def rebuild_c_terminal(complex: oechem.OEGraphMol) -> oechem.OEGraphMol:
# Delete and rebuild C-terminal residue because Spruce causes issues with this
# See: 6m2n 6lze
pred = oechem.OEIsCTerminalAtom()
for atom in complex.GetAtoms():
if pred(atom):
for nbor in atom.GetAtoms():
if oechem.OEGetPDBAtomIndex(nbor) == oechem.OEPDBAtomName_O:
complex.DeleteAtom(nbor)
return complex
def _OEFixConnectionNH(protein):
"""
Temporary fix, thanks to Jesper!
"""
for atom in protein.GetAtoms(
oechem.OEAndAtom(oespruce.OEIsModeledAtom(),
oechem.OEIsNitrogen())):
if oechem.OEGetPDBAtomIndex(atom) == oechem.OEPDBAtomName_N:
expected_h_count = 1
if oechem.OEGetResidueIndex(atom) == oechem.OEResidueIndex_PRO:
expected_h_count = 0
if atom.GetTotalHCount() != expected_h_count:
oechem.OESuppressHydrogens(atom)
atom.SetImplicitHCount(1)
oechem.OEAddExplicitHydrogens(protein, atom)
for nbr in atom.GetAtoms(oechem.OEIsHydrogen()):
oechem.OESet3DHydrogenGeom(protein, nbr)
def prepare_receptor(complex_pdb_filename, output_basepath, dimer=False):
"""
Parameters
----------
complex_pdb_filename : str
The complex PDB file to read in
output_basepath : str
Base path for output
dimer : bool, optional, default=False
If True, generate the dimer as the biological unit
"""
import os
basepath, filename = os.path.split(complex_pdb_filename)
prefix, extension = os.path.splitext(filename)
prefix = os.path.join(output_basepath, prefix)
# Check if receptor already exists
receptor_filename = f'{prefix}-receptor.oeb.gz'
thiolate_receptor_filename = f'{prefix}-receptor-thiolate.oeb.gz'
if os.path.exists(receptor_filename) and os.path.exists(
thiolate_receptor_filename):
return
# Read in PDB file
pdbfile_lines = [
line for line in open(complex_pdb_filename, 'r') if 'UNK' not in line
]
# If monomer is specified, drop crystal symmetry lines
if not dimer:
pdbfile_lines = [
line for line in pdbfile_lines if 'REMARK 350' not in line
]
# Reconstruct PDBFile contents
pdbfile_contents = ''.join(pdbfile_lines)
# Read the receptor and identify design units
from openeye import oespruce, oechem
from tempfile import NamedTemporaryFile
with NamedTemporaryFile(delete=False, mode='wt', suffix='.pdb') as pdbfile:
pdbfile.write(pdbfile_contents)
pdbfile.close()
complex = read_pdb_file(pdbfile.name)
# TODO: Clean up
#print('Identifying design units...')
design_units = list(oespruce.OEMakeDesignUnits(complex))
if len(design_units) == 1:
design_unit = design_units[0]
elif len(design_units) > 1:
#print('More than one design unit found---using first one')
design_unit = design_units[0]
elif len(design_units) == 0:
raise Exception(f' * No design units found for {complex_pdb_filename}')
# Prepare the receptor
#print('Preparing receptor...')
from openeye import oedocking
protein = oechem.OEGraphMol()
design_unit.GetProtein(protein)
ligand = oechem.OEGraphMol()
design_unit.GetLigand(ligand)
receptor = oechem.OEGraphMol()
oedocking.OEMakeReceptor(receptor, protein, ligand)
oedocking.OEWriteReceptorFile(receptor, receptor_filename)
with oechem.oemolostream(f'{prefix}-protein.pdb') as ofs:
oechem.OEWriteMolecule(ofs, protein)
with oechem.oemolostream(f'{prefix}-ligand.mol2') as ofs:
oechem.OEWriteMolecule(ofs, ligand)
with oechem.oemolostream(f'{prefix}-ligand.pdb') as ofs:
oechem.OEWriteMolecule(ofs, ligand)
with oechem.oemolostream(f'{prefix}-ligand.sdf') as ofs:
oechem.OEWriteMolecule(ofs, ligand)
# Filter out UNK from PDB files (which have covalent adducts)
pdbfile_lines = [
line for line in open(f'{prefix}-protein.pdb', 'r')
if 'UNK' not in line
]
with open(f'{prefix}-protein.pdb', 'wt') as outfile:
outfile.write(''.join(pdbfile_lines))
# Adjust protonation state of CYS145 to generate thiolate form
#print('Deprotonating CYS145...')
