Cookbook: Every way to make a Molecule

Every pathway through the OpenFF Toolkit boils down to four steps:

1. Using other tools, assemble a graph of a molecule, including all of its atoms, bonds, bond orders, formal charges, and stereochemistry1

2. Use that information to construct a Molecule

3. Combine a number of Molecule objects to construct a Topology

4. Call ForceField.create_openmm_system(topology) to create an OpenMM System (or, in the near future, an OpenFF Interchange for painless conversion to all sorts of MD formats)

So let’s take a look at every way there is to construct a molecule! We’ll use zwitterionic L-alanine as an example biomolecule with all the tricky bits - a stereocenter, non-zero formal charges, and bonds of different orders.

From SMILES

SMILES is the classic way to create a Molecule. SMILES is a widely-used compact textual representation of arbitrary molecules. This lets us specify an exact molecule, including stereochemistry and bond orders, very easily — though they may not be the most human-readable format.

The Molecule.from_smiles() method is used to create a Molecule from a SMILES code.

Implicit hydrogens SMILES

zw_l_alanine = Molecule.from_smiles("C[C@H]([NH3+])C(=O)[O-]")

zw_l_alanine.visualize()


Explicit hydrogens SMILES

smiles_explicit_h = Molecule.from_smiles(
"[H][C]([H])([H])[C@@]([H])([C](=[O])[O-])[N+]([H])([H])[H]",
hydrogens_are_explicit=True
)

assert zw_l_alanine.is_isomorphic_with(smiles_explicit_h)

smiles_explicit_h.visualize()


Mapped SMILES

By default, no guarantees are made about the indexing of atoms from a SMILES string. If the indexing is important, a mapped SMILES string may be used. In this case, Hydrogens must be explicit. Note that though mapped SMILES strings must start at index 1, Python lists start at index 0.

mapped_smiles = Molecule.from_mapped_smiles(
"[H:10][C:2]([H:7])([H:8])[C@@:4]([H:9])([C:3](=[O:5])[O-:6])[N+:1]([H:11])([H:12])[H:13]"
)

assert zw_l_alanine.is_isomorphic_with(mapped_smiles)

assert mapped_smiles.atoms[0].atomic_number == 7 # First index is the Nitrogen
assert all([a.atomic_number==1 for a in mapped_smiles.atoms[6:]]) # Final indices are all H

mapped_smiles.visualize()


SMILES without stereochemistry

The Toolkit won’t accept an ambiguous SMILES. This SMILES could be L- or D- alanine; rather than guess, the Toolkit throws an error:

smiles_non_isomeric = Molecule.from_smiles(
"CC([NH3+])C(=O)[O-]"
)

UndefinedStereochemistryError: Unable to make OFFMol from RDMol: Unable to make OFFMol from SMILES: RDMol has unspecified stereochemistry. Undefined chiral centers are:
- Atom C (index 1)


We can downgrade this error to a warning with the allow_undefined_stereo argument. This will not apply an improper dihedral term to the stereocenter and may lead to simulations with unphysical stereoisomerisation.

smiles_non_isomeric = Molecule.from_smiles(
"CC([NH3+])C(=O)[O-]",
allow_undefined_stereo=True
)

assert not zw_l_alanine.is_isomorphic_with(smiles_non_isomeric)

smiles_non_isomeric.visualize()


By hand

You can always construct a Molecule by building it up from individual atoms and bonds. Other methods are generally easier, but it’s a useful fallback for when you need to write your own constructor for an unsupported source format.

The Molecule() constructor and the add_atom() and add_bond() methods are used to construct a Molecule by hand.

by_hand = Molecule()
by_hand.name = "Zwitterionic l-Alanine"

atomic_number = 8, # Atomic number 8 is Oxygen
formal_charge = -1, # Formal negative charge
is_aromatic = False, # Atom is not part of an aromatic system
stereochemistry = None, # Optional argument; "R" or "S" stereochemistry
name = "O-" # Optional argument; descriptive name for the atom
)

