Sulfur has lone-pair stereochemistry issues

[jchodera]

Describe the bug
Previously, we had run into issues where the openforcefield toolkit using the OpenEye toolkit backend perceives trivalent nitrogens as stereocenters, causing issues for loading and parameterization of small molecules containing nitrogens. While we worked around this issue for nitrogens, it appears that sulfurs can also have the same problem.

The molecule on the left has no trouble being loaded by the openforcefield toolkit, while the molecule on the right cannot be loaded without allow_undefined_stereo=True.
SDF files for both the left molecule (CDK2-no-stereo-issue.sdf) and right molecule (CDK2-stereo-issue.sdf) are provided.

To Reproduce

molecule = Molecule.from_file('../CDK2-no-stereo-issue.sdf')
molecule = Molecule.from_file('../CDK2-stereo-issue.sdf')

molecules.zip

Output
With the OpenEye toolkit backend:

>>> molecule = Molecule.from_file('../CDK2-stereo-issue.sdf')

---------------------------------------------------------------------------
UndefinedStereochemistryError             Traceback (most recent call last)
<ipython-input-14-354a3db15360> in <module>
----> 1 molecule = Molecule.from_file('../CDK2-stereo-issue.sdf')

~/miniconda/lib/python3.7/site-packages/openforcefield/topology/molecule.py in from_file(file_path, file_format, toolkit_registry, allow_undefined_stereo)
   2989                 file_path,
   2990                 file_format=file_format,
-> 2991                 allow_undefined_stereo=allow_undefined_stereo)
   2992         elif hasattr(file_path, 'read'):
   2993             file_obj = file_path

~/miniconda/lib/python3.7/site-packages/openforcefield/utils/toolkits.py in from_file(self, file_path, file_format, allow_undefined_stereo)
    410         from openeye import oechem
    411         ifs = oechem.oemolistream(file_path)
--> 412         return self._read_oemolistream_molecules(ifs, allow_undefined_stereo, file_path=file_path)
    413 
    414     def from_file_obj(self,

~/miniconda/lib/python3.7/site-packages/openforcefield/utils/toolkits.py in _read_oemolistream_molecules(cls, oemolistream, allow_undefined_stereo, file_path)
    538             mol = cls.from_openeye(
    539                 oemol,
--> 540                 allow_undefined_stereo=allow_undefined_stereo)
    541             mols.append(mol)
    542 

~/miniconda/lib/python3.7/site-packages/openforcefield/utils/toolkits.py in from_openeye(oemol, allow_undefined_stereo)
    757             else:
    758                 msg = 'Unable to make OFFMol from OEMol: ' + msg
--> 759                 raise UndefinedStereochemistryError(msg)
    760 
    761         # TODO: What other information should we preserve besides name?

UndefinedStereochemistryError: Unable to make OFFMol from OEMol: OEMol has unspecified stereochemistry. oemol.GetTitle(): 31
Problematic atoms are:
Atom atomic num: 16, name: , idx: 44, aromatic: False, chiral: True with bonds:
bond order: 1, chiral: False to atom atomic num: 6, name: , idx: 10, aromatic: True, chiral: False
bond order: 2, chiral: False to atom atomic num: 8, name: , idx: 45, aromatic: False, chiral: False
bond order: 1, chiral: False to atom atomic num: 6, name: , idx: 46, aromatic: False, chiral: False

With the RDKit backend:

>>> molecule = Molecule.from_file('../CDK2-stereo-issue.sdf')

---------------------------------------------------------------------------
UndefinedStereochemistryError             Traceback (most recent call last)
<ipython-input-28-354a3db15360> in <module>
----> 1 molecule = Molecule.from_file('../CDK2-stereo-issue.sdf')

~/miniconda/lib/python3.7/site-packages/openforcefield/topology/molecule.py in from_file(file_path, file_format, toolkit_registry, allow_undefined_stereo)
   2989                 file_path,
   2990                 file_format=file_format,
-> 2991                 allow_undefined_stereo=allow_undefined_stereo)
   2992         elif hasattr(file_path, 'read'):
   2993             file_obj = file_path

