def convert_dict_to_mols(tot_dict):
"""
:param tot_dict:
:return:
"""
mol_list = []
for smiles in tot_dict:
# Now generate the molecules for that
mol = RWMol()
atoms = tot_dict[smiles]
print(atoms)
for atom in atoms:
atom = Atom(6)
mol.AddAtom(atom)
# for i in range(len(atoms)-1):
# mol.AddBond(i,i+1)
mol = mol.GetMol()
AllChem.EmbedMolecule(mol)
conf = mol.GetConformer()
for i, atom in enumerate(atoms):
point_3d = Point3D(atom[0], atom[1], atom[2])
conf.SetAtomPosition(i, point_3d)
mol = conf.GetOwningMol()
mol.SetProp("_Name", smiles)
mol_list.append(mol)
return mol_list
def posthoc_refine(self, scaffold):
"""
Averages the overlapping atoms.
:param scaffold:
:return:
"""
refined = Chem.RWMol(scaffold)
refconf = refined.GetConformer()
positions = defaultdict(list)
for h in self.hits:
hc = h.GetConformer()
for k, v in self.get_positional_mapping(scaffold, h).items():
positions[k].append([
hc.GetAtomPosition(v).x,
hc.GetAtomPosition(v).y,
hc.GetAtomPosition(v).z
])
for i in range(scaffold.GetNumAtoms()):
if len(positions[i]) == 0:
continue
warn(
f'Atom {i} {scaffold.GetAtomWithIdx(i).GetSymbol}/{refined.GetAtomWithIdx(i).GetSymbol} in scaffold that has no positions.'
)
p = np.mean(np.array(positions[i]), axis=0).astype(float)
refconf.SetAtomPosition(i, Point3D(p[0], p[1], p[2]))
Chem.SanitizeMol(
refined,
sanitizeOps=Chem.rdmolops.SanitizeFlags.SANITIZE_ADJUSTHS +
Chem.rdmolops.SanitizeFlags.SANITIZE_SETAROMATICITY,
catchErrors=True)
return refined
def test2_1_GetDonor2FeatVects(self):
'''Case 2.1: one hydrogen with sp2 arrangement'''
conf = self.mol.GetConformer(-1)
case21 = GetDonor2FeatVects(conf, [1], scale=1.5)
pos_heavy_atom = conf.GetAtomPosition(1)
#Check if there is one vector
self.assertEqual(len(case21[0]), 1, 'Incorrect number of vectors')
#Check initial point of the vector
self.assertListAlmostEqual(case21[0][0][0], pos_heavy_atom,
'Incorrect starting point of vector')
#Check direction of the vector
vec_h = conf.GetAtomPosition(8) - (pos_heavy_atom)
vec = case21[0][0][1] - case21[0][0][0]
self.assertListAlmostEqual(vec.CrossProduct(vec_h), Point3D(0, 0, 0),
'Incorrect direction of vector')
self.assertTrue(
vec.DotProduct(vec_h) > 0, 'Incorrect direction of vector')
#Check length of the vector
self.assertAlmostEqual(vec.Length(),
1.5,
msg='Incorrect length of vector')
def test3_GetDonor2FeatVects(self):
'''Case 3: no hydrogens'''
conf = self.mol.GetConformer(-1)
case3 = GetDonor2FeatVects(conf, [3], scale=1.5)
pos_heavy_atom = conf.GetAtomPosition(3)
#Check if there is one vector
self.assertEqual(len(case3[0]), 1, 'Incorrect number of vectors')
#Check initial point of the vector
self.assertListAlmostEqual(case3[0][0][0], pos_heavy_atom,
'Incorrect starting point of vector')
#Check direction of the vector
vec_nbr1 = conf.GetAtomPosition(2) - pos_heavy_atom
vec_nbr1.Normalize()
vec_nbr2 = conf.GetAtomPosition(4) - pos_heavy_atom
vec_nbr2.Normalize()
avg_vec = (vec_nbr1 + vec_nbr2)
vec = case3[0][0][1] - case3[0][0][0]
self.assertListAlmostEqual(vec.CrossProduct(avg_vec), Point3D(0, 0, 0),
'Incorrect direction of vector')
self.assertTrue(
vec.DotProduct(avg_vec) < 0, 'Incorrect direction of vector')
#Check length of the vector
self.assertAlmostEqual(vec.Length(),
1.5,
msg='Incorrect length of vector')
def _place_between(self, mol: Chem.RWMol, a: int, b: int, aromatic=True):
oribond = mol.GetBondBetweenAtoms(a, b)
if oribond is None:
print('FAIL')
return None # fail
elif aromatic:
bt = Chem.BondType.AROMATIC
else:
bt = oribond.GetBondType()
idx = mol.AddAtom(Chem.Atom(6))
neoatom = mol.GetAtomWithIdx(idx)
atom_a = mol.GetAtomWithIdx(a)
atom_b = mol.GetAtomWithIdx(b)
if aromatic:
neoatom.SetIsAromatic(True)
atom_a.SetIsAromatic(True)
atom_b.SetIsAromatic(True)
# prevent constraints
neoatom.SetBoolProp('_Novel', True)
atom_a.SetBoolProp('_Novel', True)
atom_b.SetBoolProp('_Novel', True)
# fix position
conf = mol.GetConformer()
pos_A = conf.GetAtomPosition(a)
pos_B = conf.GetAtomPosition(b)
x = pos_A.x / 2 + pos_B.x / 2
y = pos_A.y / 2 + pos_B.y / 2
z = pos_A.z / 2 + pos_B.z / 2
conf.SetAtomPosition(idx, Point3D(x, y, z))
# fix bonds
mol.RemoveBond(a, b)
mol.AddBond(a, idx, bt)
mol.AddBond(b, idx, bt)
def test2_2_GetDonor2FeatVects(self):
#Case 2.2: one hydrogen with sp3 arrangement
conf = self.mol.GetConformer(-1)
case22 = GetDonor2FeatVects(conf, [4], scale=1.5)
pos_heavy_atom = conf.GetAtomPosition(4)
#Check if there are two vectors
self.assertEqual(len(case22[0]), 2, 'Incorrect number of vectors')
#Check initial points of the vectors
self.assertListAlmostEqual(case22[0][0][0], pos_heavy_atom,
'Incorrect starting point of vector 1')
