Structure and Cl- Conductance Properties of the Open State of Human CFTR
Bibliographic record
Abstract
Abstract The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that plays a vital role in water and ion secretion on epithelial surfaces. Loss of function in CFTR causes the life-threatening disease cystic fibrosis (CF). The functionally open state of CFTR has so far eluded detailed structural characterization. Although multiple near-atomic resolution structures of CFTR have been solved under conditions that promote channel opening, they all lack a continuous ion conduction pathway. In recent molecular dynamics (MD) simulations, structural fluctuations of human CFTR in a hydrated lipid bilayer led to the observation of transient Cl- conducting states, but the stability and conduction properties of these putative open states were not established. Here, we conduct massively repeated simulations initiated from these Cl- permeable conformations. Reproducible structural relaxation of the pore leads to a stable open conformation featuring five symmetrically arranged pore-lining helices. Unlike previously reported structures, this novel penta-helical arrangement reproduces experimentally determined properties of the open pore, including a Cl- conductance close to that measured at physiological voltages. Together, our results support the validity of this newly identified pore conformation as a model of the fully open channel. Detailed analysis highlights the role of cationic pore-lining residues in the Cl- permeation mechanism and suggests that the kinks observed in several transmembrane helices play a role in channel gating.
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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 | 0.000 |
| 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 | 0.000 |
| 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".