Hydrolysis of the damaged deoxythymidine glycol nucleoside and comparison to canonical DNA
Bibliographic record
Abstract
Genomic integrity is continually under attack by both endogenous and exogenous sources. One of the most common forms of damage is oxidation of the thymine nucleobase to form (5R,6S)-dihydroxy-5,6-dihydro-thymine (thymine glycol or Tg), which stops DNA polymerases and is thus cytotoxic. Thymine glycol damage is repaired through a variety of mechanisms, including the multi-step base excision repair (BER) pathway. In the first BER step, the glycosidic bond of the dTg nucleotide is hydrolyzed by a DNA glycosylase. In order to understand the catalytic effect of the glycosylases, the corresponding uncatalyzed mechanisms and barriers are required, as well as an appreciation of the relative reactivity of the glycosidic bond with respect to the corresponding canonical nucleoside. To this end, the PCM-B3LYP/6-31+G(d) reaction potential energy surfaces (PES) for deoxythymidine (dT) and dTg hydrolysis are characterized in the present study using solvent-phase optimizations and a model containing three explicit water molecules. The surfaces are comparable to those generated using functionals that account for dispersion interactions (B3LYP-D3 and M06-2X). Mapping the PES as a function of the glycosidic bond length and nucleophile-sugar distance reveals a synchronous S(N)2 mechanism as the lowest energy pathway for damaged dTg hydrolysis, which contrasts the preferred dissociative S(N)1 mechanism isolated for the deglycosylation of natural dT. As proposed for other enzymes, the difference in excision pathway may at least in part help the enzyme selectively target the damaged base and discriminate against the natural counterpart. Interestingly, the barrier to dTg deglycosylation (ΔG(‡) = 138.0 kJ mol(-1)) is much higher than for dT deglycosylation (ΔG(‡) = 112.7 kJ mol(-1)), which supports the stability of this lesion and clarifies the catalytic feat presented to DNA repair enzymes that remove this detrimental damage from the genome. Although nucleotide excision repair (NER) typically targets bulky DNA lesions, the large calculated barrier for dTg deglycosylation rationalizes why the NER mechanism also excises this non-bulky lesion from cellular DNA.
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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) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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) | 0.004 | 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".