Openff-toolkit: OpenEye adding protons to 3D molecules
Describe the bug
After loading in molecules from the MiniDrugBank.sdf, I noticed that using either the RDKit or OpenEye toolkit wrappers resulted in subtly different Molecule representations in a select few files. It seems that OpenEye is adding one or more protons at some point while reading from the file. This results in a different number of Molecule.n_atoms as shown below. Manually counting the atoms shows that OpenEye includes one extra proton than in the original sdf file or the RDKit molecule.
To Reproduce
DrugBank_178.zip
Loading DrugBank_178.sdf using Molecule.from_file with both toolkits and counting the atoms:
import openforcefield
from openforcefield.utils import get_data_file_path
from openforcefield.utils.toolkits import RDKitToolkitWrapper, OpenEyeToolkitWrapper
from openforcefield.topology.molecule import Molecule
# path to DrugBank_178.sdf file
drug_bank_file = get_data_file_path('molecules/DrugBank_178.sdf')
rdkit_toolkit_wrapper = RDKitToolkitWrapper()
open_eye_toolkit_wrapper = OpenEyeToolkitWrapper()
# Load in the molecules using separate toolkits
OFF_using_rd = Molecule.from_file(drug_bank_file,
toolkit_registry=rdkit_toolkit_wrapper,
file_format='sdf',
allow_undefined_stereo=True)
OFF_using_oe = Molecule.from_file(drug_bank_file,
toolkit_registry=open_eye_toolkit_wrapper,
file_format='sdf',
allow_undefined_stereo=True)
assert(OFF_using_rd.n_atoms == OFF_using_oe.n_atoms)
# 45 atoms 46 atoms
Output
Traceback (most recent call last):
File "/home/coda3831/anaconda3/envs/openff-dev/openforcefield/openforcefield/Connor/Issue_Adding_Protons.py", line 24, in <module>
assert(OFF_using_rd.n_atoms == OFF_using_oe.n_atoms)
AssertionError
Computing environment (please complete the following information):
- Operating system: "Ubuntu 20.04.1 LTS"
- Output of running
conda list
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Additional context
The Following molecules from /openff-dev/openforcefield/openforcefield/data/molecules/MiniDrugBank.sdf have the same problem. The common thread appears to be sulfate and phosphate groups:
problem_mols = ['DrugBank_178',
'DrugBank_246',
'DrugBank_700',
'DrugBank_1564',
'DrugBank_1634',
'DrugBank_1700',
'DrugBank_1962',
'DrugBank_2052',
'DrugBank_2082',
'DrugBank_2148',
'DrugBank_2210',
'DrugBank_2519',
'DrugBank_2642',
'DrugBank_3930',
'DrugBank_4662',
'DrugBank_5043',
'DrugBank_5418',
'DrugBank_5847']
connordavel
All 8 comments
Thanks for the concise report, @connordavel. I've seen all sorts of problems with phosphates and sulfates before, and I wonder how many of them can be attributed to this.
CC #762 -- I think this behavior in OpenEyeToolkitWrapper might be a bug that we WANT to avoid, instead of adding it to RDKitToolkitWrapper as well.
j-wags
on 28 Jan 2021
Just to weigh in on this - I think this is a bug but a bug in the RDKit toolkit wrapper. DrugBank_178 has an implicit hydrogen on the hydroxyl oxygen which is part of the sulfuric acid monoester group.
While the OpenEye wrapper correctly converts this to an explicit hydrogen before conversion to an OpenFF molecule, the RDKit wrapper does not and hence this is incorrectly missing on the final OpenFF molecule.
# path to DrugBank_178.sdf file
drug_bank_file = 'DrugBank_178.sdf'
rd_molecule = next(iter(Chem.SupplierFromFilename(
drug_bank_file, removeHs=False, sanitize=False, strictParsing=True
)))
oe_stream = oechem.oemolistream(drug_bank_file)
oe_molecule = next(iter(oe_stream.GetOEMols()))
n_oe_implicit = sum(atom.GetImplicitHCount() for atom in oe_molecule.GetAtoms())
>>> 1
n_rd_implicit = sum(atom.GetNumImplicitHs() for atom in rd_molecule.GetAtoms())
>>> 1
oe_index = [atom.GetIdx() for atom in oe_molecule.GetAtoms() if atom.GetImplicitHCount() > 0][0]
>>> 18
rd_index = [atom.GetIdx() for atom in rd_molecule.GetAtoms() if atom.GetNumImplicitHs() > 0][0]
>>> 18
So arguably RDKit not converting implicit hydrogens to explicit hydrogens is a critical bug, and #762 a critical bug fix.
SimonBoothroyd
on 28 Jan 2021
Does the above behavior hold true for other molecules in that list?
mattwthompson
on 28 Jan 2021
Here's the results of reading and writing the attached file using OpenEyeToolkitWrapper and RDKitToolkitWrapper:
Initial:
OpenEyeToolkitWrapper roundtripped:
RDKitToolkitWrapper roundtripped:
Is there something in the SDF's non-3D information to indicate that there should really be an hydrogen on the sulfate?