pred = oechem.OEAtomMatchResidue(["CYS:145: :A"])
for atom in protein.GetAtoms(pred):
if oechem.OEGetPDBAtomIndex(atom) == oechem.OEPDBAtomName_SG:
oechem.OESuppressHydrogens(atom)
atom.SetFormalCharge(-1)
atom.SetImplicitHCount(0)
# Adjust protonation states
#print('Re-optimizing hydrogen positions...')
place_hydrogens_opts = oechem.OEPlaceHydrogensOptions()
place_hydrogens_opts.SetBypassPredicate(pred)
protonate_opts = oespruce.OEProtonateDesignUnitOptions(
place_hydrogens_opts)
success = oespruce.OEProtonateDesignUnit(design_unit, protonate_opts)
design_unit.GetProtein(protein)
# Old hacky way to adjust protonation states
#opts = oechem.OEPlaceHydrogensOptions()
#opts.SetBypassPredicate(pred)
#describe = oechem.OEPlaceHydrogensDetails()
#success = oechem.OEPlaceHydrogens(protein, describe, opts)
#if success:
# oechem.OEUpdateDesignUnit(design_unit, protein, oechem.OEDesignUnitComponents_Protein)
# Write thiolate form of receptor
receptor = oechem.OEGraphMol()
oedocking.OEMakeReceptor(receptor, protein, ligand)
oedocking.OEWriteReceptorFile(receptor, thiolate_receptor_filename)
with oechem.oemolostream(f'{prefix}-protein-thiolate.pdb') as ofs:
oechem.OEWriteMolecule(ofs, protein)
# Filter out UNK from PDB files (which have covalent adducts)
pdbfile_lines = [
line for line in open(f'{prefix}-protein-thiolate.pdb', 'r')
if 'UNK' not in line
]
with open(f'{prefix}-protein-thiolate.pdb', 'wt') as outfile:
outfile.write(''.join(pdbfile_lines))
def prepare_receptor(complex_pdb_filename,
output_basepath,
dimer=False,
retain_water=False):
"""
Parameters
----------
complex_pdb_filename : str
The complex PDB file to read in
output_basepath : str
Base path for output
dimer : bool, optional, default=False
If True, generate the dimer as the biological unit
retain_water : bool, optional, default=False
If True, will retain waters
"""
# Check whether this is a diamond SARS-CoV-2 Mpro structure or not
import re
is_diamond_structure = (re.search('-x\d+_', complex_pdb_filename)
is not None)
import os
basepath, filename = os.path.split(complex_pdb_filename)
prefix, extension = os.path.splitext(filename)
prefix = os.path.join(output_basepath, prefix)
# Check if receptor already exists
receptor_filename = f'{prefix}-receptor.oeb.gz'
thiolate_receptor_filename = f'{prefix}-receptor-thiolate.oeb.gz'
if os.path.exists(receptor_filename) and os.path.exists(
thiolate_receptor_filename):
return
# Read in PDB file, skipping UNK atoms (left over from processing covalent ligands)
pdbfile_lines = [
line for line in open(complex_pdb_filename, 'r') if 'UNK' not in line
]
# Check if biological symmetry header is present
has_biological_symmetry_header = False
for line in pdbfile_lines:
if 'REMARK 350' in line:
has_biological_symmetry_header = True
break
# Prepend REMARK 350 (biological symmetry) header lines for Mpro (from 5RGG) if not present
if is_diamond_structure and (not has_biological_symmetry_header):
pdbfile_lines = [
line + '\n' for line in BIOLOGICAL_SYMMETRY_HEADER.split('\n')
] + pdbfile_lines
