The type IA topoisomerase catalytic cycle: A normal mode analysis and molecular dynamics simulation
Bibliographic record
Abstract
Type IA topoisomerases alter the topological state of DNA to relax the supercoils introduced during the DNA replication and transcription process, giving them critical roles in many cellular functions. To manipulate the DNA, type IA topoisomerases first cleave one DNA strand and form a covalent linkage between a catalytic tyrosine residue and the 5'-phosphoryl of the DNA. This is followed by a movement of domain III of the topoisomerase to accommodate the second DNA strand in the center channel of the topoisomerase. Domain III is then closed for religation of the cleaved DNA and subsequently reopened to release the passing strand. Although numerous biophysical and biochemical studies have examined this catalytic cycle, fundamental questions remain such as how domain III opens and closes during this process. We have used computational simulation methods, namely normal mode analysis and molecular dynamics, to investigate the catalytic cycle of Escherichia coli topoisomerase III as a representative of the type IA topoisomerases. It was found that domain II is intrinsically flexible and may empower the enzyme to perform its function by triggering domain III opening and closing. A molecular dynamics simulation and MM-PBSA analysis shows that topoisomerase III alone cannot overcome the large energy barrier of the conformational transition. A detailed examination of the DNA binding sites suggests that the processing DNA cooperates with the topoisomerase to accomplish this dramatic conformational change. These findings will guide future mutagenesis studies of type IA topoisomerases aimed at dissecting the driving forces and conformations in the catalytic cycle.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".