Research/Review: Structure and Linkage Disequilibrium Analysis of Adamantane Resistant Mutations in Influenza Virus M2 Proton Channel
Bibliographic record
Abstract
The M2 proton channel is translated by the M gene segment of influenza viruses, and has been adopted as an attractive target for influenza A viruses, on which a series of adamantane-based drugs act. However, recently epidemic influenza viruses have had strong resistant effects against the adamantane-based drugs. In this paper, we combined evolutionary analyses, linkage disequilibrium as well as molecular dynamics simulations to explore the drug resistance of the M2 proton channel, with an aim of providing an in-depth understanding of the resistant mechanism for adamantane-based drugs. We collected 2746 coding sequences for swine, avian, and human M2 proteins. After evolutionary and linkage disequilibrium analyses, we found that the some residues in the C-terminal were associated with the famed resistant mutation S31N. Subsequently, we constructed the 3D structures of the swine, avian as well as human M2 channel, and performed MD simulations on these channels with a typical adamantane-based drug rimantadine. From the simulation trajectories, we found that the resistance against the adamantane-based drugs for the M2 channel from 2009 A(H1N1) viruses was derived from the structural allostery in the transmembrane and C-terminal regions. The helices in the transmembrane region were irregular in formation and employed larger distances between the adjacent 2 helices, which can weaken the interactions between the adjacent 2 helices and destabilize the helix-helix assembly, resulting in a comparatively loosely structure. The helices in the C-terminal region show a disordered configuration, giving chances for solvent molecules to enter into the channel pore.
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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 | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.003 | 0.004 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".