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 < 2 Å against crystallographic pose. If fails, fix preparation or grid before screening.
Critical Parameters
Parameter
Recommended
When to change
exhaustiveness
32
64+ for >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
