Effects of Nucleophile, Oxidative Damage, and Nucleobase Orientation on the Glycosidic Bond Cleavage in Deoxyguanosine
Bibliographic record
Abstract
Deglycosylation of nucleotides occurs during many essential biological processes, including DNA repair, and is initiated by a variety of nucleophiles. In the present work, density functional theory (B3LYP) was used to investigate the thermodynamics and kinetics of the glycosidic bond cleavage reaction in the model nucleoside forms of guanine and its major oxidation product, 8-oxoguanine. Base excision facilitated by four different nucleophiles (hydroxyl anion (fully activated water), formate-water complex (partially activated water), lysine, and proline) was considered, which spans nucleophiles involved in a collection of spontaneous and enzyme-catalyzed processes. Because some enzymes that catalyze deglycosylation can accommodate more than one orientation of the base with respect to the sugar moiety, the effects of the (anti/syn) base orientation on the barrier height were also considered. We find that the nucleophile has a very large effect on the overall (gas-phase) reaction energetics. Although this effect decreases in different (polar) environments, the nucleophile has the greatest influence on the overall reaction as compared to whether the base is damaged or to the base orientation. Furthermore, the effects are significant in environments that most closely resemble (nonpolar) enzymatic active sites. Our results provide a greater understanding of the relative effects of the nucleophile, damage to the nucleobase, and the nucleobase orientation with respect to the sugar moiety on the deglycosylation pathway, which provide qualitative explanations for relative base excision rates observed in some biological systems.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".