RDKit Conformer Generation

Quick Start

Check CLI help:

uv run <skill_path>/scripts/rdkit_conf_helper.py --help
uv run <skill_path>/scripts/rdkit_conf_helper.py conf --help

Disable environment printing (optional):

uv run <skill_path>/scripts/rdkit_conf_helper.py --no-env conf --smiles "CCO" --output out.sdf

Core Tasks

1) Generate 3D conformers (SDF output, default)

Single SMILES:

uv run <skill_path>/scripts/rdkit_conf_helper.py conf \
    --smiles "CCO" \
    --output /tmp/CCO.sdf

Single SMILES with a custom molecule name:

uv run <skill_path>/scripts/rdkit_conf_helper.py conf \
    --smiles "c1ccccc1" \
    --name benzene \
    --output /tmp/benzene.sdf

From CSV (default SMILES column: smiles):

uv run <skill_path>/scripts/rdkit_conf_helper.py conf \
    --file data.csv \
    --smiles-col smiles \
    --output data.sdf

From CSV with a name column:

uv run <skill_path>/scripts/rdkit_conf_helper.py conf \
    --file data.csv \
    --smiles-col smiles \
    --name-col compound_id \
    --output data.sdf

From SMI (second token per line is used as name automatically):

uv run <skill_path>/scripts/rdkit_conf_helper.py conf \
    --file molecules.smi \
    --output molecules.sdf

2) Control conformer sampling count

Default (10 conformers sampled, lowest-energy kept):

uv run <skill_path>/scripts/rdkit_conf_helper.py conf \
    --file data.csv --output data.sdf

Single conformer (fastest, least thorough):

uv run <skill_path>/scripts/rdkit_conf_helper.py conf \
    --file data.csv --num-confs 1 --output data.sdf

Increase sampling for flexible or macrocyclic molecules:

uv run <skill_path>/scripts/rdkit_conf_helper.py conf \
    --file data.csv --num-confs 50 --output data.sdf

3) Choose force-field minimization

MMFF94s (default, falls back to UFF if unavailable):

uv run <skill_path>/scripts/rdkit_conf_helper.py conf \
    --file data.csv --ff mmff94s --output data.mmff.sdf

UFF (universal force field):

uv run <skill_path>/scripts/rdkit_conf_helper.py conf \
    --file data.csv --ff uff --output data.uff.sdf

Skip force-field optimization (raw ETKDG geometry only):

uv run <skill_path>/scripts/rdkit_conf_helper.py conf \
    --file data.csv --ff none --output data.etkdg_raw.sdf

4) XYZ output

uv run <skill_path>/scripts/rdkit_conf_helper.py conf \
    --file data.csv \
    --format xyz \
    --output data.xyz

5) Tuning embedding for difficult molecules

Large or macrocyclic molecules sometimes fail standard ETKDG; try random initial coordinates:

uv run <skill_path>/scripts/rdkit_conf_helper.py conf \
    --file macrocycles.csv \
    --use-random-coords \
    --max-attempts 500 \
    --output macrocycles.sdf

Use a different random seed (reproducibility):

uv run <skill_path>/scripts/rdkit_conf_helper.py conf \
    --file data.csv --seed 123 --output data.seed123.sdf

Non-deterministic embedding (seed = -1):

uv run <skill_path>/scripts/rdkit_conf_helper.py conf \
    --file data.csv --seed -1 --output data.sdf

6) Suppress hydrogen addition

By default explicit H atoms are added before embedding for more accurate 3D geometry. Use --no-hs to keep the molecule as-is (heavy atoms only):

uv run <skill_path>/scripts/rdkit_conf_helper.py conf \
    --file data.csv --no-hs --output data.noh.sdf

7) Custom log file paths

uv run <skill_path>/scripts/rdkit_conf_helper.py conf \
    --file data.csv \
    --output data.sdf \
    --error-log logs/skipped.csv \
    --fallback-log logs/used_2d.csv

3D Embedding Pipeline Details

For each molecule, the script runs the following steps in order:

1. Parse SMILES via Chem.MolFromSmiles.
2. Add hydrogens (Chem.AddHs) -- skipped with --no-hs.
3. Multi-conformer 3D embedding (EmbedMultipleConfs, --num-confs candidates, default 10): tries ETKDGv3, then ETKDGv2, then ETDG, then ETDG+useRandomCoords as a fallback chain until at least one conformer is embedded.
4. Force-field minimization (if --ff is not none): each successfully embedded conformer is individually optimized. MMFF94s transparently falls back to UFF if parameters are unavailable for that molecule.
5. Lowest-energy selection: the conformer with the minimum post-optimization energy is retained; all others are discarded. If --ff none, the first embedded conformer is kept without energy ranking.
6. 2D fallback (if all 3D attempts yield zero conformers): generates a flat 2D layout via Compute2DCoords (Z=0 for all atoms), prints a [WARN] to stderr, and records the molecule in the fallback log.

Output Format Notes

SDF output (--format sdf, default):

• Standard V2000 multi-molecule SDF, one conformer per molecule.
• Molecule name (from --name, --name-col, or auto-generated mol_<i>) is written to the SDF header line.
• Compatible with most cheminformatics tools (RDKit, OpenBabel, Schrodinger, etc.).

XYZ output (--format xyz):

• Concatenated XYZ blocks (element, x, y, z per atom).
• Molecule name is written as the comment line (second line of each block).
• Coordinates are in Angstroms.
• Note: if --no-hs is used, hydrogen atoms are absent from the XYZ.

Fallback log (*.fallback.csv):

• Written only when at least one molecule fell back to 2D.
• Columns: idx, smiles, name, dim (always 2), ff (always 2d_fallback), note.

Skipped log (*.skipped.csv):

• Written only when at least one SMILES was skipped.
• Columns: idx, smiles, error.

Agent Checklist

When using this skill for users:

1. Confirm input format:
   • .csv requires a SMILES column (default smiles)
   • .smi uses the first token per line as SMILES, second token (if present) as name
2. Quote SMILES containing special shell characters (brackets/parentheses):
   • Example: --smiles "[C@@H](O)(F)Cl"
3. For CSV workflows, verify column names:
   • --smiles-col for the SMILES column
   • --name-col (optional) for molecule identifiers to embed in SDF/XYZ headers
4. Check the [INFO] Done: summary line for the 3D/2D/skip breakdown.
5. If 2D fallbacks occurred, inspect *.fallback.csv:
   • Consider --use-random-coords or --max-attempts tuning for the affected SMILES.
   • 2D conformers have Z=0 and are not suitable for 3D-based applications (docking, 3D QSAR).
6. Always capture absolute output paths:
   • Look for [RESULT] ...=/abs/path in stdout.
7. If debugging is needed, enable full traceback:
   • RDKIT_CONF_HELPER_TRACE=1 uv run <skill_path>/scripts/rdkit_conf_helper.py ...

GPUMD integration

RDKit conformer generation can produce initial molecular geometries for Packmol packing or as starting structures for GPUMD molecular simulations. XYZ output can be converted to GPUMD model.xyz format via dpdata or ASE.

References

• RDKit conformer generation guide: https://www.rdkit.org/docs/GettingStartedInPython.html#working-with-3d-molecules
• ETKDG paper: Riniker & Landrum, J. Chem. Inf. Model. 2015, 55, 2562
• ETKDGv3: Wang et al., J. Chem. Inf. Model. 2020, 60, 2044