~/miniconda/lib/python3.7/site-packages/openforcefield/utils/toolkits.py in from_file(self, file_path, file_format, allow_undefined_stereo)
   1556                     continue
   1557                 Chem.SetAromaticity(rdmol, Chem.AromaticityModel.AROMATICITY_MDL)
-> 1558                 mol = self.from_rdkit(rdmol, allow_undefined_stereo=allow_undefined_stereo)
   1559                 mols.append(mol)
   1560 

~/miniconda/lib/python3.7/site-packages/openforcefield/utils/toolkits.py in from_rdkit(self, rdmol, allow_undefined_stereo)
   1877         # Check for undefined stereochemistry.
   1878         self._detect_undefined_stereo(rdmol, raise_warning=allow_undefined_stereo,
-> 1879                                       err_msg_prefix="Unable to make OFFMol from RDMol: ")
   1880 
   1881         # Create a new openforcefield Molecule

~/miniconda/lib/python3.7/site-packages/openforcefield/utils/toolkits.py in _detect_undefined_stereo(cls, rdmol, err_msg_prefix, raise_warning)
   2425             else:
   2426                 msg = 'Unable to make OFFMol from RDMol: ' + msg
-> 2427                 raise UndefinedStereochemistryError(msg)
   2428 
   2429     @staticmethod

UndefinedStereochemistryError: Unable to make OFFMol from RDMol: Unable to make OFFMol from RDMol: RDMol has unspecified stereochemistry. RDMol name: 31Undefined chiral centers are:
 - Atom S (index 44)

When specifying allow_undefined_stereo=True, the OpenEye toolkit properly gives a warning about unspecified stereochemistry:

Warning (not error because allow_undefined_stereo=True): OEMol has unspecified stereochemistry. oemol.GetTitle(): 31
Problematic atoms are:
Atom atomic num: 16, name: , idx: 44, aromatic: False, chiral: True with bonds:
bond order: 1, chiral: False to atom atomic num: 6, name: , idx: 10, aromatic: True, chiral: False
bond order: 2, chiral: False to atom atomic num: 8, name: , idx: 45, aromatic: False, chiral: False
bond order: 1, chiral: False to atom atomic num: 6, name: , idx: 46, aromatic: False, chiral: False

but the RDKit does not:

>>> molecule = Molecule.from_file('../CDK2-stereo-issue.sdf', allow_undefined_stereo=True)
Warning (not error because allow_undefined_stereo=True): 

The warning is not actually printed.

Computing environment (please complete the following information):

