Molecular io

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

• Heller et al., J. Cheminformatics 7:23 (2015) -- InChI design, layout, and algorithms; software version 1.04. https://doi.org/10.1186/s13321-015-0068-4
• O'Boyle, J. Cheminformatics 4:22 (2012) -- Universal SMILES representation based on InChI. https://doi.org/10.1186/1758-2946-4-22
• InChI Trust, "Technical FAQ" -- InChIKey layout and collision estimates. https://www.inchi-trust.org/technical-faq/
• Daylight Chemical Information Systems, SMILES theory -- atom-local formal-charge and stereochemical syntax. https://www.daylight.com/dayhtml/doc/theory/theory.smiles.html
• RDKit Book, "Aromaticity" -- RDKit and MDL aromaticity-model rules. https://www.rdkit.org/docs/RDKit_Book.html#aromaticity
• RCSB PDB (2024), "Removal of MMTF files from RCSB PDB." https://www.rcsb.org/news/6661c73362451e4e35915f7b

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)