Exploring the Identity of the General Base for a DNA Polymerase Catalyzed Reaction Using QM/MM: The Case Study of Human Translesion Synthesis Polymerase η
Bibliographic record
Abstract
DNA replication is a fundamental process for life. Despite previous experimental and computational studies of the reaction pathway catalyzed by a variety of DNA polymerases, certain features of the mechanism remain unclear, especially for the more recently identified translesion synthesis (TLS) polymerases. A pressing question in the TLS polymerase literature is: what is the identity of the general base that initiates the reaction? The current work uses computational techniques to shed light on this topic by exploring the mechanism for the chemical step catalyzed by a human TLS polymerase, namely polymerase η. This enzyme was chosen due to its critical role in the replication of damaged DNA and its biomedical importance. A consistent theoretical framework is used to investigate all possibilities for the general base based on previous proposals from experimental and computational studies on polymerase η and other DNA polymerases. Our MD and ONIOM quantum mechanics/molecular mechanics (QM/MM) calculations suggest that the dNTP α-phosphate moiety and active site water interacting with bulk solvent or the catalytic Mg2+ ion are not optimal choices for the general base due to high energy intermediates. Although proton transfer to an active site hydroxide ion or to Glu116 through Ser113 is energetically feasible, the pathway that best aligns with our dynamical (MD/umbrella sampling) structural information and available experimental kinetic and mutational data invokes Glu116 directly abstracting a proton to initiate the nucleotidyl transfer reaction. Together, these results help answer a long-standing question in the DNA replication literature.
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 | 0.001 | 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 | 0.000 | 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".