Per the Accelerys/Biovia/Dassault CTFile spec (pp 40-41), the columns of the ATOM block should be
xxxxx.xxxxyyyyy.yyyyzzzzz.zzzzaaaddcccssshhhbbbvvvHHHrrriiimmmnnneee
where hhh is "number of implicit Hs". In DrugBank178's ATOM block [1], all hhh values are 0. Confusingly, all ccc values are ALSO zero, even though we'd expect the O with the single bond to have either a negative charge or a proton.
So I think it's ambiguous. I've subconsciously developed a few "rule of thumbs" for cases like this, and the one that applies best here is "Since the molecule has at least SOME explicit hydrogens, the user must be referencing this EXACT protonation state, and I shouldn't consider any hyrdrogens to be implicit".
[1] DrugBank_178.sdf, truncated before BONDS block
45 48 0 0 1 0 0 0 0 0999 V2000
#(Adding the column string above for reference, though I'm not sure if I've aligned columns correctly re:whitespace on the left)
xxxxx.xxxxyyyyy.yyyyzzzzz.zzzzaaaddcccssshhhbbbvvvHHHrrriiimmmnnneee
-1.9269 -0.1803 0.9467 C 0 0 0 0 0 0 0 0 0 0 0 0
-0.7191 0.4635 0.6693 C 0 0 0 0 0 0 0 0 0 0 0 0
-1.3722 2.2905 2.0886 C 0 0 0 0 0 0 0 0 0 0 0 0
-2.8751 0.3890 1.8150 C 0 0 0 0 0 0 0 0 0 0 0 0
-2.5958 1.6575 2.3697 C 0 0 0 0 0 0 0 0 0 0 0 0
-0.4392 1.6966 1.2436 C 0 0 0 0 0 0 0 0 0 0 0 0
-7.5416 -2.2886 4.0062 C 0 0 0 0 0 0 0 0 0 0 0 0
-3.5467 2.3541 3.3125 C 0 0 0 0 0 0 0 0 0 0 0 0
-8.2489 -1.1053 4.6454 C 0 0 0 0 0 0 0 0 0 0 0 0
-4.9507 1.7565 3.3354 C 0 0 0 0 0 0 0 0 0 0 0 0
-7.1491 -0.0344 4.7031 C 0 0 0 0 0 0 0 0 0 0 0 0
-4.1795 -1.8473 2.0454 C 0 0 0 0 0 0 0 0 0 0 0 0
-5.5269 -2.5101 2.3932 C 0 0 0 0 0 0 0 0 0 0 0 0
-4.2135 -0.2943 2.0809 C 0 0 1 0 0 0 0 0 0 0 0 0
-4.8640 0.2310 3.3984 C 0 0 2 0 0 0 0 0 0 0 0 0
-6.2294 -0.4358 3.5558 C 0 0 1 0 0 0 0 0 0 0 0 0
-6.0903 -1.9657 3.7013 C 0 0 1 0 0 0 0 0 0 0 0 0
-5.2692 -2.4593 4.9069 C 0 0 0 0 0 0 0 0 0 0 0 0
2.0515 1.0684 2.6166 O 0 0 0 0 0 0 0 0 0 0 0 0
-8.0749 -3.3695 3.7938 O 0 0 0 0 0 0 0 0 0 0 0 0
3.1159 2.8635 1.3350 O 0 0 0 0 0 0 0 0 0 0 0 0
2.4831 0.7537 0.2267 O 0 0 0 0 0 0 0 0 0 0 0 0
0.7382 2.3235 0.9776 O 0 0 0 0 0 0 0 0 0 0 0 0
2.2270 1.7023 1.3100 S 0 0 0 0 0 0 0 0 0 0 0 0
-2.1104 -1.1342 0.4614 H 0 0 0 0 0 0 0 0 0 0 0 0
-0.0036 -0.0053 -0.0011 H 0 0 0 0 0 0 0 0 0 0 0 0
-1.1490 3.2578 2.5343 H 0 0 0 0 0 0 0 0 0 0 0 0
-3.1192 2.2986 4.3219 H 0 0 0 0 0 0 0 0 0 0 0 0
-3.6229 3.4152 3.0458 H 0 0 0 0 0 0 0 0 0 0 0 0
-9.0702 -0.7916 3.9947 H 0 0 0 0 0 0 0 0 0 0 0 0
-8.6160 -1.3589 5.6420 H 0 0 0 0 0 0 0 0 0 0 0 0
-5.4914 2.1600 4.1985 H 0 0 0 0 0 0 0 0 0 0 0 0
-5.5033 2.0655 2.4388 H 0 0 0 0 0 0 0 0 0 0 0 0
-7.5713 0.9670 4.5742 H 0 0 0 0 0 0 0 0 0 0 0 0
-6.6283 -0.0551 5.6664 H 0 0 0 0 0 0 0 0 0 0 0 0
-3.4019 -2.2133 2.7274 H 0 0 0 0 0 0 0 0 0 0 0 0
-3.8979 -2.1967 1.0453 H 0 0 0 0 0 0 0 0 0 0 0 0
-6.2365 -2.3328 1.5742 H 0 0 0 0 0 0 0 0 0 0 0 0
-5.3989 -3.5981 2.4477 H 0 0 0 0 0 0 0 0 0 0 0 0
-4.8602 0.0164 1.2454 H 0 0 0 0 0 0 0 0 0 0 0 0
-4.2272 -0.0285 4.2541 H 0 0 0 0 0 0 0 0 0 0 0 0
-6.7976 -0.2184 2.6346 H 0 0 0 0 0 0 0 0 0 0 0 0
-4.2195 -2.2489 4.7335 H 0 0 0 0 0 0 0 0 0 0 0 0
-5.4143 -3.5277 5.0236 H 0 0 0 0 0 0 0 0 0 0 0 0
-5.6035 -1.9441 5.8008 H 0 0 0 0 0 0 0 0 0 0 0 0
[2] I read though a [nextmove article](https://nextmovesoftware.com/blog/2013/02/27/explicit-and-implicit-hydrogens-taking-liberties-with-valence/ on this, but I'm not sure if it applies here or provides a clear answer
j-wags
on 28 Jan 2021
