Protonation problem

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    • #16059
      Marcos Villarreal
      Guest

      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
      #—————————————————————————————————————-

    • #16179
      Jacob Durrant
      Keymaster

      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.

    • #16184
      Marcos Villarreal
      Guest

      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.

    • #16245
      Jacob Durrant
      Keymaster

      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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