Single-molecule approaches to prion protein misfolding
Bibliographic record
Abstract
The structural conversion of the prion protein PrP into a transmissible, misfolded form is the central element of prion disease, yet there is little consensus as to how it occurs. Key aspects of conversion into the diseased state remain unsettled, from details about the earliest stages of misfolding such as the involvement of partially- or fully-unfolded intermediates to the structure of the infectious state. Part of the difficulty in understanding the structural conversion arises from the complexity of the underlying energy landscapes. Single molecule methods provide a powerful tool for probing complex folding pathways as in prion misfolding, because they allow rare and transient events to be observed directly. We discuss recent work applying single-molecule probes to study misfolding in prion proteins, and what it has revealed about the folding dynamics of PrP that may underlie its unique behavior. We also discuss single-molecule studies probing the interactions that stabilize non-native structures within aggregates, pointing the way to future work that may help identify the microscopic events triggering pathogenic conversion. Although single-molecule approaches to misfolding are relatively young, they have a promising future in prion science.
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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".