Sparsely populated folding intermediates of the Fyn SH3 domain: Matching native-centric essential dynamics and experiment
Bibliographic record
Abstract
A complete description of how a protein folds requires the characterization of intermediate conformations traversed during the folding transition. We have calculated dynamics trajectories of a simplified model of the Fyn SH3 domain with a native-centric potential energy function. Analysis of the resulting site-resolved energy trajectory identifies an ensemble of intermediate conformations for folding and another for unfolding. The model's folding intermediate is structured in the three beta-strands that make up the protein's core and is strikingly similar to intermediates detected in a recent NMR study of Fyn SH3 folding and to folding transition states elucidated in mutagenesis studies of SH3 domains. The unfolding intermediate is formed by dissociation of the folded protein's two terminal beta-strands from its core. The presence of such an intermediate is consistent with the results of a protein-engineering study on the src SH3 domain showing that these strands separate before the rate-limiting step of unfolding. Despite the presence of these conformations intermediate between the native and fully unfolded states, the computed heat capacity vs. temperature profile of the model protein indicates that its thermodynamics satisfies the usual calorimetric criterion for two-state folding. This observation highlights the fact that, if not properly interpreted, methods such as calorimetry that do not probe multiple sites in a molecule can lead to an oversimplified view of folding. The close agreement between results from this simplified model and experimental work underscores the important contributions that computational methods can make in providing insights into protein folding.
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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 | 0.000 | 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".