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
# dauparas/LigandMPNN — clone, fetch weights once, then run run.py
git clone https://github.com/dauparas/LigandMPNN && cd LigandMPNN
bash get_model_params.sh "./model_params"
python run.py \
--model_type ligand_mpnn \
--checkpoint_ligand_mpnn "./model_params/ligandmpnn_v_32_010_25.pt" \
--pdb_path complex_with_ligand.pdb \
--out_folder out/ \
--seed 111 \
--batch_size 8 --number_of_batches 4
The input PDB must contain the ligand/metal atoms (HETATM). LigandMPNN designs pocket residues
that fit that context; use --redesigned_residues/--fixed_residues to target only the site.
Output FASTA headers carry overall_confidence and ligand_confidence (0–1, higher = more
confident), averaged over the redesigned residues only.
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). Residues are named directly by chain+index — --redesigned_residues "A23 A24 B42D"
or the complement, --fixed_residues "C1 C2 …". Insertion codes are preserved (B42D), because
LigandMPNN parses structures with ProDy and keeps the original numbering rather than
renumbering. Add --ligand_mpnn_use_side_chain_context 1 to condition on the side-chain atoms
of the fixed residues as well as the backbone.
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.