Molecular dynamics study of the monomers and dimers of <i>N</i>-AcAβ(13–23)NH<sub>2</sub>: on the effect of pH on the aggregation of the amyloid beta peptide of Alzheimer’s disease
Bibliographic record
Abstract
The region encompassed by residues 13–23 of the amyloid beta peptide (Aβ(13–23)) of Alzheimer’s disease is the self-recognition site that initiates toxic oligomerization and fibrillization and also is the site of interaction of Aβ with many other proteins. We describe herein a study by molecular dynamics of N-AcAβ(13–23)NH2 (N-CH3C(O)HHQKLVFFAEDNH2) as a model of full-length Aβ(1–40) or Aβ(1–42) and of its dimers. The effect of pH at or below physiological (pH 7.4) is assessed by protonation of one or more of the His residues. The major conformation of the monomer of the systems is a flexible folded structure. Protonation of one or both His residues does not change the conformation in any significant way. The dimers of protonated and unprotonated systems exist almost exclusively as stable antiparallel β-sheets anchored at both ends by intermolecular salt bridges between Lys16 of one chain and the C-terminal residues Glu22 and Asp23 of the other. We also employ the technique of “umbrella sampling” whereby relative binding affinities of the complexes could be determined. In the case of unsymmetrically protonated species, each complex begins dissociation by releasing the weaker salt bridge, breaking interstrand hydrogen bonds, and losing the β-sheet character. The stronger salt bridge is the last to release and presumably is the first to form in the reverse process of aggregation. Umbrella sampling yields the free energy profiles of the dissociation as a function of the separation of the centres of mass. For each system, the dissociation profile has only a shallow maximum. By implication, the reverse process of assembly has almost no barrier. This is an example of entropy–enthalpy compensation that arises naturally during the molecular dynamics – umbrella sampling simulation.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".