Version Compatibility
Reference examples tested with: RDKit 2024.09+, Open Babel 3.1.1+, ChEMBL structure_pipeline 1.2+.
Before using code patterns, verify installed versions match. If versions differ:
- Python:
pip show <package> then help(module.function) to check signatures
- CLI:
obabel -V; obabel -L formats
If code throws ImportError, AttributeError, or TypeError, introspect the installed
package and adapt the example to match the actual API rather than retrying.
Molecular I/O
Parse, write, and convert molecular file formats. Most downstream errors trace back to silent I/O issues: incorrect aromaticity perception, lost stereochemistry, mishandled charges, dropped stereo bonds, or non-canonical tautomers. This skill enumerates each format's failure modes and prescribes the correct toolchain for each scenario.
For full standardization (canonicalization, salt stripping, tautomer enumeration) see chemoinformatics/molecular-standardization. For generating 3D conformers from parsed 2D molecules, see chemoinformatics/conformer-generation.
Format Taxonomy
| Format | Dim | Stereo | Charges | Strength | Fails when |
|---|
| SMILES | 2D | Atom chirality @/@@; double-bond / and \ | Atom-local formal charges | Compact, web-friendly, fast parse | Loses absolute coordinates; aromatic perception ambiguous across toolkits; tautomers not canonical |
| InChI | 2D | /b, /t, /m, /s stereo sublayers | /q charge and /p added/removed-proton sublayers; /p is not a pH model | Canonical by construction; cross-toolkit identity | Standard InChI normalizes mobile-H forms; limited organometallic stereo; large molecules may require special handling |
| SDF V2000 | 2D/3D | Wedge bonds | M CHG line | Industry default; metadata via tags | 999-atom limit; cannot encode multi-component reactions; query atoms ambiguous |
| SDF V3000 | 2D/3D | Wedge + stereo flag | Inline charge | No atom limit; query support; rich properties | Some software (legacy) cannot read; verbose |
| MOL2 (Tripos) | 3D | Common records rely on 3D coordinates and toolkit perception; no portable explicit stereo field | Per-atom partial | SYBYL atom types preserved for docking | Atom-type dialects diverge (SYBYL vs Corina); RDKit MOL2 parser brittle |
| PDB | 3D | None | None standard | Universal protein format | No bond orders; aromatic perception lost; ligand names truncated to 3 chars |
| PDBQT | 3D | None | Gasteiger / AD4 | AutoDock-ready; torsion tree encoded | Specific to docking; no aromaticity layer |
| BinaryCIF (MMTF retired) | 3D | Encoded | Encoded | BinaryCIF (.bcif) is the current compact structural format; RCSB stopped serving MMTF files on July 2, 2024 and recommends BinaryCIF (RCSB PDB 2024) | Not all toolkits parse; binary format |
| CDX/CDXML | 2D | Drawing | Drawing | ChemDraw native | Not a structural format; converts unreliably |
| InChIKey | Hash | Stereo layer | n/a | Database key, fast lookup | Collision probability depends on key block and collection size; cannot recover structure |
Aromaticity Perception (most common silent error)
Different toolkits perceive aromaticity differently. The same SMILES round-tripped between toolkits may produce different canonical strings and different fingerprints.
| Model | Toolkit | Rule | Symptom of mismatch |
|---|
| Daylight | OpenEye, Daylight | 4n+2 π on planar ring | Furan, thiophene aromatic |
| RDKit default | RDKit | Daylight-like with extensions for fused / N-containing | Compatible with Daylight for drug-like molecules |
| MDL | Available in several toolkits, including RDKit as AROMATICITY_MDL | Five-membered rings are not aromatic unless part of a fused aromatic system; only C/N and one-electron donors qualify; exocyclic double bonds exclude an atom | Five-membered heteroaromatics and exocyclic-bond systems may differ from the default RDKit model |
| OpenEye | OEAroModel | Several modes | Charged thiophene non-aromatic in MDL but aromatic in OpenEye |
Fix: Always re-canonicalize via the toolkit doing analysis. If aromaticity must be reassigned explicitly in RDKit, use a concrete model, for example Chem.SetAromaticity(mol, Chem.AromaticityModel.AROMATICITY_RDKIT), after the molecule is in an appropriate sanitized or kekulized state.