atom1 = 0, # First (zero-indexed) atom specified above ("O-")
atom2 = 1, # Second atom specified above ("C")
bond_order = 1, # Single bond
is_aromatic = False, # Bond is not aromatic
stereochemistry = None, # Optional argument; "E" or "Z" stereochemistry
fractional_bond_order = None # Optional argument; Wiberg (or similar) bond order
)
by_hand.add_bond( 1,  2, 2, False) # C = O
by_hand.add_bond( 1,  3, 1, False) # C - CA
by_hand.add_bond( 3,  4, 1, False) # CA - CAH
by_hand.add_bond( 3,  5, 1, False) # CA - CB
by_hand.add_bond( 5,  6, 1, False) # CB - HB1
by_hand.add_bond( 5,  7, 1, False) # CB - HB2
by_hand.add_bond( 5,  8, 1, False) # CB - HB3
by_hand.add_bond( 3,  9, 1, False) # CB - N+
by_hand.add_bond( 9, 10, 1, False) # N+ - HN1
by_hand.add_bond( 9, 11, 1, False) # N+ - HN2
by_hand.add_bond( 9, 12, 1, False) # N+ - HN3

assert zw_l_alanine.is_isomorphic_with(by_hand)

by_hand.visualize()


From a dictionary

Rather than build up the Molecule one method at a time, the Molecule.from_dict() method can construct a Molecule in one shot from a Python dict that describes the molecule in question. This allows Molecule objects to be written to and read from disk in any format that can be interpreted as a dict; this mechanism underlies the from_bson(), from_json(), from_messagepack(), from_pickle(), from_toml(), from_xml(), and from_yaml() methods.

This format can get very verbose, as it is intended for serialization, so this example uses hydrogen cyanide rather than alanine.

molecule_dict = {
"name": "",
"atoms": [
{
"atomic_number": 1,
"formal_charge": 0,
"is_aromatic": False,
"stereochemistry": None,
"name": "H",
},
{
"atomic_number": 6,
"formal_charge": 0,
"is_aromatic": False,
"stereochemistry": None,
"name": "C",
},
{
"atomic_number": 7,
"formal_charge": 0,
"is_aromatic": False,
"stereochemistry": None,
"name": "N",
},
],
"virtual_sites": [],
"bonds": [
{
"atom1": 0,
"atom2": 1,
"bond_order": 1,
"is_aromatic": False,
"stereochemistry": None,
"fractional_bond_order": None,
},
{
"atom1": 1,
"atom2": 2,
"bond_order": 3,
"is_aromatic": False,
"stereochemistry": None,
"fractional_bond_order": None,
},
],
"properties": {},
"conformers": None,
"partial_charges": None,
"partial_charges_unit": None,
}

from_dictionary = Molecule.from_dict(molecule_dict)

from_dictionary.visualize()


From a file

We can construct a Molecule from a file or file-like object with the from_file() method. We’re a bit constrained in what file formats we can accept, because they need to provide all the information needed to construct the molecular graph; not just coordinates, but also elements, formal charges, bond orders, and stereochemistry.

From SDF file

We generally recommend the SDF format. The SDF file used here can be found on GitHub

sdf_path = Molecule.from_file("zw_l_alanine.sdf")
assert zw_l_alanine.is_isomorphic_with(sdf_path)
sdf_path.visualize()


From SDF file object

from_file() can also take a file object, rather than a path. Note that the object must be in binary mode!

with open("zw_l_alanine.sdf", mode="rb") as file:
sdf_object = Molecule.from_file(file, file_format="SDF")

assert zw_l_alanine.is_isomorphic_with(sdf_object)
sdf_object.visualize()


From PDB file

Using PDB files is not recommended, even if they have CONECT records, as they do not provide stereoisomeric information or bond orders. The RDKit backend assumes that bond orders are 1, so the toolkit refuses to use it:

from openff.toolkit.utils.toolkits import RDKitToolkitWrapper

pdb = Molecule.from_file("zw_l_alanine.pdb", "pdb", toolkit_registry=RDKitToolkitWrapper())

NotImplementedError: Toolkit The RDKit can not read file zw_l_alanine.pdb (format PDB). Supported formats for this toolkit are ['SDF', 'MOL', 'SMI'].RDKit can however read PDBs with a valid smiles string using the Molecule.from_pdb_and_smiles(file_path, smiles) constructor


OpenEye can infer bond orders and stereochemistry from the structure. This is not recommended, as it can make mistakes that may be difficult to catch. Note also that this requires a license for OpenEye, as this is proprietary software.

