RDKit — Conformers and Molecular Representations

When to Use

• User needs to generate multiple 3D conformers for a molecule
• User wants to compute molecular fingerprints or descriptors
• User needs SMILES canonicalization or InChI generation
• User wants substructure matching or molecular similarity
• User needs to embed a molecule and optimize geometry with MMFF94/UFF

Prerequisites

1. RDKit installed (python -c "from rdkit import Chem; print(Chem.__version__)")

Workflow Steps

Conformer Generation

catgo_workflow_engine(action="add_task", params={
  "workflow_id": "wf_xxx",
  "task_type": "shell",
  "name": "rdkit_conf",
  "command": "python gen_conformers.py",
  "input_files": {
    "gen_conformers.py": "<script content>"
  },
  "system_name": "caffeine_conformers"
})

Script — Conformer Generation

from rdkit import Chem
from rdkit.Chem import AllChem, rdMolDescriptors

smiles = "CN1C=NC2=C1C(=O)N(C(=O)N2C)C"  # caffeine
mol = Chem.MolFromSmiles(smiles)
mol = Chem.AddHs(mol)

# Generate conformers
params = AllChem.ETKDGv3()
params.numThreads = 0  # use all cores
params.pruneRmsThresh = 0.5  # Angstrom RMSD pruning

cids = AllChem.EmbedMultipleConfs(mol, numConfs=50, params=params)
print(f"Generated {len(cids)} conformers")

# Optimize with MMFF94
results = AllChem.MMFFOptimizeMoleculeConfs(mol, numThreads=0)

# Sort by energy and write
energies = [(cid, res[1]) for cid, res in zip(cids, results) if res[0] == 0]
energies.sort(key=lambda x: x[1])

writer = Chem.SDWriter("conformers.sdf")
for cid, energy in energies[:20]:  # top 20 lowest energy
    mol.SetProp("Energy_kcal/mol", f"{energy:.2f}")
    writer.write(mol, confId=cid)
writer.close()

Script — Molecular Descriptors

from rdkit import Chem
from rdkit.Chem import Descriptors, rdMolDescriptors

mol = Chem.MolFromSmiles("CCO")

print(f"MW:       {Descriptors.MolWt(mol):.2f}")
print(f"LogP:     {Descriptors.MolLogP(mol):.2f}")
print(f"HBD:      {rdMolDescriptors.CalcNumHBD(mol)}")
print(f"HBA:      {rdMolDescriptors.CalcNumHBA(mol)}")
print(f"TPSA:     {Descriptors.TPSA(mol):.2f}")
print(f"RotBonds: {Descriptors.NumRotatableBonds(mol)}")

Script — Fingerprints and Similarity

from rdkit import Chem, DataStructs
from rdkit.Chem import AllChem

mol1 = Chem.MolFromSmiles("c1ccccc1")  # benzene
mol2 = Chem.MolFromSmiles("c1ccncc1")  # pyridine

fp1 = AllChem.GetMorganFingerprintAsBitVect(mol1, radius=2, nBits=2048)
fp2 = AllChem.GetMorganFingerprintAsBitVect(mol2, radius=2, nBits=2048)

tanimoto = DataStructs.TanimotoSimilarity(fp1, fp2)
print(f"Tanimoto similarity: {tanimoto:.3f}")

Script — SMILES to XYZ

from rdkit import Chem
from rdkit.Chem import AllChem

mol = Chem.MolFromSmiles("CCO")
mol = Chem.AddHs(mol)
AllChem.EmbedMolecule(mol, AllChem.ETKDGv3())
AllChem.MMFFOptimizeMolecule(mol)

# Write XYZ
conf = mol.GetConformer()
symbols = [a.GetSymbol() for a in mol.GetAtoms()]
coords = conf.GetPositions()

with open("molecule.xyz", "w") as f:
    f.write(f"{len(symbols)}\n")
    f.write("Generated by RDKit\n")
    for sym, (x, y, z) in zip(symbols, coords):
        f.write(f"{sym} {x:.6f} {y:.6f} {z:.6f}\n")

Parameter Guidance

Parameter	Typical value	Notes
numConfs	50-200	More for flexible molecules
pruneRmsThresh	0.5 Ang	Remove near-duplicate conformers
MMFF94 vs UFF	MMFF94 preferred	UFF as fallback for metals
Morgan radius	2	ECFP4 equivalent
nBits	2048	Fingerprint length

Common Pitfalls

1. Forgetting AddHs — RDKit molecules from SMILES have implicit H. Call Chem.AddHs() before 3D embedding.
2. Embedding failure — EmbedMolecule returns -1 on failure. Check return value; retry with useRandomCoords=True.
3. MMFF94 unsupported atoms — MMFF94 does not cover all elements. Use UFF for organometallics.
4. Stereo loss — ensure SMILES include stereochemistry (/, \, @, @@) if relevant.
5. Large flexible molecules — conformer generation for molecules with >10 rotatable bonds needs many conformers (200+).
6. Sanitization errors — invalid SMILES cause MolFromSmiles to return None. Always check for None.