Conformational Flexibility of C8-Phenoxyl-2′-deoxyguanosine Nucleotide Adducts
Bibliographic record
Abstract
Previous computational work suggests that isolated C8-phenoxyl-2'-deoxyguanosine nucleoside adducts preferentially adopt a syn orientation about the glycosidic bond, which is the first step in the mechanism by which many bulky C8 adducts exert their mutagenic effects. Since it is not clear whether these results can be directly extrapolated to the preferred conformation in DNA helices, approaches that more accurately reflect the physiological environment were used in the present study to understand the anti/syn preference of the ortho and para C8-phenoxyl-2'-deoxyguanosine adducts. Using nucleoside models and methods (B3LYP) similar to those previously implemented, we determine that the syn conformer is less stable than previously predicted when geometries relevant to B-DNA are considered. This indicates that the conformational energy trend is model dependent and stresses the importance of considering models that better mimic the DNA environment when determining the conformational preference of damaged bases. Therefore, we expanded our computational model to include the 5'-monophosphate group. Since the correct anti/syn energy trend for 2'-deoxyguanosine (dG) 5'-monophosphate has only been found using very specific computational models and prior knowledge of the biologically relevant nucleotide conformation, which is unavailable for most damaged systems, we initially benchmark our computational approach by studying the natural nucleotide. Despite the wide use of gas-phase optimizations in the current literature, only through the implementation of solvation-phase optimizations, as well as the use of a counterion model for the phosphate backbone, is the correct anti/syn energy trend predicted. Indeed, this is the first time in the literature that a biologically relevant syn structure is characterized for dG using methods suitable for studying bulky DNA adducts. Subsequently, our newly identified approach for DNA lesions was used to study C8-phenoxyl DNA adducts. In contrast to previously published results, we predict that the ortho and para adducts may adopt both the anti and syn conformations in DNA helices. These results have implications for the base-pairing properties and mutagenicity of these adducts, which must be further considered in future work.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 | 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 | 0.001 | 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".