Protonation problem

[Marcos Villarreal]

Hello,
I am observing a inconsistent behavior in the protonation of a simple phenol molecule, running a simple example
python3 run_gypsum_dl.py –source ./examples/sample_molecules2.smi –output_folder out2 –min_ph 6 –max_ph 7 –pka_precision 1 –max_variants_per_compound 1 –separate_output_files –use_durrant_lab_filters

When repeating this same command I get different protonation states from time to time.
Below are the outputs when you can see that some times in the ionization step the molecules is
Mol #0: Oc1ccccc1 and after a reptetion it is ionized as Mol #0: [O-]c1ccccc1

Let me know if you need more information in order to reproduce this isseue.
Best Regards, Marcos

First time :
#——————————————————————————————————————–
Loading molecules from sample_molecules2.smi…
Desalting all molecules (i.e., keeping only largest fragment).
Contents of MolContainers
MolContainer #0 (phenol)
Mol #0: Oc1ccccc1
Ionizing all molecules…
Contents of MolContainers
MolContainer #0 (phenol)
Mol #0: Oc1ccccc1
#—————————————————————————————————————-

Second time with the same command :
#—————————————————————————————————————-
Loading molecules from sample_molecules2.smi…
Desalting all molecules (i.e., keeping only largest fragment).
Contents of MolContainers
MolContainer #0 (phenol)
Mol #0: Oc1ccccc1
Ionizing all molecules…
Contents of MolContainers
MolContainer #0 (phenol)
Mol #0: [O-]c1ccccc1
#—————————————————————————————————————-

[Jacob Durrant]

Hi Marcos. Much thanks for your interest in Gypsum. The algorithm isn’t actually deterministic, so it makes sense that you could get different outputs. Given your choice of min_ph, max_ph, and pka_precision, Gypsum is likely producing both the protonated and deprotonated form internally. But because max_variants_per_compound is 1, Gypsum must pick between the two. A certain percentage of the time it picks one, and at other times it picks the other. Hope this answer helps.

[Marcos Villarreal]

Hi Jacob,
Thank you for your answer. I realize that I did not mention that the pKa of phenol is around 9, that is why I was surprised to get the phenolate (O-) instead of the phenol (OH) at this pH range (6 to 7).

Is there a combination of flags to tell gypsum to output only the most probable protonation state at a given pH?
Regards, Marcos.

[Jacob Durrant]

Hi Marcos.You could try parameters like these:


--min_ph 7.0
--max_ph 7.0
--pka_precision 0.0


For what it’s worth, it looks like the pKa values of phenols vary quite a bit depending on other moieties: https://www.chem.ucla.edu/~cantrill/30A_S05/Acids_Bases_2.pdf

The average pKa value of the phenols used to parameterize Dimorphite-DL was particularly low: https://git.durrantlab.pitt.edu/jdurrant/dimorphite_dl/-/blob/1.2.4/site_substructures.smarts#L37

But I believe using the parameters above should always protonate your phenol molecules.

Take care,

Jacob

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