Molecular Docking

Molecular Docking — Pipeline Skill (Thin Scaffold)

Overview

Adds decision logic for receptor/ligand preparation tool selection, grid box sizing, exhaustiveness tuning, and validation protocol. Focuses on gotchas that produce silently wrong poses.

Usage

• Activate when choosing preparation tools (obabel vs ADFR/meeko) for a docking campaign
• Activate when defining grid box dimensions or placement
• Activate when validating docking setup via redocking

Core Concepts

Decision Logic

Receptor preparation tool:
├── Quick exploration / single ligand → obabel (-d, reduce, -xr)
└── Production virtual screen → prepare_receptor (ADFR) or meeko
    └── Handles altlocs, metals, non-standard residues correctly

Ligand preparation:
├── Single ligand from SMILES/SDF → obabel --gen3d -h
├── Large library (>100 ligands) → meeko (mk_prepare_ligand.py)
└── Stereocenters undefined? → Enumerate explicitly BEFORE docking

Grid box placement:
├── Co-crystal ligand available → Center on ligand centroid
└── No co-crystal → Use pocket predictor (fpocket, P2Rank, SiteMap)

Grid box sizing:
└── Ligand longest diameter + 10–15 Å padding per axis
    └── Typical: 20–30 Å per side for drug-like molecules

Exhaustiveness:
├── Quick exploration → 8 (Vina default)
├── Production / ranking → 32
└── Large/flexible ligands (>8 rotatable bonds) → 64+

Validation gate (MUST pass before trusting screen results): Redock co-crystal ligand → RMSD 8 rotatable bonds | | num_modes | 10 | Increase for ensemble analysis | | energy_range | 3 kcal/mol | Widen to capture diverse poses | | Box padding | +10–15 Å | Larger for allosteric sites | | Protonation pH | 7.0 (reduce default) | Use PROPKA/H++ for acidic pockets (e.g., aspartyl proteases pH 4.5) |

Score interpretation:

• Vina scores are only comparable within the SAME receptor + grid setup
• Typical drug-like hits: -7 to -12 kcal/mol
• Scores are NOT transferable across different targets or grid configurations

Common Mistakes

• Wrong: Leaving crystallographic waters in the receptor

Right: Strip HOH/WAT residues before PDBQT conversion (unless explicit-water docking) Why: Waters block the binding site and produce unphysical poses

• Wrong: Using default pH 7 protonation for all binding sites

Right: Use PROPKA or H++ for acidic/basic pockets Why: Wrong protonation alters H-bond networks and produces incorrect poses

• Wrong: Grid box barely enclosing the binding site

Right: Ligand diameter + 10–15 Å padding per axis Why: Under-padding clips the site and biases poses toward box center

• Wrong: Default exhaustiveness = 8 for large/flexible ligands

Right: Use 32+ for production; 64+ for >8 rotatable bonds Why: Low exhaustiveness misses global minima, unreliable rankings

• Wrong: Skipping redocking validation before screening

Right: Redock co-crystal ligand, verify RMSD < 2 Å Why: RMSD ≥ 2 Å means preparation or grid is wrong; screen results untrustworthy

• Wrong: Using obabel -xr PDBQT for production virtual screens

Right: Use prepare_receptor (ADFR) or meeko for production Why: obabel may miss altlocs, metals, or non-standard residues

• Wrong: Running obabel --gen3d on SMILES with undefined stereocenters

Right: Provide isomeric SMILES or enumerate stereoisomers explicitly Why: Undefined stereocenters resolved arbitrarily — may dock wrong enantiomer

• Wrong: Comparing Vina affinities across different receptors or grid configs

Right: Only compare within same receptor + grid; re-rank when changing either Why: Scores are context-dependent, not transferable

Response Format

• Lead with the command or code the user needs — explain after
• Structure as: confirm inputs → working code → key parameters explained → gotchas
• One complete working example per task; do not show every alternative
• Keep code comments minimal and functional (what, not why-it-exists)
• Target: 50-100 lines of code with brief surrounding explanation

Source & license

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

• Author: awslabs
• Source: awslabs/hcls-agent-skills
• License: MIT-0

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