self.assertListAlmostEqual(case22[0][1][0], pos_heavy_atom,
'Incorrect starting point of vector 2')
#Check directions of the vectors
vec_h = conf.GetAtomPosition(11) - pos_heavy_atom
vec_nbr1 = conf.GetAtomPosition(3) - pos_heavy_atom
vec_nbr1.Normalize()
vec_nbr2 = conf.GetAtomPosition(5) - pos_heavy_atom
vec_nbr2.Normalize()
avg_vec = (vec_nbr1 + vec_nbr2)
vec_1 = case22[0][0][1] - case22[0][0][0]
vec_2 = case22[0][1][1] - case22[0][1][0]
self.assertListAlmostEqual(vec_1.CrossProduct(vec_h), Point3D(0, 0, 0),
'Incorrect direction of vector 1')
self.assertTrue(
vec_1.DotProduct(vec_h) > 0, 'Incorrect direction of vector 1')
self.assertListAlmostEqual(vec_2.CrossProduct(avg_vec),
Point3D(0, 0, 0),
'Incorrect direction of vector 2')
self.assertTrue(
vec_2.DotProduct(avg_vec) < 0, 'Incorrect direction of vector 2')
#Check length of the vectors
self.assertAlmostEqual(vec_1.Length(),
1.5,
msg='Incorrect length of vector 1')
self.assertAlmostEqual(vec_2.Length(),
1.5,
msg='Incorrect length of vector 2')
def RDMolFromGraphs(node_list, adjacency_matrix, xyz_coord, remap=None):
#xyz_mean = [0.5567917341433811, 0.10013086135351022, 0.006413393431574624]
#xyz_std = [3.40762324684836, 2.6455335437418093, 2.3609727916942096]
#print(xyz_coord)
#xyz_coord = xyz_coord * xyz_std + xyz_mean
#print(xyz_coord)
# create empty editable mol object
mol = Chem.RWMol()
conformer = Chem.Conformer(len(node_list))
#print(xyz_coord)
# add atoms to mol and keep track of index
node_to_idx = {}
for i in range(len(node_list)):
a = Chem.Atom(node_list[i])
atom_position = Point3D(xyz_coord[i, 0], xyz_coord[i, 1], xyz_coord[i,
2])
#print(a)
conformer.SetAtomPosition(i, atom_position)
molIdx = mol.AddAtom(a)
node_to_idx[i] = molIdx
# add bonds between adjacent atoms
xx, yy = np.where(np.triu(adjacency_matrix, k=1))
vv = adjacency_matrix[xx, yy]
for ix, iy, bond in zip(xx, yy, vv):
# add relevant bond type (there are many more of these)
if remap is not None:
bond = remap[bond]
if bond == 1.:
bond_type = Chem.rdchem.BondType.SINGLE
mol.AddBond(node_to_idx[ix], node_to_idx[iy], bond_type)
elif bond == 1.5:
bond_type = Chem.rdchem.BondType.AROMATIC
mol.AddBond(node_to_idx[ix], node_to_idx[iy], bond_type)
elif bond == 2.:
bond_type = Chem.rdchem.BondType.DOUBLE
mol.AddBond(node_to_idx[ix], node_to_idx[iy], bond_type)
elif bond == 3.:
bond_type = Chem.rdchem.BondType.TRIPLE
mol.AddBond(node_to_idx[ix], node_to_idx[iy], bond_type)
else:
raise ValueError("Invalid bond type in matrix")
# Convert RWMol to Mol object
mol = mol.GetMol()
Chem.Kekulize(mol)
Chem.SanitizeMol(mol)
# Convert RWMol to SMILES
# Chem.RemoveHs(mol)
smiles = Chem.MolToSmiles(mol, kekuleSmiles=False)
#print(smiles)
# Add 3D conformation to RDKit molecule
added_conformer = mol.AddConformer(conformer, assignId=True)
return smiles, mol
def mol_from_json(symbols, connectivity, geometry, permute_xyz=False):
"""
Generate RDkit.Chem.Mol from QCSchema molecule specs.
Parameters
----------
inp_molecule: dict
Must include symbols and connectivity. Geometry is optional. If geometry is given, stereochemistry will be taken
from coordinates
Returns
-------
molecule: rdkit.Chem.Mol
"""
from rdkit.Geometry.rdGeometry import Point3D
_BO_DISPATCH_TABLE = {
1: Chem.BondType.SINGLE,
2: Chem.BondType.DOUBLE,
3: Chem.BondType.TRIPLE
}
geometry = geometry.reshape(int(len(geometry) / 3), 3)
conformer = Chem.Conformer(len(symbols))
has_geometry = True
molecule = Chem.Mol()
em = Chem.RWMol(molecule)
for i, s in enumerate(symbols):
atom = em.AddAtom(Chem.Atom(_symbols[s]))
atom_position = Point3D(geometry[i][0], geometry[i][1], geometry[i][2])
conformer.SetAtomPosition(atom, atom_position)
# Add connectivity
for bond in connectivity:
bond_type = _BO_DISPATCH_TABLE[bond[-1]]
em.AddBond(bond[0], bond[1], bond_type)
molecule = em.GetMol()
try:
Chem.SanitizeMol(molecule)
except:
raise RuntimeError("Could not sanitize molecule")
# Add coordinates
if has_geometry:
initial_conformer_id = molecule.AddConformer(conformer, assignId=True)
# Assign stereochemistry from coordinates
from rdkit.Chem import rdmolops
rdmolops.AssignStereochemistryFrom3D(molecule,
confId=initial_conformer_id,
replaceExistingTags=True)
if not permute_xyz:
# Add a tag to keep current order
molecule.SetProp("_json_geometry", '1')
return molecule
def coordinates(self, positions):
"""
Parameter
--------
positions; numpy [natoms,3]
"""
conf = self._mol.GetConformer()
for i, p in enumerate(positions.astype(np.float64)):
p3d = Point3D(p[0], p[1], p[2])
conf.SetAtomPosition(i, p3d)
def posthoc_refine(self,
scaffold,
indices: Optional[List[int]] = None) -> Chem.Mol:
"""
Averages the overlapping atoms.
