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Different behavior with mol and smiles when tautomerizing #5937

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bjonnh-work opened this issue Jan 5, 2023 · 2 comments
Open

Different behavior with mol and smiles when tautomerizing #5937

bjonnh-work opened this issue Jan 5, 2023 · 2 comments
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@bjonnh-work
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Describe the bug

When tautomerizing a molecule directly from a specific molfile or its smiles conversion, the behavior is different. And this behavior is extremely dependent on the structure.

To Reproduce

ketched="""
          04090817072D 1   1.00000     0.00000     0

 32 36  0     0  0            999 V2000
    2.9414   -0.4414    0.0000 N   0  0  0  0  0  0           0  0  0
    3.9655   -0.4414    0.0000 C   0  0  0  0  0  0           0  0  0
    2.4310   -1.3207    0.0000 C   0  0  0  0  0  0           0  0  0
    2.2586    0.3172    0.0000 C   0  0  0  0  0  0           0  0  0
    4.4759   -1.3207    0.0000 C   0  0  0  0  0  0           0  0  0
    4.4759    0.4448    0.0000 C   0  0  0  0  0  0           0  0  0
    1.4310   -1.1069    0.0000 N   0  0  0  0  0  0           0  0  0
    2.9414   -2.2103    0.0000 C   0  0  0  0  0  0           0  0  0
    1.3207   -0.0931    0.0000 N   0  0  0  0  0  0           0  0  0
    2.4690    1.3172    0.0000 O   0  0  0  0  0  0           0  0  0
    3.9655   -2.2103    0.0000 C   0  0  0  0  0  0           0  0  0
    5.5000   -1.3207    0.0000 C   0  0  0  0  0  0           0  0  0
    5.5000    0.4448    0.0000 C   0  0  0  0  0  0           0  0  0
    2.4310   -3.0966    0.0000 C   0  0  0  0  0  0           0  0  0
    0.4345    0.4172    0.0000 C   0  0  0  0  0  0           0  0  0
    6.0138   -0.4414    0.0000 C   0  0  0  0  0  0           0  0  0
    6.0138    1.3310    0.0000 C   0  0  0  0  0  0           0  0  0
   -0.4517   -0.0931    0.0000 C   0  0  0  0  0  0           0  0  0
   -1.3379    0.4172    0.0000 N   0  0  0  0  0  0           0  0  0
   -2.2276   -0.0931    0.0000 C   0  0  0  0  0  0           0  0  0
   -3.1138    0.4172    0.0000 C   0  0  0  0  0  0           0  0  0
   -2.2276   -1.1138    0.0000 O   0  0  0  0  0  0           0  0  0
   -4.0448   -0.0034    0.0000 C   0  0  0  0  0  0           0  0  0
   -3.2138    1.4345    0.0000 N   0  0  0  0  0  0           0  0  0
   -4.7276    0.7621    0.0000 C   0  0  0  0  0  0           0  0  0
   -4.2552   -0.9966    0.0000 C   0  0  0  0  0  0           0  0  0
   -4.2172    1.6483    0.0000 C   0  0  0  0  0  0           0  0  0
   -5.7517    0.7621    0.0000 C   0  0  0  0  0  0           0  0  0
   -4.7276    2.5345    0.0000 C   0  0  0  0  0  0           0  0  0
   -6.2621    1.6483    0.0000 C   0  0  0  0  0  0           0  0  0
   -6.2621   -0.1276    0.0000 O   0  0  0  0  0  0           0  0  0
   -5.7517    2.5345    0.0000 C   0  0  0  0  0  0           0  0  0
  1  2  1  0     0  0
  1  3  1  0     0  0
  1  4  1  0     0  0
  2  5  1  0     0  0
  2  6  2  0     0  0
  3  7  2  0     0  0
  3  8  1  0     0  0
  4  9  1  0     0  0
  4 10  2  0     0  0
  5 11  1  0     0  0
  5 12  2  0     0  0
  6 13  1  0     0  0
  8 14  1  0     0  0
  9 15  1  0     0  0
 12 16  1  0     0  0
 13 17  1  0     0  0
 15 18  1  0     0  0
 18 19  1  0     0  0
 19 20  1  0     0  0
 20 21  1  0     0  0
 20 22  2  0     0  0
 21 23  2  0     0  0
 21 24  1  0     0  0
 23 25  1  0     0  0
 23 26  1  0     0  0
 24 27  1  0     0  0
 25 28  1  0     0  0
 27 29  1  0     0  0
 28 30  1  0     0  0
 28 31  2  0     0  0
 29 32  1  0     0  0
  7  9  1  0     0  0
  8 11  2  0     0  0
 13 16  2  0     0  0
 25 27  2  0     0  0
 30 32  1  0     0  0
M  END
"""

def my_preprocess_normalizations(mol: Chem.Mol) -> Chem.Mol:
    return rdMolStandardize.TautomerEnumerator().Canonicalize(mol)

m1=my_preprocess_normalizations(Chem.MolFromMolBlock(ketched))
m2=my_preprocess_normalizations(Chem.MolFromSmiles(Chem.MolToSmiles(Chem.MolFromMolBlock(ketched))))

Interestingly deleting bonds or changing N or O far from the tautomerization site totally stops the issue.

