Contingency between Historical Substitutions in the Acetylcholine Receptor Pore
Bibliographic record
Abstract
Human adult muscle-type acetylcholine receptors incorporating a reconstructed ancestral β-subunit exhibit reduced single-channel conductance when compared to wild-type. The ancestral and wild-type β-subunits differ by 132 amino acids, including substitution of residues that line the lumen of the channel pore, near its narrowest constriction. Here we show that a single historical substitution in this region of the ancestral β-subunit accounts for the difference in conductance. Furthermore, the contribution of the substituted residue to conductance is dependent upon its ancestral or wild-type background, and it can be modulated by a neighboring residue that has also evolved throughout the β-subunit history. Using an expanded molecular phylogeny, we track the order in which these two mutations occurred and then show that the order in which they are installed upon the ancestral, but not the human, background determines their individual contribution to conductance. Our results show how the contribution of amino acids to acetylcholine receptor conductance is contingent upon their evolutionary history and that the order in which substitutions occurred was important for shaping conductance in the modern-day receptor.
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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".