpins in RNA repeat sequences with implications for phase separation.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Article
- Interpreting Transient Interactions of Intrinsically Disordered Proteins.The journal of physical chemistry. B · 2023Article
- Energy landscapes of Aβ monomers are sculpted in accordance with Ostwald's rule of stages.Science advances · 2023Article
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3 authors.
Funding
Abstract
The early events in the aggregation of the intrinsically disordered peptide, amyloid-β (Aβ), involve transitions from the disordered free energy ground state to assembly-competent states. Are the fingerprints of order found in the amyloid fibrils encoded in the conformations that the monomers access at equilibrium? If so, could the enhanced aggregation rate of Aβ42 compared to Aβ40 be rationalized from the sparsely populated high free energy states of the monomers? Here, we answer these questions in the affirmative using coarse-grained simulations of the self-organized polymer-intrinsically disordered protein (SOP-IDP) model of Aβ40 and Aβ42. Although both the peptides have practically identical ensemble-averaged properties, characteristic of random coils (RCs), the conformational ensembles of the two monomers exhibit sequence-specific heterogeneity. Hierarchical clustering of conformations reveals that both the peptides populate high free energy aggregation-prone ([Formula: see text]) states, which resemble the monomers in the fibril structure. The free energy gap between the ground (RC) and the [Formula: see text] states of Aβ42 peptide is smaller than that for Aβ40. By relating the populations of excited states of the two peptides to the fibril formation time scales using an empirical formula, we explain nearly quantitatively the faster aggregation rate of Aβ42 relative to Aβ40. The [Formula: see text] concept accounts for fibril polymorphs, leading to the prediction that the less stable [Formula: see text] state of Aβ42, encoding for the U-bend fibril, should form earlier than the structure with the S-bend topology, which is in accord with Ostwald's rule rationalizing crystal polymorph formation.
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