Is Oxidative Damage by β-Amyloid and Prion Peptides Mediated by Hydrogen Atom Transfer from Glycine α-Carbon to Methionine Sulfur within β-Sheets?
Bibliographic record
Abstract
Methionine in glycine-rich regions of both β-amyloid peptide and prion peptide is thought to be crucial to their neurotoxic properties. We postulate here a role for methionine in the propagation of oxidative damage. The S−H bond dissociation enthalpies, BDE(S−H)s, of dimethylsulfonium ion (CH 3 ) 2 SH + and a S-protonated methionine residue of a polypeptide strand are estimated to be 351 and 326−331 kJ mol - 1, respectively, by the application of calculations at the B3LYP level with large basis sets. These species are direct products of H atom abstraction by radical cations of sulfides. The reactions between a glycine residue and the radical cations of (CH 3 ) 2 S and Met were investigated and the transition structures for H atom transfer located. The results suggest that it is thermodynamically feasible for the S-ionized form of Met to cause oxidative damage at the α C−H site of almost any amino acid residue of a nearby polypeptide strand (BDE( α C−H) = 330−360 kJ mol - 1 ) or to nearby lipids with a bis(allylic) methylene group (BDE(C−H) = 335 kJ mol - 1 ). However, a key observation is that, when the Met residue is incorporated into an antiparallel β-sheet, only a Gly residue is exposed and susceptible to oxidation at the α C−H site. Furthermore, the Gly must lie on a strand of the β-sheet different from that containing Met and must be part of a (5,5) rather than a (3,3) cycle. The same considerations apply to the methyl-deprotonated form of the sulfide radical cation but not the methylene-deprotonated form. These findings suggest a possible mechanism for generating and propagating oxidative damage via a Met residue of the Aβ peptide of Alzheimer's disease and of the prion peptide of Creutzfeldt−Jakob disease. To our knowledge, this is the first proposed mechanism that accounts for the radical damage in either of these diseases and requires peptide β-sheets and amino acids, methionine and glycine.
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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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 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".