Distinct Morphologies for Amyloid Beta Protein Monomer: Aβ<sub>1–40</sub>, Aβ<sub>1–42</sub>, and Aβ<sub>1–40</sub>(D23N)
Bibliographic record
Abstract
Numerous experimental studies indicate that amyloid beta protein (Aβ) oligomers as small as dimers trigger Alzheimer's disease. Precise solution conformation of Aβ monomer is missing since it is highly dynamic and aggregation prone. Such a knowledge is however crucial to design drugs inhibiting oligomers and fibril formation. Here, we determine the equilibrium structures of the Aβ1-40, Aβ1-42, and Aβ1-40(D23N) monomers using an accurate coarse-grained force field coupled to Hamiltonian-temperature replica exchange molecular dynamics simulations. We observe that even if these three alloforms are mostly disordered at the monomeric level, in agreement with experiments and previous simulations on Aβ1-40 and Aβ1-42, striking morphological differences exist. For instance, Aβ1-42 and Aβ1-40(D23N) have higher β-strand propensities at the C-terminal, residues 30-42, than Aβ1-40. The D23N mutation enhances the conformational freedom of the residues 22-29 and the propensity for turns and β-strands in the other regions. It also changes the network of contacts; the N-terminal (residues 1-16) becoming more independent from the rest of the protein, leading to a less compact morphology than the wild-type sequence. These structural properties could explain in part why the kinetics and the final amyloid products vary so extensively between the Aβ1-40 and the Aβ1-40(D23N) peptides.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".