Investigating Binding Mechanisms of Small Molecules to Quadruplex DNA
Bibliographic record
Abstract
Guanine quadruplexes (G4) are dynamic structures found naturally in guanine-rich DNA. When folded, they have been found to block the expression of genes related to diseases including cancer1 and are therefore of significant interest in the field of biomedical research. Our research group has developed a family of chemical binders which strongly stabilize folded G4. This project focuses on quantifying the interaction of these binders with various quadruplexes, through their binding constant (a measure of relative preference for the bound vs unbound state). This constants can be determined through the use of a Fluorescence Intercalation Displacement (FID) biophysical assay,2 a method which measures the competitive binding of the binder molecule and a fluorescent probe to the quadruplex (see figure 1). As a preliminary step, we perform direct titrations of the fluorescent probe, Thiazole Orange (TO), with quadruplex DNA, to determine its binding constant and TO:DNA stoichiometry. TO fluoresces only when bound to a substrate,3 allowing us to track the formation of the TO*DNA complex through an increase in fluorescence. In the FID titration, however, the binder displaces the fluorescent probe, and a decrease in fluorescence intensity is observed. We also discuss mathematical methods used to fit the experimental data in order to determine binding constants for both the fluorescent probe and our binders. A robust model should give evidence in support of the expected binding phenomena. References 1. Hurley, L. et. al. The Febs Journal, 2010, 277, 3459-3469 2. Monchaud, D. et. al. Biochimie, 2008, 90: 1209-1223 3. Yaron, D. et. al. The Journal of Physical Chemistry A. 2008, 112, 9692-9701
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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 | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.002 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".