Structural Rationalization for the Nonmutagenic and Mutagenic Bypass of the Tobacco-Derived O4-4-(3-Pyridyl)-4-oxobut-1-yl-thymine Lesion by Human Polymerase η: A Multiscale Computational Study
Bibliographic record
Abstract
Tobacco-derived pyridyloxobutyl (POB) DNA adducts are unique due to the large size and flexibility of the alkyl chain connecting the pyridyl ring to the nucleobase. Recent experimental work suggests that the O4-4-(3-pyridyl)-4-oxobut-1-yl-T (O4-POB-T) lesion can undergo both nonmutagenic (dATP) and mutagenic (dGTP) insertion by the translesion synthesis (TLS) polymerase (pol) η in human cells. Interestingly, the mutagenic rate for O4-POB-T replication is reduced compared to that for the smaller O4-methylthymine (O4-Me-T) lesion, and O4-POB-T yields a different mutagenic profile than the O2-POB-T variant (dTTP insertion). The present work uses a combination of density functional theory calculations and molecular dynamics simulations to probe the impact of the size and flexibility of O4-POB-T on pol η replication outcomes. Due to changes in the Watson-Crick binding face upon damage of canonical T, O4-POB-T does not form favorable hydrogen-bonding interactions with A. Nevertheless, dATP is positioned for insertion in the pol η active site by a water chain to the template strand, which suggests a pol η replication pathway similar to that for abasic sites. Although a favorable O4-POB-T:G mispair forms in the pol η active site and DNA duplexes, the inherent dynamical nature of O4-POB-T periodically disrupts interstrand hydrogen bonding that would otherwise facilitate dGTP insertion and stabilize damaged DNA duplexes. In addition to explaining the origin of the experimentally reported pol η outcomes associated with O4-POB-T replication, comparison to structural data for the O4-Me-T and O2-POB-T adducts highlights an emerging common pathway for the nonmutagenic replication of thymine alkylated lesions by pol η, yet underscores the broader impacts of bulky moiety size, flexibility, and position on the associated mutagenic outcomes.
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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 | 0.001 | 0.001 |
| 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".