If we instead provide a SMILES code, a PDB file can be used to populate the Molecule object’s conformers attribute and provide atom ordering, as well as check that the SMILES code matches the PDB file. This method is the recommended way to create a Molecule from a PDB file. The PDB file used here can be found on GitHub

Important

Note that the Toolkit doesn’t guarantee that the coordinates in the PDB are correctly assigned to atoms. It makes an effort, but you should check that the results are reasonable.

pdb_with_smiles = Molecule.from_pdb_and_smiles(
"zw_l_alanine.pdb",
"C[C@H]([NH3+])C(=O)[O-]"
)

assert zw_l_alanine.is_isomorphic_with(pdb_with_smiles)

pdb_with_smiles.visualize()


Other string identification formats

The OpenFF Toolkit supports a few text based molecular identity formats other than SMILES (see above)

From InChI

The Molecule.from_inchi() method constructs a Molecule from an IUPAC InChI string. Note that InChI cannot distinguish the zwitterionic form of alanine from the neutral form (see section 13.2 of the InChI Technical FAQ), so the toolkit defaults to the neutral form.

Warning

The OpenFF Toolkit makes no guarantees about the atomic ordering produced by the from_inchi method. InChI is not intended to be an interchange format.

inchi = Molecule.from_inchi("InChI=1S/C3H7NO2/c1-2(4)3(5)6/h2H,4H2,1H3,(H,5,6)/t2-/m0/s1")

inchi.visualize()


From IUPAC name

The Molecule.from_iupac() method constructs a Molecule from an IUPAC name.

Important

This code requires the OpenEye toolkit.

iupac = Molecule.from_iupac("(2S)-2-azaniumylpropanoate")

assert zw_l_alanine.is_isomorphic_with(iupac)

iupac.visualize()

ValueError: No registered toolkits can provide the capability "from_iupac" for args "('(2S)-2-azaniumylpropanoate',)" and kwargs "{'allow_undefined_stereo': False, '_cls': <class 'openff.toolkit.topology.molecule.Molecule'>}"
Available toolkits are: [ToolkitWrapper around The RDKit version 2021.09.2, ToolkitWrapper around AmberTools version 21.0, ToolkitWrapper around Built-in Toolkit version None]


Remapping an existing Molecule

Most Molecule creation methods don’t specify the ordering of atoms in the new Molecule. The Molecule.remap() method allows a new ordering to be applied to an existing Molecule.

Warning

The Molecule.remap() method is experimental and subject to change.

# Note that this mapping is off-by-one from the mapping taken
# by the remap method, as Python indexing is 0-based but SMILES
# is 1-based
print("Before remapping:", zw_l_alanine.to_smiles(mapped=True))

# Flip the positions of the oxygen atoms
remapped = zw_l_alanine.remap({0: 0, 1: 1, 2: 2, 3: 3, 4: 4, 5: 6, 6: 5, 7: 7, 8: 8, 9: 9, 10: 10, 11: 11, 12: 12})

print("After remapping: ", remapped.to_smiles(mapped=True))

# Doesn't affect the identity of the molecule
assert zw_l_alanine.is_isomorphic_with(remapped)
remapped.visualize()

Before remapping: [C:1]([C@:2]([N+:3]([H:11])([H:12])[H:13])([C:4](=[O:5])[O-:6])[H:10])([H:7])([H:8])[H:9]
After remapping:  [C:1]([C@:2]([N+:3]([H:11])([H:12])[H:13])([C:4](=[O:5])[O-:7])[H:10])([H:6])([H:8])[H:9]


Via Topology objects

The Topology class represents a biomolecular system; it is analogous to the similarly named objects in GROMACS, MDTraj or OpenMM. Notably, it does not include co-ordinates and may represent multiple copies of a particular molecular species or even more complex mixtures of molecules. Topology objects are usually built up one species at a time from Molecule objects.

The Molecule.from_topology() method constructs a Molecule from a Topology. This is usually going backwards, but the method does allow construction of Molecule objects from a few sources that represent molecular mixtures, like the aforementioned Topology or System.

Constructor methods that are available for Topology but not Molecule generally require a Molecule to be provided via the unique_molecules keyword argument. The provided Molecule is used to provide the identity of the molecule, including aromaticity, bond orders, formal charges, and so forth. These methods therefore don’t provide a route to the graph of the molecule, but can be useful for reordering atoms to match another software package.

