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

# dauparas/LigandMPNN CLI — TODO(verify) flags/checkpoint names against your checkout
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.