:param scaffold:
:return:
"""
if indices is None:
indices = list(range(scaffold.GetNumAtoms()))
refined = Chem.RWMol(scaffold)
refconf = refined.GetConformer()
positions = defaultdict(list) # coordinates
equivalence = defaultdict(list) # atom indices of hits.
for h in self.hits:
if h.GetProp('_Name') in self.unmatched:
continue
hc = h.GetConformer()
for k, v in self.get_positional_mapping(scaffold, h).items():
positions[k].append([
hc.GetAtomPosition(v).x,
hc.GetAtomPosition(v).y,
hc.GetAtomPosition(v).z
])
equivalence[k].append(f'{h.GetProp("_Name")}.{v}')
for i in range(scaffold.GetNumAtoms()):
if i not in indices:
continue
elif len(positions[i]) == 0:
refined.GetAtomWithIdx(i).SetDoubleProp('_Stdev', 0.)
refined.GetAtomWithIdx(i).SetDoubleProp('_Max', 0.)
refined.GetAtomWithIdx(i).SetProp('_Origin', 'none')
# warn(f'Atom {i} {scaffold.GetAtomWithIdx(i).GetSymbol}/{refined.GetAtomWithIdx(i).GetSymbol} '+ \
# 'in scaffold that has no positions.')
else:
p = np.mean(np.array(positions[i]), axis=0).astype(float)
# sd = np.mean(np.std(np.array(positions[i]), axis=0)).astype(float)
ds = [np.linalg.norm(p - pi) for pi in positions[i]]
sd = np.std(ds)
md = np.max(ds)
refined.GetAtomWithIdx(i).SetProp('_Origin',
json.dumps(equivalence[i]))
refined.GetAtomWithIdx(i).SetDoubleProp('_Stdev', sd)
refined.GetAtomWithIdx(i).SetDoubleProp('_Max', md)
if self.average_position:
refconf.SetAtomPosition(i, Point3D(p[0], p[1], p[2]))
Chem.SanitizeMol(
refined,
sanitizeOps=Chem.rdmolops.SanitizeFlags.SANITIZE_ADJUSTHS +
Chem.rdmolops.SanitizeFlags.SANITIZE_SETAROMATICITY,
catchErrors=True)
return refined
def test1_GetDonor2FeatVects(self):
'''Case 1: two hydrogens'''
conf = self.mol.GetConformer(-1)
case1 = GetDonor2FeatVects(conf, [2], scale=1.5)
pos_heavy_atom = conf.GetAtomPosition(2)
#Check if there are two vectors
self.assertEqual(len(case1[0]), 2, 'Incorrect number of vectors')
#Check initial points of the vectors
self.assertListAlmostEqual(case1[0][0][0], pos_heavy_atom,
'Incorrect starting point of vector 1')
self.assertListAlmostEqual(case1[0][1][0], pos_heavy_atom,
'Incorrect starting point of vector 2')
#Check directions of the vectors
vec_h1 = conf.GetAtomPosition(9) - pos_heavy_atom
vec_h2 = conf.GetAtomPosition(10) - pos_heavy_atom
vec_1 = case1[0][0][1] - case1[0][0][0]
vec_2 = case1[0][1][1] - case1[0][1][0]
self.assertListAlmostEqual(vec_1.CrossProduct(vec_h1),
Point3D(0, 0, 0),
'Incorrect direction of vector 1')
self.assertTrue(
vec_1.DotProduct(vec_h1) > 0, 'Incorrect direction of vector 1')
self.assertListAlmostEqual(vec_2.CrossProduct(vec_h2),
Point3D(0, 0, 0),
'Incorrect direction of vector 2')
self.assertTrue(
vec_2.DotProduct(vec_h2) > 0, 'Incorrect direction of vector 2')
#Check length of the vectors
self.assertAlmostEqual(vec_1.Length(),
1.5,
msg='Incorrect length of vector 1')
self.assertAlmostEqual(vec_2.Length(),
1.5,
msg='Incorrect length of vector 2')
def estimate_geometry_of_mol(rdmol):
'''Wrapper to estimate the geometry of general molecule using rdkit. The method is mainly meant for dealing with
dummy atoms and metals in the molecule'''
# TODO: generalize method for metals / dummy atoms
rdmol.UpdatePropertyCache(strict=False)
rdmol = Chem.rdchem.RWMol(rdmol)
# checks for dative bonds in struct and removing atoms
remove_atoms = []
neighbor_atoms = []
for atom in rdrdmol.GetAtoms():
if len(atom.GetBonds()) > 3 and atom.GetAtomicNum() > 10:
remove_atoms.append(atom)
neighbor_atoms.append(atom.GetNeighbors())
for atom in remove_atoms:
rdmol.RemoveAtom(atom.GetIdx())
# calculating geometry
AllChem.EmbedMolecule(rdmol)
# fixing coordinates for fragments
frags_idxs = list(Chem.rdmolops.GetMolFrags(rdmol))
conf = rdmol.GetConformer()
if len(frags_idxs) > 1:
for frag_idxs in frags_idxs:
diff = (0.5 - np.random.rand()) * 5 * np.ones(3)
for idx in frag_idxs:
vec = conf.GetAtomPos(idx)
vec = np.array([vec.x, vec.y, vec.z]) + diff
conf.SetAtomPosition(i, Point3D(vec[0], vec[1], vec[2]))
# adding dative atoms and setting coords
for atom, nbors in zip(remove_atoms, neighbor_atoms):
coords = np.zeros(0)
for neighbor in nbors:
vec = conf.GetAtomPosition(neighbor.GetIdx())
coord += np.array([vec.x, vec.y, vec.z])
rdmol.AddAtom(atom)
rdmol.AddBond(atom.GetIdx(), neighbor.GetIdx(), order=Chem.rdchem.BondType.DATIVE)
coords = coords / len(nbors)
conf.SetAtomPosition(atom.GetIdx(), Point3D(coords[0], coords[1], coords[2]))
rdmol.UpdatePropertyCache(strict=False)
Chem.GetSymmSSSR(rdmol)
return rdmol
def substructure_centre(mol, mol_sub):
"""
This function takes a molecule and a list of atom indices
in that molecule and returns an RDKit Point3D representing
the geometric centre of the atoms in the list
"""
sum = Point3D()
for i in mol_sub:
sum += mol.GetConformer().GetAtomPosition(i)
return sum / len(mol_sub)
def add_canvas_atom(self, point):
rwmol = Chem.rdchem.RWMol(self.mol)
if rwmol.GetNumAtoms() == 0:
point.x = 0.0
point.y = 0.0
newatom = Chem.rdchem.Atom(self.atomtype)
newidx = rwmol.AddAtom(newatom)
#This should only trigger if we have an empty canvas
if not rwmol.GetNumConformers():
rdDepictor.Compute2DCoords(rwmol)
conf = rwmol.GetConformer(0)
p3 = Point3D(point.x, point.y, 0)
conf.SetAtomPosition(newidx, p3)
self.mol = rwmol
def _place_between(self,
a: int,
b: int,
aromatic: Optional[bool] = None,
atomic_number: int = 6) -> None:
"""
Places an C atom, possibly of type aromatic, between atom of index a, and of b.
