Simulating Protein-Ligand Binding with Neural Network Potentials
Bibliographic record
Abstract
Drug molecules adopt a range of conformations both in solution and in their protein-bound state. The strain and reduced flexibility of bound drugs can partially counter the intermolecular interactions that drive protein–ligand binding. To make accurate computational predictions of drug binding affinities, computational chemists have attempted to develop efficient empirical models of these interactions, although these methods are not always reliable. Machine learning has allowed the development of highly-accurate neural-network potentials (NNPs), which are capable of predicting the stability of molecular conformations with accuracy comparable to state-of-the-art quantum chemical calculations but at a billionth of the computational cost. Here, we demonstrate that these methods can be used to represent the intramolecular forces of protein-bound drugs within molecular dynamics simulations. These simulations are shown to be capable of predicting the protein–ligand binding pose and conformational component of the absolute Gibbs energy of binding for a set of drug molecules. Notably, the conformational energy for anti-cancer drug erlotinib binding to its target was found to considerably overestimated by a molecular mechanical model, while the NNP predicts a more moderate value. Although the ANI-1ccX NNP was not trained to describe ionic molecules, reasonable binding poses are predicted for charged ligands, although this method is not suitable for modeling the ligands in solution.
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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 | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".