Prediction and biological significance of small changes in binding of leiomodin to tropomyosin
Bibliographic record
Abstract
In cardiac muscle, regulation of actin polymerization at the thin filament pointed end is controlled by two structurally similar but functionally antagonistic proteins, leiomodin-2 and tropomodulin-1. Both proteins contain tropomyosin-binding site 1, which is essential for their recruitment to the pointed end. Using circular dichroism, we determined changes in melting temperatures (ΔTm) for complexes of tropomyosin and leiomodin-2 fragments containing several hypomorphic mutations, which moderately affect binding to tropomyosin. We ran molecular dynamics simulations for the complexes and calculated standard Gibbs free energies of binding, which we found to strongly correlate with the ΔTm. We found that the E34Q mutation in leiomodin-2 resulted in a decrease in the melting temperature of the complex of tropomyosin and leiomodin-2 fragments, indicating a decrease in the affinity of leiomodin-2 for tropomyosin. Although modest, this change in in vitro affinity made leiomodin-2 a weaker competitor for tropomyosin than tropomodulin-1 in cardiomyocytes. This mutation significantly reduced the ability of leiomodin-2 to displace tropomodulin-1 at thin filament pointed ends and affected the ability of leiomodin-2 to elongate thin filaments. Our results highlight the essential role of the tropomyosin-binding site in the dynamic equilibrium between tropomodulin-1 and leiomodin-2 at the pointed end of thin filaments. Our data also suggest the potential use of the correlation between ΔTm and the modeled standard Gibbs free energies of binding to predict changes in the stability of complexes between tropomyosin and leiomodin or tropomodulin isoforms.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 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) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".