:param a: index of atom A
:param b: index of atom B
:param aromatic: bool of aromaticity (False = Single, None = copy, True = aromatic)
:param atomic_number: Carbon is 6.
:return:
"""
oribond = self.rwmol.GetBondBetweenAtoms(a, b)
if oribond is None:
self.journal.critical(
f'FAIL. There should be a bond btween {a} and {b}')
return None # fail
elif aromatic is True:
bt = Chem.BondType.AROMATIC
elif aromatic is False:
bt = Chem.BondType.SINGLE
else:
bt = oribond.GetBondType()
idx = self.rwmol.AddAtom(Chem.Atom(atomic_number))
neoatom = self.rwmol.GetAtomWithIdx(idx)
atom_a = self.rwmol.GetAtomWithIdx(a)
atom_b = self.rwmol.GetAtomWithIdx(b)
if aromatic:
neoatom.SetIsAromatic(True)
atom_a.SetIsAromatic(True)
atom_b.SetIsAromatic(True)
# prevent constraints
neoatom.SetBoolProp('_Novel', True)
atom_a.SetBoolProp('_Novel', True)
atom_b.SetBoolProp('_Novel', True)
# fix position
conf = self.rwmol.GetConformer()
pos_A = conf.GetAtomPosition(a)
pos_B = conf.GetAtomPosition(b)
x = pos_A.x / 2 + pos_B.x / 2
y = pos_A.y / 2 + pos_B.y / 2
z = pos_A.z / 2 + pos_B.z / 2
conf.SetAtomPosition(idx, Point3D(x, y, z))
# fix bonds
self.rwmol.RemoveBond(a, b)
self.rwmol.AddBond(a, idx, bt)
self.rwmol.AddBond(b, idx, bt)
def add_conformer(self, mol, conformer_coordinates):
"""
Add a new conformation to the rdkit molecule
:param conformer_coordinates: A numpy array of the coordinates to be added
:param mol: The rdkit molecule instance
:return: The rdkit molecule with the conformer added
"""
conformer = Chem.Conformer()
for i, coord in enumerate(conformer_coordinates):
atom_position = Point3D(*coord)
conformer.SetAtomPosition(i, atom_position)
mol.AddConformer(conformer, assignId=True)
return mol
def _place_ring_atoms(self, mol, rings):
conf = mol.GetConformer()
for ring in rings:
# atom addition
for i in range(len(ring['elements'])):
d = self._get_expansion_for_atom(ring, i)
if self._is_present(mol, d['ori_i']):
natom = self._get_new_index(mol, d['ori_i'], search_collapsed=False)
if self._debug_draw:
print(f"{natom} (formerly {d['ori_i']} existed already!")
else:
n = mol.AddAtom(Chem.Atom(d['element']))
natom = mol.GetAtomWithIdx(n)
conf.SetAtomPosition(n, Point3D(d['x'], d['y'], d['z']))
natom.SetIntProp('_ori_i', d['ori_i'])
natom.SetDoubleProp('_x', d['x'])
natom.SetDoubleProp('_y', d['y'])
natom.SetDoubleProp('_z', d['z'])
natom.SetProp('_ori_name', d['ori_name'])
def add_conformer(rdkit_mol: Chem.Mol,
conformer_coordinates: np.ndarray) -> Chem.Mol:
"""
Add a new conformation to the rdkit molecule.
Args:
rdkit_mol:
The rdkit molecule instance
conformer_coordinates:
A numpy array of the coordinates to be added
return:
The rdkit molecule with the conformer added
"""
conformer = Chem.Conformer()
for i, coord in enumerate(conformer_coordinates):
atom_position = Point3D(*coord)
conformer.SetAtomPosition(i, atom_position)
rdkit_mol.AddConformer(conformer, assignId=True)
return rdkit_mol
def z_rotation(vector, theta):
"""Rotates 3-D vector around z-axis"""
R = np.array([[np.cos(theta), -np.sin(theta), 0],
[np.sin(theta), np.cos(theta), 0], [0, 0, 1]])
output = np.dot(R, [vector.x, vector.y, vector.z])
return Point3D(output[0], output[1], output[2])
def collapse_ring(self, mol: Chem.Mol) -> Chem.Mol:
"""
Collapses a ring(s) into a single dummy atom(s).
Stores data as JSON in the atom.
