Structural Analysis of Macrocyclic Peptides bound to Huntingtin
Bibliographic record
Abstract
Huntington's Disease (HD) is a neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and psychiatric disturbances, driven by an expanded polyglutamine tract in the huntingtin (HTT) protein. Despite extensive research, understanding HTT has been limited by the scarcity of high-quality reagents. Using the RaPID method, our lab identified six macrocycles with high affinity for HTT and/or HTT-HAP40 complexes, confirmed by surface plasmon resonance spectroscopy. Four macrocycles (HHL1, HHD3, HD4, and HL2) were found to bind and affinity purify HTT and/or HTT-HAP40 from cell extracts. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) revealed binding pockets, guiding CryoEM for structural elucidation. In my work, I modeled, refined and analyzed cryo-EM structures of the protein-ligand complexes. The macrocycles bound to deep, conserved pockets in the HTT-HAP40 complex. I hypothesize that identified macrocycles target functionally important regions and that they can be used as tools to unravel the function of these pockets.
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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) | 0.002 | 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".