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I want to preface this by saying I am really new to computational chemistry and this kind of programming in general, but I am having real trouble figuring out how to use OpenBabel's gen3d function in a Python notebook. I want to use it to make a single force field optimized conformer from a SMILES string but I don't really know how to call it on my SMILES string. Any help or links would be greatly appreciated! Thank you!

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    $\begingroup$ +1 and welcome to our new community! Thank you for contributing your question here and we hope to see much more of you in the future!! Please make note of the edits that I just made on your question so that others don't have to spend time making similar edits in the future. $\endgroup$ Mar 19, 2023 at 18:55

3 Answers 3

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Here is a simple python recipe in addition to the CLI approach mentioned in the other answer, for more details see the docs:

from openbabel import pybel as pb # pybel is syntax sugar for openbabel

smiles = '[O-]C(=O)[C@H]([NH3+])Cc1ccc(O)cc1' # your smiles
mol = pb.readstring('smiles', smiles) # first argument is a string format

mol.addh() # add Hs for 3D
mol.make3D() # generate 3D coordinates

However, my experience shows that open babel is not very reliable for 3D generation. I recommend looking through the RDKit library, which is in my opinion more powerful and handy tool if you need to work with molecules:

from rdkit import Chem # main tools
from rdkit.Chem import AllChem # additional tools, including 3D

smiles = '[O-]C(=O)[C@H]([NH3+])Cc1ccc(O)cc1' # your smiles
mol = Chem.MolFromSmiles(smiles) # initialize molecule

mol = Chem.AddHs(mol) # adding explicit Hs for 3D generation
cid = AllChem.EmbedMolecule(mol) # returns the id of the generated conformer,
                                 # and -1 if no conformers were generated

AllChem.MMFFOptimizeMolecule(mol) # optimize molecule with MMFF94
Chem.MolToMolFile(mol, 'some_amino_acid.mol') # save to MOL-file

For multiple conformers use AllChem.EmbedMultipleConformers and AllChem.MMFFOptimizeMoleculeConfs, for more details see the docs, they are written really nicely in contrast to OpenBabel.

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    $\begingroup$ Strangely, my anecdotal experience is that openbabel works for multi-ring (fused rings) better and rdkit often fails to even generate 3D geometry. $\endgroup$
    – S R Maiti
    Mar 20, 2023 at 20:41
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    $\begingroup$ @SRMaiti If your molecule contains several C6 cycles (even non-condensed), when there are 95% probability that at least one ring will be in twist conformation :-) Though for more complex systems (especially extremely sterically hindered ones) RDKit gives some conformation, and OB fails. To the best of my knowledge, the reason is the difference in a 3D generation engine: RDKit uses distance geometry, and OB constructs molecule from fragments $\endgroup$ Mar 21, 2023 at 11:44
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From the openbabel documentation :

Open Babel will not generate coordinates unless asked, so while a conversion from SMILES to SDF will generate a valid SDF file, the resulting file will not contain coordinates. To generate coordinates, use either the --gen3d or the --gen2d option.

The command line option --conformer allows performing conformer searches using a range of different algorithms and options.

To generate 3D coordinates and conformer searching you can do the following:

In a text editor add the SMILES, one per line, and save the file with .smi extension.

For example add the following in a .smi file:

CC
CCN
CO

After that you can use the --gen3d and --conformer as follows:

obabel infile.smi -O outfile.sdf --gen3d --conformer --nconf 20 --weighted

nconf is the number of conformers.

The output file will look like this:

OpenBabel03192322333D

  8  7  0  0  0  0  0  0  0  0999 V2000
    0.9292   -0.0246   -0.0664 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.4251   -1.1907    0.7537 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.5744    0.9217    0.3526 H   0  0  0  0  0  0  0  0  0  0  0  0
    0.5744   -0.0990   -1.0987 H   0  0  0  0  0  0  0  0  0  0  0  0
    2.0230   -0.0076   -0.0784 H   0  0  0  0  0  0  0  0  0  0  0  0
    0.7799   -1.1164    1.7859 H   0  0  0  0  0  0  0  0  0  0  0  0
   -0.6687   -1.2078    0.7657 H   0  0  0  0  0  0  0  0  0  0  0  0
    0.7799   -2.1371    0.3346 H   0  0  0  0  0  0  0  0  0  0  0  0
  1  2  1  0  0  0  0
  1  3  1  0  0  0  0
  1  4  1  0  0  0  0
  1  5  1  0  0  0  0
  2  6  1  0  0  0  0
  2  7  1  0  0  0  0
  2  8  1  0  0  0  0
M  END
$$$$