# If monomer is specified, drop crystal symmetry lines
if not dimer:
pdbfile_lines = [
line for line in pdbfile_lines if 'REMARK 350' not in line
]
# Filter out waters
if not retain_water:
pdbfile_lines = [line for line in pdbfile_lines if 'HOH' not in line]
# Filter out LINK records to covalent inhibitors so we can model non-covalent complex
pdbfile_lines = [line for line in pdbfile_lines if 'LINK' not in line]
# Reconstruct PDBFile contents
pdbfile_contents = ''.join(pdbfile_lines)
# Append SEQRES to all structures if they do not have it
seqres = """\
SEQRES 1 A 306 SER GLY PHE ARG LYS MET ALA PHE PRO SER GLY LYS VAL
SEQRES 2 A 306 GLU GLY CYS MET VAL GLN VAL THR CYS GLY THR THR THR
SEQRES 3 A 306 LEU ASN GLY LEU TRP LEU ASP ASP VAL VAL TYR CYS PRO
SEQRES 4 A 306 ARG HIS VAL ILE CYS THR SER GLU ASP MET LEU ASN PRO
SEQRES 5 A 306 ASN TYR GLU ASP LEU LEU ILE ARG LYS SER ASN HIS ASN
SEQRES 6 A 306 PHE LEU VAL GLN ALA GLY ASN VAL GLN LEU ARG VAL ILE
SEQRES 7 A 306 GLY HIS SER MET GLN ASN CYS VAL LEU LYS LEU LYS VAL
SEQRES 8 A 306 ASP THR ALA ASN PRO LYS THR PRO LYS TYR LYS PHE VAL
SEQRES 9 A 306 ARG ILE GLN PRO GLY GLN THR PHE SER VAL LEU ALA CYS
SEQRES 10 A 306 TYR ASN GLY SER PRO SER GLY VAL TYR GLN CYS ALA MET
SEQRES 11 A 306 ARG PRO ASN PHE THR ILE LYS GLY SER PHE LEU ASN GLY
SEQRES 12 A 306 SER CYS GLY SER VAL GLY PHE ASN ILE ASP TYR ASP CYS
SEQRES 13 A 306 VAL SER PHE CYS TYR MET HIS HIS MET GLU LEU PRO THR
SEQRES 14 A 306 GLY VAL HIS ALA GLY THR ASP LEU GLU GLY ASN PHE TYR
SEQRES 15 A 306 GLY PRO PHE VAL ASP ARG GLN THR ALA GLN ALA ALA GLY
SEQRES 16 A 306 THR ASP THR THR ILE THR VAL ASN VAL LEU ALA TRP LEU
SEQRES 17 A 306 TYR ALA ALA VAL ILE ASN GLY ASP ARG TRP PHE LEU ASN
SEQRES 18 A 306 ARG PHE THR THR THR LEU ASN ASP PHE ASN LEU VAL ALA
SEQRES 19 A 306 MET LYS TYR ASN TYR GLU PRO LEU THR GLN ASP HIS VAL
SEQRES 20 A 306 ASP ILE LEU GLY PRO LEU SER ALA GLN THR GLY ILE ALA
SEQRES 21 A 306 VAL LEU ASP MET CYS ALA SER LEU LYS GLU LEU LEU GLN
SEQRES 22 A 306 ASN GLY MET ASN GLY ARG THR ILE LEU GLY SER ALA LEU
SEQRES 23 A 306 LEU GLU ASP GLU PHE THR PRO PHE ASP VAL VAL ARG GLN
SEQRES 24 A 306 CYS SER GLY VAL THR PHE GLN
"""
has_seqres = 'SEQRES' in pdbfile_contents
if not has_seqres:
#print('Adding SEQRES')
pdbfile_contents = seqres + pdbfile_contents
# Read the receptor and identify design units
from openeye import oespruce, oechem
from tempfile import NamedTemporaryFile
with NamedTemporaryFile(delete=False, mode='wt', suffix='.pdb') as pdbfile:
pdbfile.write(pdbfile_contents)
pdbfile.close()
complex = read_pdb_file(pdbfile.name)
# TODO: Clean up
# Strip protons from structure to allow SpruceTK to add these back
# See: 6wnp, 6wtj, 6wtk, 6xb2, 6xqs, 6xqt, 6xqu, 6m2n
#print('Suppressing hydrogens')
#print(f' Initial: {sum([1 for atom in complex.GetAtoms()])} atoms')
for atom in complex.GetAtoms():
if atom.GetAtomicNum() > 1:
oechem.OESuppressHydrogens(atom)
#print(f' Final: {sum([1 for atom in complex.GetAtoms()])} atoms')
# Delete and rebuild C-terminal residue because Spruce causes issues with this
# See: 6m2n 6lze
#print('Deleting C-terminal residue O')