:param mol:
:return:
"""
self.store_positions(mol)
mol = Chem.RWMol(mol)
conf = mol.GetConformer()
center_idxs = []
morituri = []
old2center = defaultdict(list)
for atomset in mol.GetRingInfo().AtomRings():
morituri.extend(atomset)
neighs = []
neighbonds = []
bonds = []
xs = []
ys = []
zs = []
elements = []
# add elemental ring
c = mol.AddAtom(Chem.Atom('C'))
center_idxs.append(c)
central = mol.GetAtomWithIdx(c)
name = mol.GetProp('_Name') if mol.HasProp('_Name') else '???'
central.SetProp('_ori_name', name),
# get data for storage
for i in atomset:
old2center[i].append(c)
atom = mol.GetAtomWithIdx(i)
neigh_i = [a.GetIdx() for a in atom.GetNeighbors()]
neighs.append(neigh_i)
bond = [mol.GetBondBetweenAtoms(i, j).GetBondType().name for j in neigh_i]
bonds.append(bond)
pos = conf.GetAtomPosition(i)
xs.append(pos.x)
ys.append(pos.y)
zs.append(pos.z)
elements.append(atom.GetSymbol())
# store data in elemental ring
central.SetIntProp('_ori_i', -1)
central.SetProp('_ori_is', json.dumps(atomset))
central.SetProp('_neighbors', json.dumps(neighs))
central.SetProp('_xs', json.dumps(xs))
central.SetProp('_ys', json.dumps(ys))
central.SetProp('_zs', json.dumps(zs))
central.SetProp('_elements', json.dumps(elements))
central.SetProp('_bonds', json.dumps(bonds))
conf.SetAtomPosition(c, Point3D(*[sum(axis) / len(axis) for axis in (xs, ys, zs)]))
for atomset, center_i in zip(mol.GetRingInfo().AtomRings(), center_idxs):
# bond to elemental ring
central = mol.GetAtomWithIdx(center_i)
neighss = json.loads(central.GetProp('_neighbors'))
bondss = json.loads(central.GetProp('_bonds'))
for neighs, bonds in zip(neighss, bondss):
for neigh, bond in zip(neighs, bonds):
if neigh not in atomset:
bt = getattr(Chem.BondType, bond)
if neigh not in morituri:
mol.AddBond(center_i, neigh, bt)
else:
for other_center_i in old2center[neigh]:
if center_i != other_center_i:
if not mol.GetBondBetweenAtoms(center_i, other_center_i):
mol.AddBond(center_i, other_center_i, bt)
break
else:
raise ValueError(f'Cannot find what {neigh} became')
for i in sorted(set(morituri), reverse=True):
mol.RemoveAtom(self._get_new_index(mol, i))
return mol.GetMol()
def _join_atoms(self,
combo: Chem.RWMol,
anchor_A: int,
anchor_B: int,
distance: float,
linking: bool = True):
"""
extrapolate positions between. by adding linkers if needed.
"""
conf = combo.GetConformer()
pos_A = conf.GetAtomPosition(anchor_A)
pos_B = conf.GetAtomPosition(anchor_B)
n_new = int(round(distance / 1.22) - 1)
xs = np.linspace(pos_A.x, pos_B.x, n_new + 2)[1:-1]
ys = np.linspace(pos_A.y, pos_B.y, n_new + 2)[1:-1]
zs = np.linspace(pos_A.z, pos_B.z, n_new + 2)[1:-1]
# correcting for ring marker atoms
def is_ring_atom(anchor: int) -> bool:
atom = combo.GetAtomWithIdx(anchor)
if atom.HasProp('_ori_i') and atom.GetIntProp('_ori_i') == -1:
return True
else:
return False
if is_ring_atom(anchor_A):
distance -= 1.35 + 0.2 # Arbitrary + 0.2 to compensate for the ring not reaching (out of plane).
n_new -= 1
xs = xs[1:]
ys = ys[1:]
zs = zs[1:]
if is_ring_atom(anchor_B):
distance -= 1.35 + 0.2 # Arbitrary + 0.2 to compensate for the ring not reaching (out of plane).
n_new -= 1
xs = xs[:-1]
ys = ys[:-1]
zs = zs[:-1]
# notify that things could be leary.
if distance < 0:
self.journal.debug(
f'Two ring atoms detected to be close. Joining for now.' +
' They will be bonded/fused/spiro afterwards')
# check if valid.
if distance > self.joining_cutoff:
msg = f'Atoms {anchor_A}+{anchor_B} are {distance} Å away. Cutoff is {self.joining_cutoff}.'
self.journal.warning(msg)
raise ConnectionError(msg)
# place new atoms
self.journal.debug(
f'Molecules will be joined via atoms {anchor_A}+{anchor_B} ({distance} Å) via the addition of {n_new} atoms.'
)
previous = anchor_A
if linking is False and n_new > 0:
self.journal.warning(
f'Was going to bond {anchor_A} and {anchor_B} but reconsidered.'
)
elif linking is True and n_new <= 0:
combo.AddBond(previous, anchor_B, Chem.BondType.SINGLE)
new_bond = combo.GetBondBetweenAtoms(previous, anchor_B)
BondProvenance.set_bond(new_bond, 'main_novel')
elif linking is False and n_new <= 0:
combo.AddBond(previous, anchor_B, Chem.BondType.SINGLE)
new_bond = combo.GetBondBetweenAtoms(previous, anchor_B)
BondProvenance.set_bond(new_bond, 'other_novel')
elif linking is True and n_new > 0:
for i in range(n_new):
# make oxygen the first and last bridging atom.
if i == 0 and combo.GetAtomWithIdx(
anchor_A).GetSymbol() == 'C':
new_atomic = 8
elif i > 2 and i == n_new - 1 and combo.GetAtomWithIdx(
anchor_B).GetSymbol() == 'C':
new_atomic = 8
else:
new_atomic = 6
idx = combo.AddAtom(Chem.Atom(new_atomic))
new = combo.GetAtomWithIdx(idx)
new.SetBoolProp('_Novel', True)
new.SetIntProp('_ori_i', 999)
conf.SetAtomPosition(
idx, Point3D(float(xs[i]), float(ys[i]), float(zs[i])))
combo.AddBond(idx, previous, Chem.BondType.SINGLE)
new_bond = combo.GetBondBetweenAtoms(idx, previous)
BondProvenance.set_bond(new_bond, 'linker')
previous = idx
combo.AddBond(previous, anchor_B, Chem.BondType.SINGLE)
new_bond = combo.GetBondBetweenAtoms(previous, anchor_B)
BondProvenance.set_bond(new_bond, 'linker')
else:
raise ValueError('Impossible')
return combo.GetMol()
def calculate_charges(smiles, resp_type, overwrite=False):
"""Run the charge calculation for the molecule defined by smiles
Parameters
----------
smiles: str
the smiles string of the desired molecule
resp_type: str
the type of RESP to perform (RESP1 or RESP2)
overwrite: boolean, optional, default=False
overwrite the previous results if they exist
Returns
-------
Raises
------
InvalidMoleculeError
if the smiles string is invalid
"""
smiles = canonicalize_smiles(smiles)
iupac_name = smiles_to_iupac(smiles)
mol_path = Path.joinpath(LIB_PATH, iupac_name)
if not mol_path.is_dir():
raise RESPLibraryError(
f"The directory for the molecule: '{smiles}' with name "
f"{iupac_name} does not exist. Please run "
"resp_library.prepare_charge_calculation() first.")
