Drug Protein Prep

protein-prep

Goal

To prepare protein (and optionally nucleic acid) receptor structures for molecular docking (e.g., AutoDock Vina) by: 1) retrieving coordinates from RCSB PDB (optional), 2) fixing common structural issues (missing atoms, nonstandard residues), 3) adding hydrogens at a target pH.

> Note: This skill handles structure cleanup and protonation. To convert the result to PDBQT for docking, use the mcp_drugdisc_convert_to_pdbqt tool.

Instructions

1. Prepare a receptor to PDB (Cleanup + Hydrogens)

This script manages missing atoms, nonstandard residues, and protonation.

# Env: drugdisc-agent
python .agents/skills/drug-protein-prep/scripts/prepare_protein.py \
  --pdb_id 1iep \
  --chains A \
  --ph 7.0 \
  --heterogens none \
  --missing_residues ignore \
  --output_dir protein_prep/

2. Convert to PDBQT (for AutoDock Vina)

Use the MCP tool to convert the prepared PDB to PDBQT format.

mcp_drugdisc_convert_to_pdbqt(
    input_data="protein_prep/1IEP_prepared.pdb",
    output_path="protein_prep/1IEP.pdbqt",
    input_type="pdb"
)

3. Keep cofactors/metal ions

# Env: drugdisc-agent
python .agents/skills/drug-protein-prep/scripts/prepare_protein.py \
  --pdb_id 1iep \
  --chains A \
  --heterogens non-water \
  --delete_resname SO4 GOL \
  --output_dir protein_prep_keep_cofactors/

4. Use a biological assembly (recommended when oligomerization matters)

# Env: drugdisc-agent
python .agents/skills/drug-protein-prep/scripts/prepare_protein.py \
  --pdb_id 1iep \
  --assembly 1 \
  --chains A \
  --output_dir protein_prep_assembly1/

5. Prepare from a local structure file

# Env: drugdisc-agent
python .agents/skills/drug-protein-prep/scripts/prepare_protein.py \
  --pdb_file receptor.pdb \
  --heterogens none \
  --output_dir protein_prep_local/

6. Validate the output (strongly recommended)

After preparation:

• Inspect the JSON summary for missing residues, nonstandard residue replacements, and atoms added.
• Visually inspect the binding site and check for:
• correct oligomeric state,
• retained/removed cofactors and metal ions,
• sensible protonation (especially histidines),
• alternate locations resolved appropriately.

If protonation is critical, consider a hydrogen optimization / pKa-aware tool (e.g., Reduce/Reduce2, PROPKA/PDB2PQR/H++), then regenerate PDBQT from the protonated receptor.

Examples

Full Workflow: HIV-1 Protease

1. Prepare the structure:

# Env: drugdisc-agent
python .agents/skills/drug-protein-prep/scripts/prepare_protein.py \
  --pdb_id 1hsg \
  --chains A B \
  --heterogens none \
  --ph 7.0 \
  --output_dir hiv_prep/

1. Convert to PDBQT:

mcp_drugdisc_convert_to_pdbqt(
    input_data="hiv_prep/1HSG_prepared.pdb",
    output_path="hiv_prep/1HSG.pdbqt",
    input_type="pdb"
)

Constraints

• Environment: Requires drugdisc-agent.
• Core dependencies: pdbfixer, openmm.
• Protonation: Default pH-based hydrogen addition is a baseline.
• Missing residues: By default, missing residues are ignored to avoid introducing uncertain loop models.
• PDBQT: PDBQT conversion is delegated to the mcp_drugdisc_convert_to_pdbqt tool (which uses Meeko).

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Author: Matthew Cox Contact: GitHub @mcox3406

Source & license

This open-source skill is cataloged on AgentStack and links to its original source — we do not rehost the code.

• Author: learningmatter-mit
• Source: learningmatter-mit/AtomisticSkills
• License: MIT
• Homepage: https://arxiv.org/abs/2605.24002

Install and usage instructions live in the source repository linked above.