• Operating system: osx
• Output of running conda list

Click to expand

``` # packages in environment at /Users/choderaj/miniconda: # # Name Version Build Channel alabaster 0.7.12 py_0 conda-forge ambermini 16.16.0 7 omnia ambertools 19.0 0 AmberMD apbs 1.5 h1de35cc_3 schrodinger appnope 0.1.0 py37_1000 conda-forge arrow 0.15.4 py37_0 conda-forge atomicwrites 1.3.0 py_0 conda-forge attrs 19.3.0 py_0 conda-forge autograd 1.3 py_0 conda-forge babel 2.7.0 py_0 conda-forge backcall 0.1.0 py_0 conda-forge beautifulsoup4 4.8.1 py37_0 conda-forge behave 1.2.6 pypi_0 pypi binaryornot 0.4.4 py_1 conda-forge bleach 3.1.0 py_0 conda-forge blosc 1.17.0 h6de7cb9_1 conda-forge bokeh 1.4.0 py37_0 conda-forge boost 1.70.0 py37haf112f3_1 conda-forge boost-cpp 1.70.0 h75728bb_2 conda-forge bson 0.5.8 py_0 conda-forge bzip2 1.0.8 h01d97ff_1 conda-forge ca-certificates 2019.11.28 hecc5488_0 conda-forge cairo 1.16.0 he1c11cd_1002 conda-forge certifi 2019.11.28 py37_0 conda-forge cffi 1.13.2 py37h33e799b_0 conda-forge cftime 1.0.4.2 py37h3b54f70_0 conda-forge chardet 3.0.4 py37_1003 conda-forge click 7.0 py_0 conda-forge cloudpickle 1.2.2 py_0 conda-forge colorama 0.4.1 pypi_0 pypi conda 4.7.12 py37_0 conda-forge conda-build 3.18.11 py37_0 conda-forge conda-package-handling 1.6.0 py37h01d97ff_0 conda-forge cookiecutter 1.6.0 py37_1000 conda-forge coverage 4.5.4 py37h0b31af3_0 conda-forge cryptography 2.8 py37hafa8578_0 conda-forge curl 7.65.3 h22ea746_0 conda-forge cycler 0.10.0 py_2 conda-forge cython 0.29.14 py37h4a8c4bd_0 conda-forge cytoolz 0.10.1 py37h0b31af3_0 conda-forge dask 2.7.0 py_0 conda-forge dask-core 2.7.0 py_0 conda-forge dbus 1.13.6 h2f22bb5_0 conda-forge decorator 4.4.1 py_0 conda-forge defusedxml 0.6.0 py_0 conda-forge distributed 2.7.0 py_0 conda-forge docutils 0.15.2 py37_0 conda-forge entrypoints 0.3 py37_1000 conda-forge et-xmlfile 1.0.1 pypi_0 pypi expat 2.2.5 h4a8c4bd_1004 conda-forge fftw3f 3.3.4 2 omnia filelock 3.0.10 py_0 conda-forge fontconfig 2.13.1 h6b1039f_1001 conda-forge freemol 1.158 py37_1 schrodinger freetype 2.10.0 h24853df_1 conda-forge fsspec 0.5.2 py_0 conda-forge future 0.18.2 py37_0 conda-forge gettext 0.19.8.1 h46ab8bc_1002 conda-forge glew 2.1.0 h4a8c4bd_0 conda-forge glib 2.58.3 py37h577aef8_1002 conda-forge glob2 0.7 py_0 conda-forge h5py 2.10.0 nompi_py37h106b333_100 conda-forge hdf4 4.2.13 h84186c3_1003 conda-forge hdf5 1.10.5 nompi_h3e39495_1104 conda-forge heapdict 1.0.1 py_0 conda-forge icu 64.2 h6de7cb9_1 conda-forge idna 2.8 py37_1000 conda-forge imagesize 1.1.0 py_0 conda-forge importlib_metadata 0.23 py37_0 conda-forge ipykernel 5.1.3 py37h5ca1d4c_0 conda-forge ipython 7.9.0 py37h5ca1d4c_0 conda-forge ipython_genutils 0.2.0 py_1 conda-forge ipywidgets 7.5.1 py_0 conda-forge jdcal 1.4.1 pypi_0 pypi jedi 0.15.1 py37_0 conda-forge jinja2 2.10.3 py_0 conda-forge jinja2-time 0.2.0 py_2 conda-forge jpeg 9c h1de35cc_1001 conda-forge jsonschema 3.1.1 py37_0 conda-forge jupyter 1.0.0 py_2 conda-forge jupyter_client 5.3.3 py37_1 conda-forge jupyter_console 6.0.0 py_0 conda-forge jupyter_core 4.5.0 py_0 conda-forge kiwisolver 1.1.0 py37ha1b3eb9_0 conda-forge krb5 1.16.3 hcfa6398_1001 