Computational insights into the mutagenicity of two tobacco-derived carcinogenic DNA lesions
Bibliographic record
Abstract
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is a potent carcinogen found in all tobacco products that leads to a variety of DNA lesions in cells, including O6-[4-oxo-4-(3-pyridyl)butyl]guanine (POB-G) and O6-[4-hydroxy-4-(3-pyridyl)butyl]guanine (PHB-G), which differ by only a single substituent in the bulky moiety. This work uses a multiscale computational approach to shed light on the intrinsic conformational and base-pairing preferences of POB-G and PHB-G, and the corresponding properties in DNA and the polymerase η active site. Our calculations reveal that both lesions form stable pairs with C and T, with the T pairs being the least distorted relative to canonical DNA. This rationalizes the experimentally reported mutational profile for POB-G and validates our computational model. The same approach predicts that PHB-G is more mutagenic than POB-G due to a difference in the bulky moiety hydrogen-bonding pattern, which increases the stability of the PHB-G:T pair. The mutagenicity of PHB-G is likely further increased by stabilization of an intercalated DNA conformation that is associated with deletion mutations. This work thereby uncovers structural explanations for the reported mutagenicity of POB-G, provides the first clues regarding the mutagenicity of PHB-G and complements a growing body of literature highlighting that subtle chemical changes can affect the biological outcomes of DNA adducts.
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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 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".