Design of peptides with non-canonical amino acids using flow matching
Bibliographic record
Abstract
MOTIVATION: The canonical vocabulary of 20 amino acids limits the chemical space available to proteins and peptides. Expanding this vocabulary to hundreds of noncanonical amino acids (ncAAs) allows the engineering of proteins with novel function and activity, and is of particular interest for therapeutic peptides such as macrocycles, where ncAAs can improve proteolytic stability, membrane permeability, and immunogenicity. However, existing structure-based design tools either cannot model ncAAs at all, or are restricted to a small, fixed vocabulary of ncAAs seen during training, and ncAA data in the Protein Data Bank is scarce and heavily biased. RESULTS: We present NCFlow, a flow matching generative model that places any arbitrary ncAA into a given protein backbone using only its atom types and bond connectivity, and therefore generalizes to ncAAs never seen during training. To supplement sparse training data in the Protein Data Bank, NCFlow is pretrained on millions of small molecule structures and a large set of protein-ligand complexes before finetuning on native noncanonicals found within proteins. NCFlow outperforms AlphaFold3-based methods in the structure prediction of unseen ncAAs. We further present a peptide design pipeline akin to in silico deep mutational scanning, and propose a scoring strategy combining deep learning-based and molecular dynamics-based alchemical binding free energy calculations to identify improved peptide variants. We apply the method on four protein-peptide complex test cases, and observe that incorporating noncanonicals can improve predicted binding affinity by up to -7.0 kcal/mol. AVAILABILITY AND IMPLEMENTATION: NCFlow is freely available at https://github.com/mjslee0921/ncflow.
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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 | 0.001 |
| 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 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| 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".