pred = oechem.OEIsCTerminalAtom()
for atom in complex.GetAtoms():
if pred(atom):
for nbor in atom.GetAtoms():
if oechem.OEGetPDBAtomIndex(nbor) == oechem.OEPDBAtomName_O:
complex.DeleteAtom(nbor)
#pred = oechem.OEAtomMatchResidue(["GLN:306:.*:.*:.*"])
#for atom in complex.GetAtoms(pred):
# if oechem.OEGetPDBAtomIndex(atom) == oechem.OEPDBAtomName_O:
# print('Deleting O')
# complex.DeleteAtom(atom)
#het = oespruce.OEHeterogenMetadata()
#het.SetTitle("LIG") # real ligand 3 letter code
#het.SetID("CovMoonShot1234") # in case you have corporate IDs
#het.SetType(oespruce.OEHeterogenType_Ligand)
# mdata.AddHeterogenMetadata(het)
#print('Identifying design units...')
# Produce zero design units if we fail to protonate
# Log warnings
errfs = oechem.oeosstream(
) # create a stream that writes internally to a stream
oechem.OEThrow.SetOutputStream(errfs)
oechem.OEThrow.Clear()
oechem.OEThrow.SetLevel(
oechem.OEErrorLevel_Verbose) # capture verbose error output
opts = oespruce.OEMakeDesignUnitOptions()
#print(f'ligand atoms: min {opts.GetSplitOptions().GetMinLigAtoms()}, max {opts.GetSplitOptions().GetMaxLigAtoms()}')
opts.GetSplitOptions().SetMinLigAtoms(
7) # minimum fragment size (in heavy atoms)
mdata = oespruce.OEStructureMetadata()
opts.GetPrepOptions().SetStrictProtonationMode(True)
# Both N- and C-termini should be zwitterionic
# Mpro cleaves its own N- and C-termini
# See https://www.pnas.org/content/113/46/12997
opts.GetPrepOptions().GetBuildOptions().SetCapNTermini(False)
opts.GetPrepOptions().GetBuildOptions().SetCapCTermini(False)
# Don't allow truncation of termini, since force fields don't have parameters for this
opts.GetPrepOptions().GetBuildOptions().GetCapBuilderOptions(
).SetAllowTruncate(False)
# Build loops and sidechains
opts.GetPrepOptions().GetBuildOptions().SetBuildLoops(True)
opts.GetPrepOptions().GetBuildOptions().SetBuildSidechains(True)
# Don't flip Gln189
#pred = oechem.OEAtomMatchResidue(["GLN:189: :A"])
pred = oechem.OEAtomMatchResidue(["GLN:189:.*:.*:.*"])
protonate_opts = opts.GetPrepOptions().GetProtonateOptions()
place_hydrogens_opts = protonate_opts.GetPlaceHydrogensOptions()
#place_hydrogens_opts.SetBypassPredicate(pred)
place_hydrogens_opts.SetNoFlipPredicate(pred)
#protonate_opts = oespruce.OEProtonateDesignUnitOptions(place_hydrogens_opts)
#opts.GetPrepOptions().SetProtonateOptions(protonate_options);
# Make design units
design_units = list(oespruce.OEMakeDesignUnits(complex, mdata, opts))
# Restore error stream
oechem.OEThrow.SetOutputStream(oechem.oeerr)
# Capture the warnings to a string
warnings = errfs.str().decode("utf-8")
if len(design_units) >= 1:
design_unit = design_units[0]
print('')
print('')
print(f'{complex_pdb_filename} : SUCCESS')
print(warnings)
elif len(design_units) == 0:
print('')
print('')
print(f'{complex_pdb_filename} : FAILURE')
print(warnings)
msg = f'No design units found for {complex_pdb_filename}\n'
msg += warnings
msg += '\n'
raise Exception(msg)
# Prepare the receptor
#print('Preparing receptor...')