From an OpenMM Topology

The Topology.from_openmm() method constructs an OpenFF Topology from an OpenMM Topology. The method requires that all the unique molecules in the Topology are provided as OpenFF Molecule objects, as the structure of an OpenMM Topology doesn’t include the concept of a molecule. When using this method to create a Molecule, this limitation means that the method really only offers a pathway to reorder the atoms of a Molecule to match that of the OpenMM Topology.

from simtk.openmm.app.pdbfile import PDBFile

openmm_topology = PDBFile('zw_l_alanine.pdb').getTopology()
openff_topology = Topology.from_openmm(openmm_topology, unique_molecules=[zw_l_alanine])

from_openmm_topology = Molecule.from_topology(openff_topology)

print(zw_l_alanine.to_smiles(mapped=True))
print(from_openmm_topology.to_smiles(mapped=True))

from_openmm_topology.visualize()

Warning: importing 'simtk.openmm' is deprecated.  Import 'openmm' instead.

ModuleNotFoundError: No module named 'simtk.openmm.app.pdbfile'


From an MDTraj Topology

The Topology.from_mdtraj() method constructs an OpenFF Topology from an MDTraj Topology. The method requires that all the unique molecules in the Topology are provided as OpenFF Molecule objects to ensure that the graph of the molecule is correct. When using this method to create a Molecule, this limitation means that the method really only offers a pathway to reorder the atoms of a Molecule to match that of the MDTraj Topology.

from mdtraj import load_pdb

openff_topology = Topology.from_openmm(openmm_topology, unique_molecules=[zw_l_alanine])

from_mdtraj_topology = Molecule.from_topology(openff_topology)

print(zw_l_alanine.to_smiles(mapped=True))
print(from_mdtraj_topology.to_smiles(mapped=True))

from_mdtraj_topology.visualize()


From Toolkit objects

The OpenFF Toolkit calls out to other software to perform low-level tasks like reading SMILES or files. These external software packages are called toolkits, and presently include RDKit and the OpenEye Toolkit. OpenFF Molecule objects can be created from the equivalent objects in these toolkits.

From RDKit Mol

The Molecule.from_rdkit() method converts an rdkit.Chem.rdchem.Mol object to an OpenFF Molecule.

from rdkit import Chem
rdmol = Chem.MolFromSmiles("C[C@H]([NH3+])C([O-])=O")

print("rdmol is of type", type(rdmol))

from_rdmol = Molecule.from_rdkit(rdmol)

assert zw_l_alanine.is_isomorphic_with(from_rdmol)
from_rdmol.visualize()


From OpenEye OEMol

The Molecule.from_openeye() method converts an object that inherits from openeye.oechem.OEMolBase to an OpenFF Molecule.

from openeye import oechem

oemol = oechem.OEGraphMol()
oechem.OESmilesToMol(oemol, "C[C@H]([NH3+])C([O-])=O")

assert isinstance(oemol, oechem.OEMolBase)

from_oemol = Molecule.from_openeye(oemol)

assert zw_l_alanine.is_isomorphic_with(from_oemol)
from_oemol.visualize()


From QCArchive

QCArchive is a repository of quantum chemical calculations on small molecules. The Molecule.from_qcschema() method creates a Molecule from a record from the archive. Because the identity of a molecule can change of the course of a QC calculation, the Toolkit accepts records only if they contain a hydrogen-mapped SMILES code.

Note

These examples use molecules other than l-Alanine because of their availability in QCArchive

From a QCArchive molecule record

The Molecule.from_qcschema() method can take a molecule record queried from the QCArchive and create a Molecule from it.

from qcportal import FractalClient

client = FractalClient()
query = client.query_molecules(molecular_formula="C16H20N3O5")

from_qcarchive = Molecule.from_qcschema(query[0])

from_qcarchive.visualize()


From a QCArchive optimisation record

Molecule.from_qcschema() can also take an optimisation record and create the corresponding Molecule.

optimization_dataset = client.get_collection(
"OptimizationDataset",
"SMIRNOFF Coverage Set 1"
)
dimethoxymethanol_optimization = optimization_dataset.get_entry('coc(o)oc-0')

from_optimisation = Molecule.from_qcschema(dimethoxymethanol_optimization)

from_optimisation.visualize()


1

Note that this stereochemistry must be defined on the graph of the molecule. It’s not good enough to just co-ordinates with the correct stereochemistry. But if you have the co-ordinates, you can try getting the stereochemistry automatically with rdkit or openeye — If you dare!