Thrombin all ligands: should the primary amine be charged or neutral?

[hannahbaumann]

All ligands have a primary amine which is not charged, while it was protonated in the Hahn et al. PLB. Similar case/question as above.

[hannahbaumann]

The primary amine points towards the solvent and is not buried in the binding pocket.

[hannahbaumann]

Changed protonation state of the primary amine of all ligands to +1 since that is the protonation state of the ligands both in the PLB by Hahn et al. as well as in the Schrodinger benchmark set (https://github.com/schrodinger/public_binding_free_energy_benchmark/tree/main/fep_benchmark_inputs/structure_inputs) commit dc84b6733b2c0b974d4d1c170c80298cd6b7fe4b

New ligand.sdf file was generated using Openeye:

from openeye.oechem import*
from openeye.oequacpac import *  

ligs = 'ligands_old.sdf'

# Read your molecule with OEReader
istream = oemolistream(ligs)
# Output file
ofs = oemolostream('ligands.sdf')
omol = oechem.OEGraphMol()
# Get the tautomers, only write out first tautomer
for inx,lig in enumerate(istream.GetOEGraphMols()):
    tautomerOptions = OETautomerOptions()
    pKaNorm = True
    indx = 0
    for tautomer in OEGetReasonableTautomers(lig, tautomerOptions, pKaNorm):
        if indx == 0:
            OEWriteMolecule(ofs, tautomer)
        indx += 1

[hannahbaumann]

From this pka prediction (done with Simulations Plus ADMETpredictor V.11 in the context of the OpenFF consortium for method development) it looks like both protonation states are present at pH=7.4 (assay condition)