Author response: Hydrogen bonds as molecular timers for slow inactivation in voltage-gated potassium channels
Bibliographic record
Abstract
Proteins are made from long chains of smaller molecules, called amino acids. These chains twist and bend into complex three-dimensional shapes, and sometimes two or more chains, or ‘subunits’, are packed into a protein. These shapes are often held together by hydrogen bonds between some of the amino acids. Moreover, since the shape of a protein defines its function, some proteins must be able to switch between different shapes to function properly. Ion channels are proteins that form pores through cell membranes, allowing ions to flow in and out of the cell. Potassium ion channels, which are found in neurons and heart muscle cells, have four subunits that move to open or close the central pore in response to various signals. The closing of the channels can be ‘fast’ or ‘slow’. When the channels are closed quickly (called fast inactivation), a small part of the protein ‘plugs’ the pore from the inside of the cell. However, the mechanism behind slow inactivation remained obscure. It was thought to involve hydrogen bonds between some of the bulky amino acids that are found at the edge the pore. However, testing this hypothesis—by replacing these amino acids with alternatives that cannot form hydrogen bonds—was tricky because none of the 20 naturally occurring amino acids were alike enough to be suitable replacements. Now, Pless et al. have overcome this limitation by using synthetic amino acids that form hydrogen bonds that are stronger or weaker than those formed by the amino acids they are replacing. The results suggest that two types of hydrogen bond keep the pore open: one is a bond between two amino acids in the same subunit, and the other is an inter-subunit bond between amino acids in neighbouring subunits. Pless et al. suggest that opening the channel causes small movements that gradually weaken, and eventually break, these bonds in one of the four subunits. Specific amino acids within the pore are then free to twist and—via a cascade of similar movements in the other three subunits—block the pore and halt the flow of ions. As such, these networks of hydrogen bonds act as pre-set breaking points allowing channels to close, even in response to continued stimulation. Since regulated potassium channel activity underpins healthy neurons and heart muscles; understanding what controls their inactivation rate may lead to new approaches to tune their activity and treatments for important diseases.
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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 | 0.002 | 0.013 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.002 | 0.002 |
| Scholarly communication | 0.003 | 0.003 |
| Open science | 0.002 | 0.003 |
| Research integrity | 0.009 | 0.009 |
| Insufficient payload (model declined to judge) | 0.119 | 0.043 |
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".