Augmented base pairing networks encode RNA-small molecule binding preferences
Bibliographic record
Abstract
A bstract Motivation The binding of small molecules to RNAs is an important mechanism which can stabilize 3D structures or activate key molecular functions. To date, computational and experimental efforts toward small molecule binding prediction have primarily focused on protein targets. Considering that a very large portion of the genome is transcribed into non-coding RNAs but only few regions are translated into proteins, successful annotations of RNA elements targeted by small-molecule would likely uncover a vast repertoire of biological pathways and possibly lead to new therapeutic avenues. Results Our work is a first attempt at bringing machine learning approaches to the problem of RNA drug discovery. RNAmigos takes advantage of the unique structural properties of RNA to predict small molecule ligands for unseen binding sites. A key feature of our model is an efficient representation of binding sites as augmented base pairing networks (ABPNs) aimed at encoding important structural patterns. We subject our ligand predictions to two virtual screen settings and show that we are able to rank the known ligand on average in the 73rd percentile, showing a significant improvement over several baselines. Furthermore, we observe that graphs which are augmented with non-Watson Crick (a.k.a non-canonical) base pairs are the only representation which is able to retrieve a significant signal, suggesting that non-canonical interactions are an necessary source of binding specificity in RNAs. We also find that an auxiliary graph representation task significantly boosts performance by providing efficient structural embeddings to the low data setting of ligand prediction. RNAmigos shows that RNA binding data contains structural patterns with potential for drug discovery, and provides methodological insights which can be applied to other structure-function learning tasks. Availability Code and data is freely available at http://csb.cs.mcgill.ca/RNAmigos . Contact jerome@cs.mcgill.ca
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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) | 0.001 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".