# Initialize RESP stuff
resp_type = resp_type.upper()
resp_path = Path.joinpath(mol_path, resp_type)
if not overwrite:
if Path.joinpath(resp_path, "results").is_dir():
raise RESPLibraryError(
"It appears that this partial charge calculation "
"has already been attempted or performed. If you wish "
"to re-run this calculation, please remove the 'results', "
"'structures', and 'esp_grids' directories before proceeding.")
inp, log = _initialize_resp(resp_path)
# Molecule definition
assert inp['smiles'] == smiles
assert inp['resp']['type'].upper() == resp_type
# Parse the YAML file
n_conformers = inp['conformer_generation']['n_conformers']
rms_threshold = inp['conformer_generation']['rms_threshold']
energy_threshold = inp['conformer_generation'][
'energy_threshold'] # kJ/mol
conformer_seed = inp['conformer_generation']['random_seed']
charge_constraints = inp['resp']['charge_constraints']
equality_constraints = inp['resp']['equality_constraints']
point_density = inp['resp']['point_density']
vdw_scale_factors = inp['resp']['vdw_scale_factors']
if resp_type == "RESP1":
esp_method = "hf"
esp_basis_set = "6-31g*"
elif resp_type == "RESP2":
esp_method = "pw6b95"
esp_basis_set = "aug-cc-pV(D+d)Z"
else:
raise RESPLibraryError(
"Invalid RESP type. Only 'RESP1' and 'RESP2' are supported.")
# Create the molecule, add H's
rdmol = Chem.MolFromSmiles(smiles)
rdmol = Chem.AddHs(rdmol)
# Get the net charge
net_charge = Chem.rdmolops.GetFormalCharge(rdmol)
log.log(f"The net charge is {net_charge}.")
# Get the elements
elements = [a.GetSymbol() for a in rdmol.GetAtoms()]
vdw_radii = {
elem_sym: ele.element_from_symbol(elem_sym).radius_bondi
for elem_sym in elements
}
# Generate conformers
cids = AllChem.EmbedMultipleConfs(rdmol,
numConfs=500,
pruneRmsThresh=rms_threshold,
randomSeed=conformer_seed)
AllChem.AlignMolConformers(rdmol)
if len(cids) < n_conformers:
raise ValueError(
"Not enough conformers found. Please reduce the "
"'rms_threshold' or the 'n_conformers'. For molecules "
"with < 5 atoms it may be difficult to generate more "
"than 2 conformers.")
# Select n_conformers at random
np.random.seed(conformer_seed)
conformer_ids = np.random.choice([i for i in range(len(cids))],
size=n_conformers,
replace=False)
remove = [i for i in range(len(cids)) if i not in conformer_ids]
for idx in remove:
rdmol.RemoveConformer(idx)
# Renumber conformers
for idx, c in enumerate(rdmol.GetConformers()):
c.SetId(idx)
optimized_p4molecules = []
optimized_energies = []
# For each conformer, geometry optimize with psi4
for conformer in rdmol.GetConformers():
p4mol = build_p4mol(elements, conformer.GetPositions(), net_charge)
p4mol, energy = _geometry_optimize(p4mol, resp_type)
# Save optimized structure and energy
optimized_p4molecules.append(p4mol)
optimized_energies.append(energy)
# Extract optimized coordinates; update coordinates RDKIT molecule
coords = p4mol.geometry().to_array() * BOHR_TO_ANGSTROM
for i in range(rdmol.GetNumAtoms()):
x, y, z = coords[i]
conformer.SetAtomPosition(i, Point3D(x, y, z))
# Check energies and remove high energy conformers
_check_relative_conformer_energies(rdmol, optimized_p4molecules,
optimized_energies, energy_threshold,
log)
# Align conformers for easier visual comparison
_save_aligned_conformers(rdmol, log)
# Save the conformers used for resp
Path("structures/optimized_geometries.pdb").write_text(
Chem.rdmolfiles.MolToPDBBlock(rdmol))
log.log(
"Wrote the final optimized gemoetries to 'optimized_geometries.pdb'.\n\n"
)
# Finally we do multi-conformer RESP
pcm = False
charges = _perform_resp(
optimized_p4molecules,
charge_constraints,
equality_constraints,
esp_method,
esp_basis_set,
pcm,
point_density,
vdw_radii,
vdw_scale_factors,
log,
)
_write_results(elements, charges, equality_constraints, "vacuum", log)
if resp_type == "RESP2":
pcm = True
charges = _perform_resp(
optimized_p4molecules,
charge_constraints,
equality_constraints,
esp_method,
esp_basis_set,
pcm,
point_density,
vdw_radii,
vdw_scale_factors,
log,
)
_write_results(elements, charges, equality_constraints, "pcm", log)
log.close()
def apply_shift(mol: rdkit.Mol, shift, conformer=-1):
"""
Shifts the coordinates of all atoms.
This does not modify the molecule. A modified copy is returned.
Parameters
----------
shift : :class:`numpy.array`
A numpy array holding the value of the shift along each
axis.
conformer : :class:`int`, optional
The id of the conformer to use.
Returns
-------
:class:`rdkit.Chem.rdchem.Mol`
A copy of the molecule where the coordinates have been
shifted by `shift`.
