Hydrophobic association of α-helices, steric dewetting, and enthalpic barriers to protein folding
Bibliographic record
Abstract
Efficient protein folding implies a microscopic funnel-like multidimensional free-energy landscape. Macroscopically, conformational entropy reduction can manifest itself as part of an empirical barrier in the traditional view of folding, but experiments show that such barriers can also entail significant unfavorable enthalpy changes. This observation raises the puzzling possibility, irrespective of conformational entropy, that individual microscopic folding trajectories may encounter large uphill moves and thus the multidimensional free-energy landscape may not be funnel-like. Here, we investigate how nanoscale hydrophobic interactions might underpin this salient enthalpic effect in biomolecular assembly by computer simulations of the association of two preformed polyalanine or polyleucine helices in water. We observe a high, positive enthalpic signature at room temperature when the helix separation is less than a single layer of water molecules. Remarkably, this unfavorable enthalpy change, with a parallel increase in void volume, is largely compensated for by a concomitant increase in solvent entropy, netting only a small or nonexistent microscopic free-energy barrier. Thus, our findings suggest that high enthalpic folding barriers can be consistent with a funnel picture of folding and are mainly a desolvation phenomenon indicative of a cooperative mechanism of simultaneous formation of multiple side-chain contacts at the rate-limiting step.
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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 | 0.001 |
| 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".