Mechanistic and Conformational Flexibility of the Covalent Linkage Formed during β-Lyase Activity on an AP-Site: Application to hOgg1
Bibliographic record
Abstract
The β/δ-lyase activity of bifunctional glycosylases on damaged nucleotides in DNA involves the formation of a covalent linkage between the protein (lysine or N-terminal proline) and DNA (C1' of the damaged nucleotide). In the present study, the conformational and mechanistic flexibility of the cross-link is examined. Repair of 8-oxoguanine damage by hOgg1 is considered as a representative system, and the glycosylase through β-lyase steps are investigated using density functional theory. (PCM/SMD)-M06-2X/6-311+G(2df,2p)//PCM-B3LYP/6-31G(d) energetics were determined for eight unique mechanisms differing in the conformation of the imine linkage (E/Z), the proton (pro-S/R) abstracted during elimination, and whether the ring-opening step is base catalyzed. This initial study used a model system limited to the damaged nucleoside 3'-monophosphate and a model nucleophile to investigate this series of complex reaction steps. The great flexibility exhibited by the linkage and clustered β-elimination energetics indicate sterics will play a large role in predicting the preferred lyase mechanism for a given enzyme. The stationary points identified herein can be overlaid into a protein structure to assist in generating initial guesses for large model systems. By comparing the characterized geometries and enzyme active sites, methods for catalysis of the various chemical steps can be identified, and these possibilities are discussed in detail for hOgg1. Interestingly, the most stable structure on the potential energy surface occurs before elimination of the 3'-phosphate. Hydrolysis of the protein-DNA cross-link at this point would yield an AP-site, which provides support for the recently observed monofunctional activity of hOgg1.
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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 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".