Stereochemistry Layers
Stereo loss is the second most common silent error. Each format encodes stereo differently:
- SMILES:
@/@@ for tetrahedral, / and \ for cis/trans double bonds
- InChI:
/b for double-bond stereo, /t for tetrahedral stereo, and /m plus /s for inversion/overall stereo type
- SDF: wedge/hash bond + parity 0/1/2; cis/trans encoded via bond direction
- MOL2: common Tripos records provide 3D coordinates but no portable wedge or explicit stereo field; verify toolkit perception by round trip
Round-trip tests: If Chem.MolToSmiles(Chem.MolFromSmiles(smi), isomericSmiles=True) does not preserve the represented stereochemistry, inspect whether the source contained stereo markers and whether any step called Chem.RemoveStereochemistry() or discarded stereochemical coordinates/bond directions. Sanitization alone does not intentionally remove valid stereochemistry. If MolFromMolFile returns a molecule missing wedge bonds, inspect the source's coordinates, bond directions, and parity encoding.
Reading SMILES with Stereo Preservation
Goal: Parse SMILES while preserving stereo and aromatic-flag consistency.
Approach: Use Chem.MolFromSmiles(smi) with sanitization on, verify with round-trip canonicalization, and set explicit stereochemistry where the toolkit's perception missed it.
from rdkit import Chem
from rdkit.Chem import AllChem
def parse_smiles_safe(smi):
mol = Chem.MolFromSmiles(smi)
if mol is None:
return None, 'parse_failure'
Chem.AssignStereochemistry(mol, cleanIt=True, force=True)
canon = Chem.MolToSmiles(mol)
round_trip = Chem.MolFromSmiles(canon)
if Chem.MolToSmiles(round_trip) != canon:
return mol, 'round_trip_unstable'
return mol, 'ok'
Reading SDF with Property Carryover
Goal: Load a multi-record SDF preserving per-molecule properties (Name, ID, IC50, etc.) used by downstream filtering and ML labeling.
Approach: Iterate via SDMolSupplier(removeHs=False, sanitize=True), filter None (parse failures), and capture properties via mol.GetPropsAsDict().
from rdkit import Chem
supplier = Chem.SDMolSupplier('library.sdf', removeHs=False, sanitize=True)
mols = []
fails = []
for i, mol in enumerate(supplier):
if mol is None:
fails.append(i)
continue
props = mol.GetPropsAsDict()
mols.append((mol, props))
print(f'parsed: {len(mols)}; failed: {len(fails)}')
If a large fraction fails, try sanitize=False then Chem.SanitizeMol(mol, catchErrors=True) to identify per-step failures (kekulization, valence, aromaticity).
Open Babel for MOL2 / PDBQT
RDKit's MOL2 parser is incomplete (SYBYL atom-type sets differ). Open Babel is more robust for MOL2 and PDBQT.
from openbabel import pybel
mols = list(pybel.readfile('mol2', 'ligands.mol2'))
for mol in mols:
smi = mol.write('smi').strip().split()[0]
inchi = mol.write('inchi').strip()
For docking output PDBQT, use Open Babel rather than RDKit:
import subprocess
subprocess.run(['obabel', 'docked.pdbqt', '-O', 'docked.sdf'], check=True)
InChI for Canonical Identity
InChI is a standardized, canonical structure identifier designed for cross-database and cross-toolkit interoperability (Heller et al. 2015; O'Boyle 2012). Standard InChI normalizes many mobile-hydrogen tautomers and has limitations for some metal stereochemistry; non-standard options such as /FixedH can distinguish additional representations. InChIKey is a fixed-length hash, so use full InChI or standardized structures when a suspected collision must be resolved (InChI Trust technical FAQ).
from rdkit.Chem.inchi import MolToInchi, MolToInchiKey, InchiToInchiKey
mol = Chem.MolFromSmiles('c1ccc2c(c1)cccc2')
inchi = MolToInchi(mol)
key = MolToInchiKey(mol)
inchi_fixedH, aux_info = Chem.MolToInchiAndAuxInfo(mol, options='/FixedH')
Caveat: Two molecules with identical std InChI may be different tautomers. Use /FixedH for tautomer-distinguishing InChI when needed.
Per-Format Failure Modes
SMILES -- ambiguous aromaticity
Trigger: Input from non-RDKit source (ChemAxon, OpenEye, Daylight) round-tripping into RDKit.
Mechanism: RDKit perceives aromaticity on input. Aromatic flags from origin toolkit are overwritten.
Symptom: Fingerprints differ between toolkits for "identical" molecules; database joins by canonical SMILES miss records.
Fix: Always re-canonicalize within the analysis toolkit. For cross-toolkit identity, use InChIKey not canonical SMILES.
SDF V2000 -- atom count >999
Trigger: Large molecules (peptides, oligonucleotides, dendrimers).
Mechanism: V2000 header uses fixed 3-character atom count field.
Symptom: Truncated atom block; parse failure with cryptic error.
Fix: Switch to V3000. RDKit auto-detects V3000 on read; explicitly request it on the writer:
writer = Chem.SDWriter('out.sdf')
writer.SetForceV3000(True)
writer.write(mol)
writer.close()
SDF -- wedge bond orientation lost
Trigger: SDF written by tools that use parity flags only (older ISIS-Draw, some pipeline tools).