conda-forge libarchive 3.4.0 h1538ba8_1 conda-forge libblas 3.8.0 14_openblas conda-forge libcblas 3.8.0 14_openblas conda-forge libclang 8.0.1 h770b8ee_1 conda-forge libcurl 7.65.3 h16faf7d_0 conda-forge libcxx 9.0.0 h89e68fa_1 conda-forge libedit 3.1.20170329 hcfe32e1_1001 conda-forge libffi 3.2.1 h6de7cb9_1006 conda-forge libgcc 4.8.5 1 conda-forge libgfortran 4.0.0 2 conda-forge libiconv 1.15 h01d97ff_1005 conda-forge libidn2 2.1.1 h1de35cc_0 conda-forge liblapack 3.8.0 14_openblas conda-forge liblief 0.9.0 h2a1bed3_1 conda-forge libllvm8 8.0.1 h770b8ee_0 conda-forge libnetcdf 4.7.1 nompi_he14bcb6_101 conda-forge libopenblas 0.3.7 h4bb4525_3 conda-forge libpng 1.6.37 h2573ce8_0 conda-forge libsodium 1.0.17 h01d97ff_0 conda-forge libssh2 1.8.2 hcdc9a53_2 conda-forge libtiff 4.1.0 h3527a1b_0 conda-forge libunistring 0.9.10 h1de35cc_0 conda-forge libxml2 2.9.10 h53d96d6_0 conda-forge libxslt 1.1.33 h320ff13_0 conda-forge llvm-openmp 9.0.0 h40edb58_0 conda-forge llvmlite 0.30.0 py37h05045ef_1 conda-forge locket 0.2.0 py_2 conda-forge lxml 4.4.1 py37he54a443_0 conda-forge lz4-c 1.8.3 h6de7cb9_1001 conda-forge lzo 2.10 h1de35cc_1000 conda-forge markupsafe 1.1.1 py37h0b31af3_0 conda-forge matplotlib 3.1.2 py37_0 conda-forge matplotlib-base 3.1.2 py37h11da6c2_0 conda-forge mdtraj 1.9.3 py37h5a8e3e4_0 conda-forge mengine 1 h1de35cc_1 schrodinger mistune 0.8.4 py37h0b31af3_1000 conda-forge mmpbsa-py 16.0 pypi_0 pypi mock 3.0.5 py37_0 conda-forge more-itertools 7.2.0 py_0 conda-forge mpeg_encode 1 h1de35cc_1 schrodinger mpiplus v0.0.1 py37_1000 conda-forge msgpack-python 0.6.2 py37ha1b3eb9_0 conda-forge mtz2ccp4_px 1.0 hdc02c5d_3 schrodinger nbconvert 5.6.1 py37_0 conda-forge nbformat 4.4.0 py_1 conda-forge ncurses 6.1 h0a44026_1002 conda-forge netcdf4 1.5.3 py37he9269ea_0 conda-forge networkx 2.4 py_0 conda-forge nose 1.3.7 py37_1003 conda-forge nose-timer 0.7.4 py_0 conda-forge notebook 6.0.1 py37_0 conda-forge nspr 4.20 h0a44026_1000 conda-forge nss 3.47 hcec2283_0 conda-forge numba 0.46.0 py37h4f17bb1_1 conda-forge numexpr 2.7.0 py37h4f17bb1_0 conda-forge numpy 1.17.3 py37hde6bac1_0 conda-forge numpydoc 0.9.1 py_0 conda-forge olefile 0.46 py_0 conda-forge openeye-toolkits 2019.10.2 py37_0 openeye openforcefield 0.6.0 py37_0 omnia openforcefields 1.0.0 py37_0 omnia openmm 7.4.0 py37_cuda101_rc_1 omnia openmmforcefields 0.4.0+41.g6245bf3.dirty pypi_0 pypi openmmtools 0.18.3+61.g8ca9fb0.dirty pypi_0 pypi openmoltools 0.8.4 py37_1 omnia openssl 1.1.1d h0b31af3_0 conda-forge packaging 19.2 py_0 conda-forge packmol-memgen 1.0.5rc0 pypi_0 pypi pandas 0.25.3 py37h4f17bb1_0 conda-forge pandoc 2.7.3 0 conda-forge pandocfilters 1.4.2 py_1 conda-forge parmed 3.2.0 pypi_0 pypi parse-type 0.5.2 pypi_0 pypi parso 0.5.1 py_0 conda-forge partd 1.0.0 py_0 conda-forge patsy 0.5.1 py_0 conda-forge pcre 8.43 h4a8c4bd_0 conda-forge pdb2pqr 2.1.1 py37_1 schrodinger pdb4amber 1.7.dev0 pypi_0 pypi pdbfixer 1.6 py37_0 omnia pexpect 4.7.0 py37_0 conda-forge pickleshare 0.7.5 py37_1000 conda-forge pillow 6.2.1 py37hb6f49c9_0 conda-forge pint 0.9 pypi_0 pypi pip 19.3.1 py37_0 conda-forge pixman 0.38.0 h01d97ff_1003 conda-forge pkginfo 1.5.0.1 py_0 