A computational study of barium blockades in the KcsA potassium channel based on multi-ion potential of mean force calculations and free energy perturbation
Bibliographic record
Abstract
Electrophysiological studies have established that the permeation of Ba(2+) ions through the KcsA K(+)-channel is impeded by the presence of K(+) ions in the external solution, while no effect is observed for external Na(+) ions. This Ba(2+) "lock-in" effect suggests that at least one of the external binding sites of the KcsA channel is thermodynamically selective for K(+). We used molecular dynamics simulations to interpret these lock-in experiments in the context of the crystallographic structure of KcsA. Assuming that the Ba(2+) is bound in site S(2) in the dominant blocked state, we examine the conditions that could impede its translocation and cause the observed "lock-in" effect. Although the binding of a K(+) ion to site S(1) when site S(2) is occupied by Ba(2+) is prohibitively high in energy (>10 kcal/mol), binding to site S0 appears to be more plausible (ΔG > 4 kcal/mol). The 2D potential of mean force (PMF) for the simultaneous translocation of Ba(2+) from site S(2) to site S(1) and of a K(+) ion on the extracellular side shows a barrier that is consistent with the concept of external lock-in. The barrier opposing the movement of Ba(2+) is very high when a cation is in site S(0), and considerably smaller when the site is unoccupied. Furthermore, free energy perturbation calculations show that site S(0) is selective for K(+) by 1.8 kcal/mol when S(2) is occupied by Ba(2+). However, the same site S(0) is nonselective when site S(2) is occupied by K(+), which shows that the presence of Ba(2+) affects the selectivity of the pore. A theoretical framework within classical rate theory is presented to incorporate the concentration dependence of the external ions on the lock-in effect.
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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 | 0.000 | 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) | 0.000 | 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".