Solublempnn Agent Skill

SolubleMPNN Solubility-Optimized 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 to set up Modal and biomodals.

Option 1: Modal (recommended)

SolubleMPNN is the soluble model type within the LigandMPNN wrapper:

cd biomodals
modal run modal_ligandmpnn.py \
  --input-pdb backbone.pdb \
  --params-str "--model_type soluble_mpnn --number_of_batches 16 --temperature 0.1"

GPU: A10G default | Timeout: 900s default

Option 2: Local installation

git clone https://github.com/dauparas/ProteinMPNN.git
cd ProteinMPNN

# The soluble weights are selected with --use_soluble_model, not a model name
python protein_mpnn_run.py \
  --pdb_path backbone.pdb \
  --out_folder output/ \
  --num_seq_per_target 16 \
  --sampling_temp "0.1" \
  --use_soluble_model

Key parameters

| Parameter | Default | Description |

|-----------|---------|-------------|

| --pdb_path | required | Input structure |

| --use_soluble_model | off | Use the solubility-trained weights |

| --num_seq_per_target | 1 | Sequences per structure |

| --sampling_temp | "0.1" | Temperature (string) |

| --model_name | v_48_020 | Noise level (0.20 A); orthogonal to solubility |

Model weights

--model_name sets the training-noise level (v_48_002 = 0.02 A, v_48_010 = 0.10 A,

v_48_020 = 0.20 A), not a solubility tier. Solubility is a separate weight set chosen

with --use_soluble_model, available for v_48_010 and v_48_020. Higher noise gives

more sequence diversity.

Output format

output/
├── seqs/backbone.fa
└── backbone_pdb/backbone_0001.pdb

Sample output

Successful run

$ python protein_mpnn_run.py --pdb_path backbone.pdb --use_soluble_model --num_seq_per_target 8
Loading soluble model weights (v_48_020)...
Designing sequences for backbone.pdb
Generated 8 sequences in 2.1 seconds

output/seqs/backbone.fa:
>backbone_0001, score=1.31, global_score=1.24, seq_recovery=0.78
MKTAYIAKQRQISFVKSHFSRQLE...
>backbone_0002, score=1.28, global_score=1.21, seq_recovery=0.81
MKTAYIAKQRQISFVKSQFSRQLD...

What good output looks like:

• Score: 1.0-2.0 (lower = more confident)
• Reduced hydrophobic patches compared to standard MPNN
• Improved charge distribution

Decision tree

Should I use SolubleMPNN?
│
├─ What expression system?
│  ├─ E. coli → SolubleMPNN ✓
│  ├─ Mammalian → ProteinMPNN (PTMs matter more)
│  └─ Yeast → Either
│
├─ History of expression problems?
│  ├─ Yes, aggregation → SolubleMPNN ✓
│  ├─ Yes, low yield → SolubleMPNN ✓
│  └─ No → ProteinMPNN is fine
│
├─ What's in the binding site?
│  ├─ Small molecule / ligand → Use LigandMPNN
│  └─ Nothing / protein only → SolubleMPNN ✓
│
└─ Optimizing for expression?
   └─ Add --use_soluble_model to ProteinMPNN

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 |

Expected improvement: +15-30% solubility score vs standard ProteinMPNN.

Verify

grep -c "^>" output/seqs/*.fa  # Should match backbone_count × num_seq_per_target

Troubleshooting

Still insoluble: Confirm --use_soluble_model is set; redesign more positions or add explicit hydrophobic-residue bias

Low diversity: Increase temperature to 0.2

Poor folding: Use standard ProteinMPNN and optimize later

Error interpretation

| Error | Cause | Fix |

|-------|-------|-----|

| RuntimeError: CUDA out of memory | Long protein or large batch | Reduce batch_size |

| FileNotFoundError: v_48_020 | Missing model weights | Download soluble weights |

Next: Structure prediction for validation → protein-qc for filtering.