SKILL.md
LigandMPNN Ligand-Aware Design
Prerequisites
| Requirement | Minimum | Recommended |
|---|---|---|
| Python | 3.8+ | 3.10 |
| CUDA | 11.0+ | 11.7+ |
| GPU VRAM | 8GB | 16GB (T4) |
| RAM | 8GB | 16GB |
How to run
First time? See [Getting started](../../docs/getting-started.md) to set up Modal and biomodals.
Option 1: Modal (recommended)
cd biomodals
# modal_ligandmpnn.py takes --input-pdb; LigandMPNN run.py args go in --params-str
modal run modal_ligandmpnn.py \
--input-pdb protein_ligand.pdb \
--params-str "--model_type ligand_mpnn --number_of_batches 16 --temperature 0.1"GPU: A10G default | Timeout: 900s default
Option 2: Local installation
git clone https://github.com/dauparas/LigandMPNN.git
cd LigandMPNN
python run.py \
--model_type ligand_mpnn \
--pdb_path protein_ligand.pdb \
--out_folder output/ \
--number_of_batches 16 \
--temperature 0.1Key parameters (LigandMPNN run.py)
| Parameter | Default | Description |
|---|---|---|
--pdb_path |
required | PDB with ligand |
--model_type |
protein_mpnn |
ligandmpnn, solublempnn, etc. |
--temperature |
0.1 | Sampling temperature |
--numberofbatches |
1 | Batches (sequences = batch_size x batches) |
--batch_size |
1 | Sequences per batch |
--ligandmpnnusesidechain_context |
0 | Use ligand side-chain context |
Ligand Specification
In PDB File
Ligand must be present as HETATM records:
ATOM ...protein atoms...
HETATM 1 C1 LIG A 999 x.xxx y.yyy z.zzz 1.00 0.00 CSupported Ligand Types
- Small molecules (HETATM)
- Metals (Zn, Fe, Mg, Ca, etc.)
- Cofactors (NAD, FAD, ATP)
- DNA/RNA
Output format
output/
├── seqs/
│ └── protein.fa # FASTA sequences
└── protein_pdb/
└── protein_0001.pdb # PDBs with designed sequenceSample output
Successful run
$ python run.py --pdb_path enzyme_substrate.pdb --out_folder output/ --num_seq_per_target 8
Loading LigandMPNN model weights...
Processing enzyme_substrate.pdb
Found ligand: LIG (12 atoms)
Generated 8 sequences in 3.1 seconds
output/seqs/enzyme_substrate.fa:
>enzyme_substrate_0001, score=1.45, global_score=1.38
MKTAYIAKQRQISFVKSHFSRQLE...
>enzyme_substrate_0002, score=1.52, global_score=1.41
MKTAYIAKQRQISFVKSQFSRQLD...What good output looks like:
- Score: 1.0-2.0 (lower = more confident)
- Ligand detected and incorporated in context
- Active site residues preserved or optimized
Decision tree
Should I use LigandMPNN?
│
├─ What's in your binding site?
│ ├─ Small molecule / ligand → LigandMPNN ✓
│ ├─ Metal ion (Zn, Fe, etc.) → LigandMPNN ✓
│ ├─ Cofactor (NAD, FAD, ATP) → LigandMPNN ✓
│ ├─ DNA/RNA → LigandMPNN ✓
│ └─ Nothing / protein only → Use ProteinMPNN
│
├─ What type of design?
│ ├─ Enzyme active site → LigandMPNN ✓
│ ├─ Metal binding site → LigandMPNN ✓
│ ├─ Protein-protein binder → Use ProteinMPNN
│ └─ De novo scaffold → Use ProteinMPNN
│
└─ Priority?
├─ Solubility/expression → Consider SolubleMPNN
└─ Ligand context accuracy → LigandMPNN ✓Typical performance
| Campaign Size | Time (T4) | Cost (Modal) | Notes |
|---|---|---|---|
| 100 backbones × 8 seq | 15-20 min | ~$2 | Standard |
| 500 backbones × 8 seq | 1-1.5h | ~$8 | Large campaign |
Throughput: ~50-100 sequences/minute on T4 GPU.
Verify
grep -c "^>" output/seqs/*.fa # Should match backbone_count × num_seq_per_targetTroubleshooting
Ligand not recognized: Check HETATM format, verify ligand residue name Poor binding residues: Increase sampling around active site Missing contacts: Verify ligand coordinates in PDB
Error interpretation
| Error | Cause | Fix |
|---|---|---|
RuntimeError: CUDA out of memory |
Long protein or large batch | Reduce batch_size |
KeyError: 'LIG' |
Ligand not found in PDB | Check HETATM records |
ValueError: no ligand atoms |
Empty ligand | Verify ligand has atoms in PDB |
Next: Structure prediction for validation → protein-qc for filtering.