| name | alterlab-ligandmpnn |
| description | Design protein sequences around bound ligands, metals, and nucleic acids with LigandMPNN (Dauparas 2023) — inverse folding that conditions on non-protein context, so binding-pocket and metal-site residues are chosen to fit the actual ligand. Use when designing a small-molecule or metal binding pocket, redesigning residues that contact a ligand/ion/nucleic acid, or doing enzyme active-site design where the substrate matters. For backbone sequence design with NO ligand/metal context prefer alterlab-proteinmpnn; to GENERATE a backbone or scaffold a functional site prefer alterlab-rfdiffusion; to validate a design by refolding prefer alterlab-alphafold; to co-fold or dock the ligand prefer alterlab-boltz or alterlab-diffdock. Part of the AlterLab Academic Skills suite. |
| license | MIT |
| allowed-tools | Read Write Edit Bash(python:*) Bash(uv:*) |
| compatibility | Runs LigandMPNN (`dauparas/LigandMPNN`, PyTorch) under `uv run python` via its `run.py`. Model checkpoints download once (small; no account). CPU works for typical sizes; a GPU only speeds large batches. Input is a structure containing the protein PLUS the ligand/metal/nucleic-acid atoms (e.g. a PDB with the HETATM records). |
| metadata | {"skill-author":"AlterLab","version":"1.0.0"} |
LigandMPNN (ligand-aware sequence design)
Overview
LigandMPNN (Dauparas et al. 2023; dauparas/LigandMPNN) extends ProteinMPNN's inverse
folding to condition on non-protein context — small-molecule ligands, metal ions, and
nucleic acids. Because the model sees the ligand/metal atoms, the residues it designs for a
binding pocket or metal site are chosen to complement what is actually bound, which
plain ProteinMPNN (protein-atoms-only) cannot do.
Use it whenever the design target is a site that contacts a ligand or ion. For sequence
design of a backbone with no bound context, use alterlab-proteinmpnn.
When to Use This Skill
Use this skill when the user wants to:
- Design a small-molecule binding pocket so the residues fit the ligand.
- Design a metal-coordinating site (e.g. Zn/Fe) with the ion in context.
- Redesign residues that contact a ligand, ion, or nucleic acid.
- Do enzyme active-site design where the substrate/cofactor should guide the choice.
Does NOT Trigger
| Scenario | Use instead |
|---|
| Sequence design for a backbone with no ligand/metal context | alterlab-proteinmpnn |
| Generate a backbone or scaffold a functional motif | alterlab-rfdiffusion |
| Validate a design by refolding | alterlab-alphafold |
| Co-fold the protein WITH the ligand from scratch | alterlab-boltz |
| Dock a ligand into a fixed pocket (pose, not sequence) | alterlab-diffdock |
Core Capabilities
1. Ligand-aware pocket design
python run.py \
--model_type ligand_mpnn \
--pdb_path complex_with_ligand.pdb \
--out_folder out/ \
--number_of_batches 8
The input PDB must contain the ligand/metal atoms (HETATM). LigandMPNN designs pocket residues
that fit that context; supply a fixed-positions/redesign spec to target only the site.
2. Metal-site and nucleic-acid context
Provide the coordinating ion or the nucleic-acid chain in the structure so the model conditions
on it — critical for metalloenzyme and DNA/RNA-binding designs.
3. Site-focused redesign
Restrict design to the residues within a shell of the ligand (redesign the pocket, keep the
scaffold), analogous to ProteinMPNN's fixed-positions workflow. Verify the exact argument names
for your version (TODO(verify)).
4. In the design pipeline
LigandMPNN provides the sequence step when the functional site involves a ligand: scaffold
or generate the site with alterlab-rfdiffusion, design the pocket sequence here, then validate
by refolding (alterlab-alphafold) and — if you need a pose/affinity — co-fold with
alterlab-boltz or dock with alterlab-diffdock.
Resources
references/ligandmpnn_usage.md — install/pinning, model types, HETATM/context input,
site-restricted design, and pipeline integration. Loaded on demand.
Part of the AlterLab Academic Skills suite.