@gedeck managed to find a smaller version that still reproduce the issue:

ketched="""
  MJ221900                      

 15 16  0  0  0  0  0  0  0  0999 V2000
   -0.2638    0.1514    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.9777    0.5625    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   -1.6945    0.1514    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.4084    0.5625    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.6945   -0.6708    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   -3.1584    0.2236    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.4889    1.3820    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   -3.7084    0.8403    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -3.3279   -0.5764    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -3.2973    1.5542    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -4.5334    0.8403    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -3.7084    2.2681    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -4.9446    1.5542    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -4.9446    0.1236    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   -4.5334    2.2681    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  1  2  1  0  0  0  0
  2  3  1  0  0  0  0
  3  4  1  0  0  0  0
  3  5  2  0  0  0  0
  4  6  2  0  0  0  0
  4  7  1  0  0  0  0
  6  8  1  0  0  0  0
  6  9  1  0  0  0  0
  7 10  1  0  0  0  0
  8 11  1  0  0  0  0
 10 12  1  0  0  0  0
 11 13  1  0  0  0  0
 11 14  2  0  0  0  0
 12 15  1  0  0  0  0
  8 10  2  0  0  0  0
 13 15  1  0  0  0  0
M  END
"""

Outside of the atom orders we didn't find obvious differences between the two molecules using Debug and looking at atom and bond properties.

Expected behavior

I would expect m1 and m2 to be the same.

Screenshots

image

Configuration (please complete the following information):

  • RDKit version: master '2023.03.1pre'
  • OS: Ubuntu 22.04
  • Python version (if relevant): Likely not but 3.10.6
  • Rdkit compiled from git with
cmake -DBUILD_SHARED_LIBS=ON -DRDK_BUILD_CPP_TESTS=OFF -DRDK_BUILD_DESCRIPTORS3D=OFF -DRDK_BUILD_MAEPARSER_SUPPORT=OFF \
   -DRDK_BUILD_SLN_SUPPORT=OFF -DRDK_BUILD_CAIRO_SUPPORT=ON -DRDK_BUILD_PYTHON_WRAPPERS=ON -DRDK_BUILD_INCHI_SUPPORT=ON \
   -DRDK_BUILD_COORDGEN_SUPPORT=ON -DRDK_TEST_MULTITHREADED=OFF -DCMAKE_BUILD_TYPE=Release -DBoost_NO_BOOST_CMAKE=ON \
   -DPYTHON_EXECUTABLE=/usr/bin/python3 -D RDK_INSTALL_STATIC_LIBS=OFF
    ..
@bjonnh-work bjonnh-work added the bug label Jan 5, 2023
@greglandrum
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Confirmed. The tautomer enumeration code is actually producing different results here:

m = Chem.MolFromMolBlock('''foo
  MJ221900

 15 16  0  0  0  0  0  0  0  0999 V2000
   -0.2638    0.1514    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.9777    0.5625    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   -1.6945    0.1514    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.4084    0.5625    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.6945   -0.6708    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   -3.1584    0.2236    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.4889    1.3820    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   -3.7084    0.8403    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -3.3279   -0.5764    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -3.2973    1.5542    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -4.5334    0.8403    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -3.7084    2.2681    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -4.9446    1.5542    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -4.9446    0.1236    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   -4.5334    2.2681    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  1  2  1  0  0  0  0
  2  3  1  0  0  0  0
  3  4  1  0  0  0  0
  3  5  2  0  0  0  0
  4  6  2  0  0  0  0
  4  7  1  0  0  0  0
  6  8  1  0  0  0  0
  6  9  1  0  0  0  0
  7 10  1  0  0  0  0
  8 11  1  0  0  0  0
 10 12  1  0  0  0  0
 11 13  1  0  0  0  0
 11 14  2  0  0  0  0
 12 15  1  0  0  0  0
  8 10  2  0  0  0  0
 13 15  1  0  0  0  0
M  END
''')
from rdkit.Chem.MolStandardize import rdMolStandardize
m2 = Chem.MolFromSmiles(Chem.MolToSmiles(m))
tenum = rdMolStandardize.TautomerEnumerator()
tauts = tenum.Enumerate(m)
tauts2 = tenum.Enumerate(m2)
len(tauts) ==len(tauts2)  # <- should be true, is False

The tautomer enumeration code is a gift that keeps on giving. :-S

@kienerj
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kienerj commented May 5, 2023

I have a similar example but the source here is two different molfiles with the same molecule. orientation and kekulized form is different which then probably leads to different tautomers:

image

(see attached notebbook, rename to ipynb)

Canonical Tautomer Issue.zip

@kienerj kienerj mentioned this issue May 31, 2023
Open
@pechersky pechersky mentioned this issue Nov 16, 2023
Open
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@greglandrum @kienerj @bjonnh-work