Decoding collagen’s thermally induced unfolding and refolding pathways
Bibliographic record
Abstract
Collagen has been evolutionarily selected as the preferred building block of extracellular structures. Despite inherent thermodynamic instability of individual proteins at body temperature, collagen manages to assemble into higher-order structures that provide mechanical support to tissues. Sequence features that enhance collagen stability have been deduced primarily from studies of collagen-mimetic peptides, as collagen's large size has precluded high-resolution studies of its structure. Thus, methods are needed to analyze the structure and mechanics of full-length collagen proteins. In this study, we used AFM imaging to investigate the thermal response of collagen type IV, a key component of basement membranes. We observed a time-dependent loss of folded structures upon exposure to body temperature, with structural destabilization along the collagenous domain reflected by shorter contour lengths (seen also for collagens type I and III). We characterized the sequence-dependent bending stiffness profile of collagen IV as a function of temperature and identified a putative initiation site for thermally induced unfolding. Interchain disulfide bonds in collagen IV were shown to enhance thermal stability and serve as primary nucleation sites for in vitro refolding. In contrast to the canonical C-to-N-terminal folding direction, we found an interchain cystine knot to enable folding in the opposite direction. A multiple sequence alignment revealed that this cystine knot is evolutionarily conserved across metazoan phyla, highlighting its significance in the stabilization of early collagen IV structures. Our findings provide mechanistic insight into the unfolding and refolding pathways of collagen IV, and how its heterogeneous sequence influences stability and mechanics.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| 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".