Mechanism: Parity alone is ambiguous without geometric coordinates; RDKit reads parity but cannot re-render wedges.
Symptom: Drawn molecule shows undefined stereo despite SDF carrying parity bits.
Fix: After read, Chem.AssignStereochemistryFrom3D(mol) if 3D coords present; otherwise stereo must be re-derived from SMILES with wedges.
PDB ligand -- no bond orders
Trigger: Parsing ligand from PDB entry (e.g., extracting co-crystal ligand).
Mechanism: PDB stores only atoms + CONECT; bond orders inferred by RDKit's AssignBondOrdersFromTemplate which requires a template molecule.
Symptom: All bonds single; aromatic rings non-aromatic; valences wrong.
Fix: Use AllChem.AssignBondOrdersFromTemplate(template, ligand) where template is a SMILES-derived mol of the expected ligand structure. Or use the PDB Ligand Expo SDF.
MOL2 -- SYBYL atom type dialect
Trigger: MOL2 produced by Corina, MOE, or Schrodinger.
Mechanism: SYBYL atom types are not perfectly standardized across vendors; RDKit's parser handles canonical SYBYL.
Symptom: Mol returns as None or with wrong atom types (Cl vs Cl.O peroxide-style).
Fix: Convert via Open Babel as intermediate: obabel input.mol2 -O temp.sdf then read SDF.
Open Babel pybel -- import path
Trigger: Code written for Open Babel 2.x.
Mechanism: OB 3.x reorganized: import pybel no longer works.
Symptom: ModuleNotFoundError: No module named 'pybel'.
Fix: from openbabel import pybel.
Charge Models on I/O
| Source | Charges in file | Use for |
|---|
| Parsed SMILES | Atom-local formal charges; no partial-charge model | Storage, similarity, ML training |
| Parsed PDB | Atomic charges typically absent | Always re-assign for downstream |
obabel --partialcharge gasteiger | Gasteiger-Marsili partial charges (empirical) | Workflows that explicitly require Gasteiger charges; Vina/Vinardo scoring itself does not require assigned atom charges |
| AM1-BCC (AmberTools antechamber) | Semi-empirical | MD, FEP setup |
| RESP (psi4, Gaussian) | Restrained fit to a quantum-mechanical ESP; protocol-specific | Force-field workflows parameterized for that RESP protocol |
The charge model must match the downstream method. Mixing AM1-BCC ligand charges with TIP3P water + AMBER protein is valid; Gasteiger charges are unsuitable for MD.
Drawing for QC
Always draw a random subset of parsed molecules. Wrong stereo, missing rings, and broken aromaticity show immediately.
from rdkit.Chem.Draw import rdMolDraw2D
def draw_grid(mols, fname, mols_per_row=5, sub_img_size=(250, 200)):
from rdkit.Chem.Draw import MolsToGridImage
img = MolsToGridImage(mols[:25], molsPerRow=mols_per_row, subImgSize=sub_img_size,
legends=[m.GetProp('_Name') if m.HasProp('_Name') else ''
for m in mols[:25]])
img.save(fname)
MolsToGridImage returns PIL image; for headless servers use MolDraw2DCairo directly.
Common Errors
| Symptom | Cause | Fix |
|---|
Chem.MolFromSmiles returns None | Invalid SMILES, bad parentheses, ring not closed | Try sanitize=False, inspect with Chem.MolFromSmiles(smi, sanitize=False) |
| Round-trip SMILES changes | Aromaticity perception drift | Always canonicalize within analysis toolkit |
| All bonds single in PDB ligand | PDB has no bond orders | AllChem.AssignBondOrdersFromTemplate(template, mol) |
| Stereo lost on SDF write | Stereo was absent, removed, or not represented by coordinates/bond directions | Verify assigned chiral tags and bond stereo before writing; preserve suitable 2D/3D coordinates and inspect the round trip |
| MOL2 parse returns None | RDKit MOL2 parser incomplete for vendor dialects | Convert via Open Babel intermediate |
| InChI differs for "same" molecule | Different tautomers, charges, or stereo | Use /FixedH to retain tautomer; compare without standardization |
| Fingerprints differ across toolkits | Aromaticity model difference | Use InChIKey for identity; re-canonicalize for similarity |
References
Related Skills
- chemoinformatics/molecular-standardization - Salt stripping, tautomer canonicalization, neutralization
- chemoinformatics/molecular-descriptors - Calculate fingerprints and properties from parsed molecules
- chemoinformatics/conformer-generation - Generate 3D coordinates from 2D inputs
- chemoinformatics/virtual-screening - Prepare ligands for docking
- structural-biology/structure-io - Protein structure handling (PDB, mmCIF)