from openeye import oedocking
protein = oechem.OEGraphMol()
design_unit.GetProtein(protein)
ligand = oechem.OEGraphMol()
design_unit.GetLigand(ligand)
# Create receptor and other files
receptor = oechem.OEGraphMol()
oedocking.OEMakeReceptor(receptor, protein, ligand)
oedocking.OEWriteReceptorFile(receptor, receptor_filename)
with oechem.oemolostream(f'{prefix}-protein.pdb') as ofs:
oechem.OEWriteMolecule(ofs, protein)
with oechem.oemolostream(f'{prefix}-ligand.mol2') as ofs:
oechem.OEWriteMolecule(ofs, ligand)
with oechem.oemolostream(f'{prefix}-ligand.pdb') as ofs:
oechem.OEWriteMolecule(ofs, ligand)
with oechem.oemolostream(f'{prefix}-ligand.sdf') as ofs:
oechem.OEWriteMolecule(ofs, ligand)
# Filter out UNK from PDB files (which have covalent adducts)
pdbfile_lines = [
line for line in open(f'{prefix}-protein.pdb', 'r')
if 'UNK' not in line
]
with open(f'{prefix}-protein.pdb', 'wt') as outfile:
outfile.write(''.join(pdbfile_lines))
# Adjust protonation state of CYS145 to generate thiolate form
#print('Deprotonating CYS145...') # DEBUG
#pred = oechem.OEAtomMatchResidue(["CYS:145: :A"])
pred = oechem.OEAtomMatchResidue(["CYS:145:.*:.*:.*"])
place_hydrogens_opts.SetBypassPredicate(pred)
for atom in protein.GetAtoms(pred):
if oechem.OEGetPDBAtomIndex(atom) == oechem.OEPDBAtomName_SG:
#print('Modifying CYS 145 SG')
oechem.OESuppressHydrogens(atom)
atom.SetFormalCharge(-1)
atom.SetImplicitHCount(0)
#print('Protonating HIS41...') # DEBUG
#pred = oechem.OEAtomMatchResidue(["HIS:41: :A"])
pred = oechem.OEAtomMatchResidue(["HIS:41:.*:.*:.*"])
place_hydrogens_opts.SetBypassPredicate(pred)
for atom in protein.GetAtoms(pred):
if oechem.OEGetPDBAtomIndex(atom) == oechem.OEPDBAtomName_ND1:
#print('Protonating HIS 41 ND1')
oechem.OESuppressHydrogens(atom) # strip hydrogens from residue
atom.SetFormalCharge(+1)
atom.SetImplicitHCount(1)
# Update the design unit with the modified formal charge for CYS 145 SG
oechem.OEUpdateDesignUnit(design_unit, protein,
oechem.OEDesignUnitComponents_Protein)
# Don't flip Gln189
#pred = oechem.OEAtomMatchResidue(["GLN:189: :A"])
#protonate_opts = opts.GetPrepOptions().GetProtonateOptions();
#place_hydrogens_opts = protonate_opts.GetPlaceHydrogensOptions()
#place_hydrogens_opts.SetNoFlipPredicate(pred)
# Adjust protonation states
#print('Re-optimizing hydrogen positions...') # DEBUG
#place_hydrogens_opts = oechem.OEPlaceHydrogensOptions()
#place_hydrogens_opts.SetBypassPredicate(pred)
#protonate_opts = oespruce.OEProtonateDesignUnitOptions(place_hydrogens_opts)
success = oespruce.OEProtonateDesignUnit(design_unit, protonate_opts)
design_unit.GetProtein(protein)
# Write thiolate form of receptor
receptor = oechem.OEGraphMol()
oedocking.OEMakeReceptor(receptor, protein, ligand)
oedocking.OEWriteReceptorFile(receptor, thiolate_receptor_filename)
with oechem.oemolostream(f'{prefix}-protein-thiolate.pdb') as ofs:
oechem.OEWriteMolecule(ofs, protein)
# Filter out UNK from PDB files (which have covalent adducts)
pdbfile_lines = [
line for line in open(f'{prefix}-protein-thiolate.pdb', 'r')
if 'UNK' not in line
]
with open(f'{prefix}-protein-thiolate.pdb', 'wt') as outfile:
outfile.write(''.join(pdbfile_lines))