Influence of the Linkage Type and Functional Groups in the Carcinogenic Moiety on the Conformational Preferences of Damaged DNA: Structural and Energetic Characterization of Carbon- and Oxygen-Linked C<sup>8</sup>-Phenolic-Guanine Adducts
Bibliographic record
Abstract
Computational (DFT, MD, and free energy) methods are used to systematically compare the structural and energetic properties of C(8)-bonded 2'-deoxyguanosine (dG) adducts derived from phenolic toxins, namely, the oxygen-linked (unsubstituted) adduct ((PhO)dG) and carbon-linked adducts ((ortho-PhOH)dG or (para-PhOH)dG) that contain a hydroxyl group in the bulky moiety. Despite restricted rotation at the C(8)-X bond due to the presence of the oxygen linker, the (PhO)dG adduct likely possesses the greatest glycosidic (anti/syn) conformational flexibility at the 5'-terminus of DNA. However, the anti/syn energy difference is the smallest for the (para-PhOH)dG nucleotide at other helical positions, which correlates with the greatest conformational heterogeneity for the corresponding (NarI) adducted DNA. Most importantly, the total number of accessible conformations of adducted DNA depend on the phenolic adduct considered. Specifically, although the only conformations accessible to (PhO)dG adducted DNA correspond to the anti adduct glycosidic orientation, the C-linked adducts can also adopt the syn orientation in the double helix. Moreover, the number of accessible conformations for DNA containing the C-linked adducts depends on the nature of discrete interactions involving the hydroxyl group in the C(8)-moiety. In fact, such interactions lead to a novel (intercalated) conformational theme in the case of the (para-PhOH)dG adduct. Together, these results indicate that the type of C(8)-linkage, and the presence and location of additional functional groups in the bulky moiety affect the conformational outcomes, which adds to the list of previously established effects including the size of the carcinogenic moiety, adduct ionization state, and sequence context on the conformational preferences of damaged DNA. Most importantly, our study provides valuable structural information that explains the experimentally observed mutagenic potential of DNA phenolic adducts and predicts the relative repair propensity of the three phenolic lesions.
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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 | 0.001 |
| 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".