Comparative analysis of essential collective dynamics and NMR-derived flexibility profiles in evolutionarily diverse prion proteins
Bibliographic record
Abstract
Collective motions on ns-μs time scales are known to have a major impact on protein folding, stability, binding and enzymatic efficiency. It is also believed that these motions may have an important role in the early stages of prion protein misfolding and prion disease. In an effort to accurately characterize these motions and their potential influence on the misfolding and prion disease transmissibility we have conducted a combined analysis of molecular dynamic simulations and NMR-derived flexibility measurements over a diverse range of prion proteins. Using a recently developed numerical formalism, we have analyzed the essential collective dynamics (ECD) for prion proteins from 8 different species including human, cow, elk, cat, hamster, chicken, turtle and frog. We also compared the numerical results with flexibility profiles generated by the random coil index (RCI) from NMR chemical shifts. Prion protein backbone flexibility derived from experimental NMR data and from theoretical computations show strong agreement with each other, demonstrating that it is possible to predict the observed RCI profiles employing the numerical ECD formalism. Interestingly, flexibility differences in the loop between second beta strand (S2) and the second alpha helix (HB) appear to distinguish prion proteins from species that are susceptible to prion disease and those that are resistant. Our results show that the different levels of flexibility in the S2-HB loop in various species are predictable via the ECD method, indicating that ECD may be used to identify disease resistant variants of prion proteins, as well as the influence of prion proteins mutations on disease susceptibility or misfolding propensity.
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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".