conda-forge pluggy 0.13.0 py37_0 conda-forge pmw 2.0.1 py37_1001 conda-forge poyo 0.5.0 py_0 conda-forge progressbar2 3.47.0 py_0 conda-forge prometheus_client 0.7.1 py_0 conda-forge prompt_toolkit 2.0.10 py_0 conda-forge psutil 5.6.5 py37h0b31af3_0 conda-forge ptyprocess 0.6.0 py_1001 conda-forge py 1.8.0 py_0 conda-forge py-lief 0.9.0 py37h6d6d4d2_1 conda-forge pycairo 1.18.2 py37h83b1bec_0 conda-forge pycosat 0.6.3 py37h0b31af3_1002 conda-forge pycparser 2.19 py37_1 conda-forge pygments 2.4.2 py_0 conda-forge pymbar 3.0.3 py37h7eb728f_3 conda-forge pymol 2.3.3 py37h95b93ae_0 schrodinger pymsmt 19.0 pypi_0 pypi pyopenssl 19.0.0 py37_0 conda-forge pyparsing 2.4.5 py_0 conda-forge pyqt 5.12.3 py37he22c54c_0 conda-forge pyqt5-sip 4.19.18 pypi_0 pypi pyqtwebengine 5.12.1 pypi_0 pypi pyrsistent 0.15.5 py37h0b31af3_0 conda-forge pysocks 1.7.1 py37_0 conda-forge pytables 3.6.1 py37h6f8395a_0 conda-forge pytest 5.2.2 py37_0 conda-forge pytest-cov 2.8.1 py_0 conda-forge pytest-runner 5.2 py_0 conda-forge python 3.7.3 h93065d6_1 conda-forge python-dateutil 2.8.1 py_0 conda-forge python-libarchive-c 2.9 py37_0 conda-forge python-utils 2.3.0 py_1 conda-forge python.app 1.2 py37h0b31af3_1201 conda-forge pytraj 2.0.5 pypi_0 pypi pytz 2019.3 py_0 conda-forge pyyaml 5.1.2 py37h0b31af3_0 conda-forge pyzmq 18.1.0 py37h4bf09a9_0 conda-forge qt 5.12.5 h1b46049_0 conda-forge qtconsole 4.5.5 py_0 conda-forge rdkit 2019.09.1 py37h3471270_0 conda-forge readline 8.0 hcfe32e1_0 conda-forge rednose 1.3.0 pypi_0 pypi requests 2.22.0 py37_1 conda-forge rigimol 1.3 2 schrodinger ripgrep 11.0.2 h01d97ff_3 conda-forge ruamel_yaml 0.15.71 py37h1de35cc_1000 conda-forge sander 16.0 pypi_0 pypi scipy 1.3.2 py37h82752d6_0 conda-forge seaborn 0.9.0 py_2 conda-forge send2trash 1.5.0 py_0 conda-forge setuptools 41.6.0 py37_1 conda-forge six 1.13.0 py37_0 conda-forge smirnoff99frosst 1.1.0 py37_1 omnia snowballstemmer 2.0.0 py_0 conda-forge sortedcontainers 2.1.0 py_0 conda-forge soupsieve 1.9.4 py37_0 conda-forge sphinx 2.2.1 py_0 conda-forge sphinxcontrib-applehelp 1.0.1 py_0 conda-forge sphinxcontrib-devhelp 1.0.1 py_0 conda-forge sphinxcontrib-htmlhelp 1.0.2 py_0 conda-forge sphinxcontrib-jsmath 1.0.1 py_0 conda-forge sphinxcontrib-qthelp 1.0.2 py_0 conda-forge sphinxcontrib-serializinghtml 1.1.3 py_0 conda-forge sqlite 3.30.1 h93121df_0 conda-forge statsmodels 0.10.1 py37h3b54f70_1 conda-forge tblib 1.4.0 py_0 conda-forge termcolor 1.1.0 py_2 conda-forge terminado 0.8.2 py37_0 conda-forge testpath 0.4.4 py_0 conda-forge tinydb 3.15.1 py_0 conda-forge tk 8.6.9 x11tk0_2000 schrodinger toml 0.10.0 py_0 conda-forge toolz 0.10.0 py_0 conda-forge tornado 6.0.3 py37h0b31af3_0 conda-forge tqdm 4.37.0 py_0 conda-forge traitlets 4.3.3 py37_0 conda-forge urllib3 1.25.7 py37_0 conda-forge wcwidth 0.1.7 py_1 conda-forge webencodings 0.5.1 py_1 conda-forge wget 1.20.1 h33e2efd_0 conda-forge wheel 0.33.6 py37_0 conda-forge whichcraft 0.6.1 py_0 conda-forge widgetsnbextension 3.5.1 py37_0 conda-forge xmltodict 0.12.0 py_0 conda-forge xz 5.2.4 h1de35cc_1001 conda-forge yaml 0.1.7 h1de35cc_1001 conda-forge zeromq 4.3.2 h6de7cb9_2 conda-forge zict 1.0.0 py_0 conda-forge zipp 0.6.0 py_0 conda-forge zlib 1.2.11 h0b31af3_1006 conda-forge zstd 1.4.3 he7fca8b_0 conda-forge ```