Would it be possible to track this molecule back to another source, which may provide more information about whether or not this hydrogen should be there? openff/toolkit/data/molecules/MiniDrugBank_ff.mol2 has no charges on this molecule, but I don't really trust that.
I'm inclined to side with OpenEye on this one - mostly because of the lack of a formal charge on the hydrogen, which seems like a marginally more glaring omission than a hydrogen, and somewhat because there's already a place in which we're missing hydrogens in the RDKit wrapper. There could also be some explanation about different functional groups are treated differently, i.e. the sulfate/phosphate groups implied to have enough implicit hydrogens to maintain charge neutrality, but hydrogens explicitly tagged to the heavy atoms in other functional groups. But, of course, not much confidence with all this ambiguity ...
mattwthompson
on 28 Jan 2021
To clarify something in my post above, the two pictures I show above are using the OpenEyeToolkitWrapper and RDKitToolkitWrapper, instead of just oechem and rdkit.Chem directly. So that's showing the results of _our usage_ of those toolkits (ie. to/from_file using the different backends), not OE and RDKit's default behavior (This doesn't contradict anything Matt just posted, I just wanted to clarify)
j-wags
on 28 Jan 2021
Does the above behavior hold true for other molecules in that list?
@mattwthompson Yes, I believe so. Many of the molecules in the list have similar groups (such as sulfates, phosphates) with ambiguous info on implicit hydrogens. In general, problem molecules include sulfurs and phosphorous (not only sulfates and phosphates). For a non-sulfate example, take the following graph of DrugBank_2642. The top graph includes all atoms from the OpenEye toolkit molecule, whereas the bottom uses the RDkit toolkit.
This molecule has a similarly ambiguous sdf block:
DrugBank_2642
OpenBabel01151909533D
5 4 0 0 0 0 0 0 0 0999 V2000
1.8389 1.9802 -1.0140 S 0 0 0 0 0 0 0 0 0 0 0 0
-1.4335 -2.4496 0.5285 S 0 0 0 0 0 0 0 0 0 0 0 0
-0.0139 1.1143 -1.1960 S 0 0 0 0 0 0 0 0 0 0 0 0
0.0838 -1.1962 1.1123 S 0 0 0 0 0 0 0 0 0 0 0 0
-0.6038 0.6980 0.7247 S 0 0 0 0 0 0 0 0 0 0 0 0
1 3 1 0 0 0 0
2 4 1 0 0 0 0
3 5 1 0 0 0 0
4 5 1 0 0 0 0
M END
$$$$
All molecules in the list follow a similar trend.
connordavel
on 29 Jan 2021
That molecule provides a nice test case; there are no explicit hydrogens to cause the ambiguity of the molecule above (a mix of explicit hydrogens and some hydrogens that could be implicit, depending on the interpretation). But that molecule is still somewhat ambiguous in terms of what it should have; I don't know if a pentavalent linear sulfur is chemically sensible or not, i.e. if that molecule really should have hydrogens or not.
mattwthompson
on 29 Jan 2021
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Most helpful comment
@mattwthompson Yes, I believe so. Many of the molecules in the list have similar groups (such as sulfates, phosphates) with ambiguous info on implicit hydrogens. In general, problem molecules include sulfurs and phosphorous (not only sulfates and phosphates). For a non-sulfate example, take the following graph of DrugBank_2642. The top graph includes all atoms from the OpenEye toolkit molecule, whereas the bottom uses the RDkit toolkit.
DrugBank_2642.zip
This molecule has a similarly ambiguous sdf block:
All molecules in the list follow a similar trend.