Allosteric Coupling Between Drug Binding and the Aromatic Cassette in the Pore Domain of the hERG1 Channel: Implications for a State-Dependent Blockade
Bibliographic record
Abstract
current. The channel has been extensively studied due to its propensity to bind chemically diverse group of drugs. The subsequent hERG1 block can lead to a prolongation of the QT interval potentially leading to an abnormal cardiac electrical activity. The recently solved cryo-EM structure featured a striking non-swapped topology of the Voltage-Sensor Domain (VSD) which is packed against the pore-domain as well as a small and hydrophobic intra-cavity space. The small size and hydrophobicity of the cavity was unexpected and challenges the already-established hypothesis of drugs binding to the wide cavity. Recently, we showed that an amphipathic drug, ivabradine, may favorably bind the channel from the lipid-facing surface and we discovered a mutant (M651T) on the lipid facing domain between the VSD and the PD which inhibited the blocking capacity of the drug. Using multi-microseconds Molecular Dynamics (MD) simulations of wild-type and M651T mutant hERG1, we suggested the block of the channel through the lipid mediated pathway, the opening of which is facilitated by the flexible phenylalanine ring (F656). In this study, we characterize the dynamic interaction of the methionine-aromatic cassette in the S5-S6 helices by combining data from electrophysiological experiments with MD simulations and molecular docking to elucidate the complex allosteric coupling between drug binding to lipid-facing and intra-cavity sites and aromatic cassette dynamics. We investigated two well-established hERG1 blockers (ivabradine and dofetilide) for M651 sensitivity through electrophysiology and mutagenesis techniques. Our electrophysiology data reveal insensitivity of dofetilide to the mutations at site M651 on the lipid facing side of the channel, mirroring our results obtained from docking experiments. Moreover, we show that the dofetilide-induced block of hERG1 occurs through the intracellular space, whereas little to no block of ivabradine is observed during the intracellular application of the drug. The dynamic conformational rearrangement of the F656 appears to regulate the translocation of ivabradine into the central cavity. M651T mutation appears to disrupt this entry pathway by altering the molecular conformation of F656.
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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".