Bibliographic record
Abstract
The type 1 Human Immunodeficiency Virus (HIV-1) transactivator of transcription (Tat) is a 101-residue protein that significantly increases the viral transcription. The full-length Tat protein (Tat101) is encoded by two exons yielding the first 72 and the last 29 residues of the protein, respectively. The function and intrinsic disorder of the first 72 residues have been studied in great detail but relatively little is known about the structure and function of the second exon product despite its conserved expression in all lentiviruses. My thesis aims to study the impact of Tat’s second exon product on the full-length protein in terms of disorder, dynamics and structural propensity. NMR spectroscopy has been used to study Tat101 protein in a fully reduced state. Multiple isotope labeling strategies were applied and the labeled protein was expressed and purified in high yield. Backbone resonance assignment, chemical shift analysis, structure propensity analysis, fast (ps-ns) and slow (ms) timescale dynamics and hydrogen exchange studies confirm the intrinsically disordered nature of the second exon product and full-length Tat. The NMR results revealed Tat’s propensities to adopt different local conformations. Reduced spectral density mapping and model-free analysis show that the fast internal motion on the ps-ns timescale dominates the relaxation, and that Tat101 has no slow motion / conformational exchange on the ms timescale. The hydrogen exchange measurements yield protection factors below 1, which can be explained by the higher local pH compared with the bulk solvent. Classical molecular dynamics simulations were used as a complementary technique to verify the NMR results and to sample the protein conformers that are invisible to NMR due to ensemble averaging. The two 100 ns trajectories from the simulations of Tat’s first exon product are dominated by non-structural elements such as coils, turns, and bends. The order parameters derived from the simulations are below 0.8 and in agreement with the NMR results, confirming the flexibility of the protein. The combination of NMR dynamics and simulation results indicate that some regions of the protein likely bind partners through a conformational-selection mechanism while other parts of protein bind their targets through an induced-fit mechanism.
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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 | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".