 OpenBabel03192322333D

 10  9  0  0  0  0  0  0  0  0999 V2000
    1.0339    0.0918    0.0081 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.5341    0.6110   -1.3285 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.0092   -0.2403   -2.4112 N   0  0  0  0  0  0  0  0  0  0  0  0
    0.6799   -0.9278    0.1942 H   0  0  0  0  0  0  0  0  0  0  0  0
    0.6696    0.7287    0.8207 H   0  0  0  0  0  0  0  0  0  0  0  0
    2.1284    0.0873    0.0482 H   0  0  0  0  0  0  0  0  0  0  0  0
   -0.5606    0.6263   -1.3329 H   0  0  0  0  0  0  0  0  0  0  0  0
    0.8849    1.6362   -1.4846 H   0  0  0  0  0  0  0  0  0  0  0  0
    0.7017    0.1435   -3.3037 H   0  0  0  0  0  0  0  0  0  0  0  0
    2.0281   -0.2323   -2.4323 H   0  0  0  0  0  0  0  0  0  0  0  0
  1  2  1  0  0  0  0
  1  4  1  0  0  0  0
  1  5  1  0  0  0  0
  1  6  1  0  0  0  0
  2  3  1  0  0  0  0
  2  7  1  0  0  0  0
  2  8  1  0  0  0  0
  3  9  1  0  0  0  0
  3 10  1  0  0  0  0
M  END
$$$$

 OpenBabel03192322333D

  6  5  0  0  0  0  0  0  0  0999 V2000
    1.0511    0.0027    0.0995 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.5766    0.8295    1.1462 O   0  0  0  0  0  0  0  0  0  0  0  0
    0.6845    0.3908   -0.8536 H   0  0  0  0  0  0  0  0  0  0  0  0
    0.6815   -1.0157    0.2421 H   0  0  0  0  0  0  0  0  0  0  0  0
    2.1439    0.0081    0.0964 H   0  0  0  0  0  0  0  0  0  0  0  0
    0.9177    0.4607    1.9788 H   0  0  0  0  0  0  0  0  0  0  0  0
  1  2  1  0  0  0  0
  1  3  1  0  0  0  0
  1  4  1  0  0  0  0
  1  5  1  0  0  0  0
  2  6  1  0  0  0  0
M  END
$$$$
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The command-line --gen3d option can do a variety of things, including coordinate generation, some force field cleanup, and a quick conformer search.

As mentioned in another answer, Pybel has make3D() which generates coordinates followed by a quick cleanup using MMFF94 or UFF (if MMFF94 doesn't work).

On the other hand, the other answer suggests (correctly) to perform a conformer search, but not how to do that in Python...

from openbabel import pybel as pb # pybel is syntax sugar for openbabel
from openbabel import openbabel as ob

smiles = '[O-]C(=O)[C@H]([NH3+])Cc1ccc(O)cc1' # your smiles
mol = pb.readstring('smiles', smiles) # first argument is a string format

mol.make3D() # generate 3D coordinates - handles adding H atoms
# also handles a quick forcefield cleanup

# now perform conformer searching
ff = pb._forcefields["mmff94"]
success = ff.Setup(mol.OBMol)
if not success:
    ff = pb._forcefields["uff"]
    success = ff.Setup(mol.OBMol)
    if not success:
        sys.exit("Cannot set up forcefield")

# feel free to tweak these to your balance of time / quality
ff.ConjugateGradients(100, 1.0e-3)
ff.FastRotorSearch(true) # permute central bonds
ff.WeightedRotorSearch(100, 25) # 100 cycles, each with 25 forcefield ops
# final optimization
ff.ConjugateGradients(250, 1.0e-4)
# update the coordinates
ff.GetCoordinates(mol.OBMol)

# or pick your favorite format or filename
mol.write("sdf", "optimized.sdf", overwrite=True)
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