"""
# The function does not modify the existing conformer, as a
# result a new instance is created and used for modification.
conf = rdkit.Conformer(mol.GetConformer(conformer))
# For each atom, get the atomic positions from the conformer
# and shift them. Create a new geometry instance from these new
# coordinate values. The geometry instance is used by rdkit to
# store the coordinates of atoms. Finally, set the conformers
# atomic position to the values stored in this newly generated
# geometry instance.
for atom in mol.GetAtoms():
# Remember the id of the atom you are currently using. It
# is used to change the position of the correct atom at the
# end of the loop.
atom_id = atom.GetIdx()
# `atom_position` in an instance holding in the x, y and z
# coordinates of an atom in its 'x', 'y' and 'z'
# attributes.
atom_position = np.array(conf.GetAtomPosition(atom_id))
# Inducing the shift.
new_atom_position = atom_position + shift
# Creating a new geometry instance.
new_coords = Point3D(*new_atom_position)
# Changes the position of the atom in the conformer to the
# values stored in the new geometry instance.
conf.SetAtomPosition(atom_id, new_coords)
# Create a new copy of the rdkit molecule instance representing
# the molecule - the original instance is not to be modified.
new_mol = rdkit.Mol(mol)
# The new rdkit molecule was copied from the one held in the
# `mol` attribute, as result it has a copy of its conformer. To
# prevent the rdkit molecule from holding multiple conformers
# the `RemoveAllConformers` method is run first. The shifted
# conformer is then given to the rdkit molecule, which is
# returned.
new_mol.RemoveAllConformers()
new_mol.AddConformer(conf)
return new_mol
def SampleDist(Heads,
Anchors,
Linkers,
n=200,
output_hist="initial_distances.hist",
hist_threshold=0.75,
min_margin=2,
homo_protac=False):
writer = Chem.SDWriter("random_sampling.sdf")
random.seed(0)
[HeadA_sdf, HeadB_sdf] = Heads
#linkers
with open(Linkers, 'r') as f:
linkers = [Chem.MolFromSmiles(f.readline().split()[0])]
#loading the heads sdf files
HeadA = Chem.SDMolSupplier(HeadA_sdf)[0]
HeadB = Chem.SDMolSupplier(HeadB_sdf)[0]
origin = Point3D(0, 0, 0)
anchor_a = HeadA.GetConformer().GetAtomPosition(Anchors[0])
translateMol(HeadA, origin, anchor_a)
anchor_b = HeadB.GetConformer().GetAtomPosition(Anchors[1])
translateMol(HeadB, origin, anchor_b)
for linker in linkers:
#h**o protacs are protacs with the same binder twice, causing self degradation of an E3 ligase
if homo_protac:
head_A = linker.GetSubstructMatches(HeadA)[0]
head_B = linker.GetSubstructMatches(HeadB)[1]
else:
mcs_A = rdFMCS.FindMCS([linker, HeadA])
mcs_patt_A = Chem.MolFromSmarts(mcs_A.smartsString)
mcs_B = rdFMCS.FindMCS([linker, HeadB])
mcs_patt_B = Chem.MolFromSmarts(mcs_B.smartsString)
#head_A_list = linker.GetSubstructMatches(HeadA, uniquify=False)
head_A_list = linker.GetSubstructMatches(mcs_patt_A,
uniquify=False)
head_A_inner = HeadA.GetSubstructMatch(mcs_patt_A)
#head_B_list = linker.GetSubstructMatches(HeadB, uniquify=False)
head_B_list = linker.GetSubstructMatches(mcs_patt_B,
uniquify=False)
head_B_inner = HeadB.GetSubstructMatch(mcs_patt_B)
print(Chem.MolToSmiles(linker))
print(Chem.MolToSmiles(HeadB))
print(head_B_list)
if len(head_A_list) == 0 or len(head_B_list) == 0:
return (None, None)
histogram = {}
seed = 0
b = 1
while True:
b_counter = 0
for i in range(n):
head_A = random.choice(head_A_list)
head_B = random.choice(head_B_list)
seed += 1
NewA = copy.deepcopy(HeadA)
NewB = copy.deepcopy(HeadB)
randomRotateMol(NewA)
randomRotateMol(NewB)
translateMol(NewB, Point3D(b, 0, 0), origin)
#the constraints for the conformation generation using the two randomized heads
cmap = {
head_A[i]:
NewA.GetConformer().GetAtomPosition(head_A_inner[i])
for i in range(len(head_A))
}
cmap.update({
head_B[i]:
NewB.GetConformer().GetAtomPosition(head_B_inner[i])
for i in range(len(head_B))
})
#only half of the atoms are required to make the constrained embedding
#this is done because using all the atoms sometimes makes it impossible
#to find solutions, the half is chosen randomly for each generation
cmap_tag = random.sample(list(cmap), int(len(cmap) / 2))
cmap_tag = {ctag: cmap[ctag] for ctag in cmap_tag}
if AllChem.EmbedMolecule(linker,
coordMap=cmap_tag,
randomSeed=seed,
useBasicKnowledge=True,
maxAttempts=1) == -1:
continue
if int(
round(
rdMolTransforms.GetBondLength(
linker.GetConformer(), head_A[Anchors[0]],
head_B[Anchors[1]]))) == b:
writer.write(linker)
b_counter += 1
histogram[b] = b_counter
if b >= 10 and b_counter == 0:
break
b += 1
with open(output_hist, 'w') as f:
for h in histogram:
f.write(str(h) + "\t" + str(histogram[h]) + '\n')
max_value = max([histogram[i] for i in histogram])
sum_mul = 0
sum_his = 0
for i in histogram:
sum_mul += i * histogram[i]
sum_his += histogram[i]
if sum_his == 0:
return (0, 0)
else:
avg_index = 1.0 * sum_mul / sum_his
threshold = max_value * hist_threshold
high_values = [i for i in histogram if histogram[i] >= threshold]
return (min(min(high_values), avg_index - min_margin),
max(max(high_values), avg_index + min_margin))
def GenConstConf(Heads,
Docked_Heads,
Head_Linkers,
output_sdf,
Anchor_A,
v_atoms_sdf,
n=100,
homo_protac=False):
writer = Chem.SDWriter(output_sdf)
with open(Head_Linkers, 'r') as f:
head_linkers = [Chem.MolFromSmiles(f.readline().split()[0])]
#loading the heads sdf files
