The dynamic binding of cholesterol to the multiple sites of C99: as revealed by coarse-grained and all-atom simulations
Bibliographic record
Abstract
contribute most to the stabilization of the tightly binding state and the loosely binding state, respectively. The other binding sites described may also be potential drug targets. Thirdly, the residues GAVILMTKF, especially IVKF play a key role in this association. The C99 model appears to suggest a new mechanism for cholesterol binding. Finally, the multiple-site dynamic cholesterol binding model better explains the hypotheses that cholesterol promotes the amyloidogenic AβPP route. The GxxxA motif in the middle of the C99 transmembrane domain is completely exposed without cholesterol sheltering, which might help γ-secretase identify the cleavage sites and then promote γ-cleavage. Our results provide a detailed picture of dynamic cholesterol binding, which is crucial to our recognition of the potential influence of cholesterol on the C99 process and the etiology of AD.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".