Additional context
cc: #382 #146

[jchodera]

Notably, even when read with allow_undefined_stereo=True, we cannot generate conformations with the OpenEye backend:

>>> molecule.generate_conformers(n_conformers=1)
---------------------------------------------------------------------------
Exception                                 Traceback (most recent call last)
<ipython-input-5-645249898b26> in <module>
----> 1 molecule.generate_conformers(n_conformers=1)

~/miniconda/lib/python3.7/site-packages/openforcefield/topology/molecule.py in generate_conformers(self, toolkit_registry, n_conformers, clear_existing)
   1978         if isinstance(toolkit_registry, ToolkitRegistry):
   1979             return toolkit_registry.call('generate_conformers', self, n_conformers=n_conformers,
-> 1980                                          clear_existing=clear_existing)
   1981         elif isinstance(toolkit_registry, ToolkitWrapper):
   1982             toolkit = toolkit_registry

~/miniconda/lib/python3.7/site-packages/openforcefield/utils/toolkits.py in call(self, method_name, *args, **kwargs)
   3023                 method = getattr(toolkit, method_name)
   3024                 try:
-> 3025                     return method(*args, **kwargs)
   3026                 except NotImplementedError:
   3027                     pass

~/miniconda/lib/python3.7/site-packages/openforcefield/utils/toolkits.py in generate_conformers(self, molecule, n_conformers, clear_existing)
   1114 
   1115         if status is False:
-> 1116             raise Exception("OpenEye Omega conformer generation failed")
   1117 
   1118         molecule2 = self.from_openeye(oemol, allow_undefined_stereo=True)

Exception: OpenEye Omega conformer generation failed

but we can with the RDKit backend, though we get an empty warning:

>>> molecule.generate_conformers(n_conformers=1)
Warning (not error because allow_undefined_stereo=True): 

[j-wags]

I see the steps toward resolving this issue as:

• Fix the missing info from the RDKit warning message (maybe this will be resolved faster as a separate issue)
• Figure out what the exchange/flipping rate of pyrimidal sulfur is. If it's faster than 1/millisecond, then don't require stereo. If it's slower, then do require stereo.
• Update table in Spec for undefined stereochemistry #146 with this decision
• Close this issue when the sulfur's stereochemistry is perceived correctly.

[jchodera]

This reference may be useful in answering the second question (if one of us can find it).

[j-wags]

Looks like UC Irvine has a copy. I'll post pictures of it on this Issue when I go there Friday.

[j-wags]

Ah, the UC Irvine library catalog is out of date, and they do not actually have a copy. I checked a few other sources in the section and wasn't able to find any sulfur flipping rates, so the question remains unanswered for now.

They do, however, have journals of Soviet physics!

[jchodera]

This paper has some useful barrier heights for smaller compounds containing N, S, and P pyramidal atoms!
pyramidal-inversion.pdf