HeadA = Chem.SDMolSupplier(Heads[0])[0]
HeadB = Chem.SDMolSupplier(Heads[1])[0]
docked_heads = Chem.SDMolSupplier(Docked_Heads)[0]
#virtual atoms around the center of mass for the neighbor atom alignment
num_atoms = docked_heads.GetConformer().GetNumAtoms()
x = []
y = []
z = []
for i in range(num_atoms):
x.append(docked_heads.GetConformer().GetAtomPosition(i).x)
y.append(docked_heads.GetConformer().GetAtomPosition(i).y)
z.append(docked_heads.GetConformer().GetAtomPosition(i).z)
v1 = Point3D(sum(x) / num_atoms, sum(y) / num_atoms, sum(z) / num_atoms)
v2 = Point3D(
sum(x) / num_atoms + 1,
sum(y) / num_atoms,
sum(z) / num_atoms)
v3 = Point3D(
sum(x) / num_atoms,
sum(y) / num_atoms + 1,
sum(z) / num_atoms)
virtual_atoms = Chem.MolFromSmarts('[#23][#23][#23]')
Chem.rdDistGeom.EmbedMolecule(virtual_atoms)
virtual_atoms.GetConformer().SetAtomPosition(1, v1)
virtual_atoms.GetConformer().SetAtomPosition(0, v2)
virtual_atoms.GetConformer().SetAtomPosition(2, v3)
v_writer = Chem.SDWriter(v_atoms_sdf)
v_writer.write(virtual_atoms)
#h**o protacs are protacs with the same binder twice, causing self degradation of an E3 ligase
if homo_protac:
docked_A = docked_heads.GetSubstructMatches(HeadA)[0]
docked_B = docked_heads.GetSubstructMatches(HeadB)[1]
else:
docked_A = docked_heads.GetSubstructMatch(HeadA)
docked_B = docked_heads.GetSubstructMatch(HeadB)
for head_linker in head_linkers:
Chem.AddHs(head_linker)
if homo_protac:
head_A = head_linker.GetSubstructMatches(HeadA)[0]
head_B = head_linker.GetSubstructMatches(HeadB)[1]
else:
head_A_list = head_linker.GetSubstructMatches(HeadA,
uniquify=False)
head_B_list = head_linker.GetSubstructMatches(HeadB,
uniquify=False)
i = 0
seed = 0
while i < n:
if seed > 10 * n:
break
if seed > n and i == 0:
break
seed += 1
random.seed(seed)
head_A = random.choice(head_A_list)
head_B = random.choice(head_B_list)
#amap for final alignment
amap = []
for j in range(len(docked_A)):
amap.append((head_A[j], docked_A[j]))
for j in range(len(docked_B)):
amap.append((head_B[j], docked_B[j]))
#the constraints for the conformation generation using the two docked heads
cmap = {
head_A[j]:
docked_heads.GetConformer().GetAtomPosition(docked_A[j])
for j in range(len(docked_A))
}
cmap.update({
head_B[j]:
docked_heads.GetConformer().GetAtomPosition(docked_B[j])
for j in range(len(docked_B))
})
#only half of the atoms are required to make the constrained embedding
#this is done because using all the atoms sometimes makes it impossible
#to find solutions, the half is chosen randomly for each generation
cmap_tag = random.sample(list(cmap), int(len(cmap) / 2))
cmap_tag = {ctag: cmap[ctag] for ctag in cmap_tag}
if AllChem.EmbedMolecule(head_linker,
coordMap=cmap_tag,
randomSeed=seed,
useBasicKnowledge=True,
maxAttempts=10) == -1:
continue
#final alignment to bring the new conformation to the position of the pose's heads
#this is needed because the constrained embedding only applies
#to distances and not to atoms position
rdMolAlign.AlignMol(head_linker, docked_heads, atomMap=amap)
#make sure the alignment is good enough for both heads (also to ensure the save isomer
#for ambiguous rings
if rmsd(head_linker,
docked_heads, head_A, docked_A) < 0.5 and rmsd(
head_linker, docked_heads, head_B, docked_B) < 0.5:
writer.write(head_linker)
i += 1
return head_A[int(Anchor_A)], v_atoms_sdf
def _get_conformer(mol: rdchem.Mol,
conformer: str = "min",
algo: str = "MMFF") -> rdchem.Mol:
"""Get molecule conformer from PDB file based on parameters
provided.
Params:
-------
mol: rdkit.Chem.rdchem.Mol
Molecule of interest, ideally with mutiple conformers.
conformer: str, optional, default="min"
Which conformer to select for 3D coordinates. If "min" (or "max"),
then the conformer with the min (or max) energy is selected. If
"first" or "last", then the first or last conformer is selected.
If "avg", then the average position of all the conformers are
averaged.
algo: str, optional, default="MMFF"
Which force field algorithm to optimize the coordinates with.
Read rdkit description to determine which one is best suited
for your application.
Returns:
--------
mol: rdkit.Chem.rdchem.Mol
Molecule with conformer of interest.
"""
forcefields = {
"MMFF": rdForceFieldHelpers.MMFFOptimizeMoleculeConfs,
"UFF": rdForceFieldHelpers.UFFOptimizeMoleculeConfs
}
if conformer == "min":
# Get idx of lowest energy conformation
idx = np.argmin(forcefields[algo](mol, maxIters=0), axis=0)[1]
conf = mol.GetConformers()[idx]
elif conformer == "max":
# Get idx of highest energy conformation
idx = np.argmax(forcefields[algo](mol, maxIters=0), axis=0)[1]
conf = mol.GetConformers()[idx]
elif conformer == "first":
conf = mol.GetConformer(0)
elif conformer == "last":
conf = mol.GetConformer(mol.GetNumConformers() - 1)
elif conformer == "avg":
allpos = [conf.GetPositions() for conf in mol.GetConformers()]
avgpos = np.average(allpos, axis=0)
# Set avg position as new position for all atoms
conf = mol.GetConformer(0)
for atom_idx in range(conf.GetNumAtoms()):
atom_coords = avgpos[atom_idx]
conf.SetAtomPosition(atom_idx, Point3D(atom_coords[0], \
atom_coords[1], atom_coords[2]))
else:
available_confs = ["min", "max", "first", "last", "avg"]
raise ValueError(
f"Cannot get `{conformer}` conformer. Choose from the "
f"following {available_confs} conformer(s).")
# Save conformer, with the position specified
mol.RemoveAllConformers()
mol.AddConformer(conf)
return mol
