import prody import prolif as plf import pandas as pd import subprocess from io import StringIO from prolif.fingerprint import Fingerprint from prolif.plotting.complex3d import Complex3D from prolif.residue import ResidueId from prolif.ifp import IFP from rdkit import Chem from tqdm import tqdm prody.confProDy(verbosity='none') INTERACTION_LIST = [ 'Anionic', 'Cationic', # Salt Bridges ~400 kJ/mol 'HBAcceptor', 'HBDonor', # Hydrogen bonds ~10 kJ/mol 'XBAcceptor', 'XBDonor', # Halogen bonds ~5-30 kJ/mol 'CationPi', 'PiCation', # 5-10 kJ/mol 'PiStacking', # ~2-10 kJ/mol 'Hydrophobic', # 1-10 kJ/mol ] INTERACTION_ALIASES = { 'Anionic': 'SaltBridge', 'Cationic': 'SaltBridge', 'HBAcceptor': 'HBAcceptor', 'HBDonor': 'HBDonor', 'XBAcceptor': 'HalogenBond', 'XBDonor': 'HalogenBond', 'CationPi': 'CationPi', 'PiCation': 'PiCation', 'PiStacking': 'PiStacking', 'Hydrophobic': 'Hydrophobic', } INTERACTION_COLORS = { 'SaltBridge': '#eba823', 'HBDonor': '#3d5dfc', 'HBAcceptor': '#3d5dfc', 'HalogenBond': '#53f514', 'CationPi': '#ff0000', 'PiCation': '#ff0000', 'PiStacking': '#e359d8', 'Hydrophobic': '#c9c5c5', } INTERACTION_IMPORTANCE = ['SaltBridge', 'HydrogenBond', 'HBAcceptor', 'HBDonor', 'CationPi', 'PiCation', 'PiStacking', 'Hydrophobic'] REDUCE_EXEC = './reduce' def remove_residue_by_atomic_number(structure, resnum, chain_id, icode): exclude_selection = f'not (chain {chain_id} and resnum {resnum} and icode {icode})' structure = structure.select(exclude_selection) return structure def read_protein(protein_path, verbose=False, reduce_exec=REDUCE_EXEC): structure = prody.parsePDB(protein_path).select('protein') hydrogens = structure.select('hydrogen') if hydrogens is None or len(hydrogens) < len(set(structure.getResnums())): if verbose: print('Target structure is not protonated. Adding hydrogens...') reduce_cmd = f'{str(reduce_exec)} {protein_path}' reduce_result = subprocess.run(reduce_cmd, shell=True, capture_output=True, text=True) if reduce_result.returncode != 0: raise RuntimeError('Error during reduce execution:', reduce_result.stderr) pdb_content = reduce_result.stdout stream = StringIO() stream.write(pdb_content) stream.seek(0) structure = prody.parsePDBStream(stream).select('protein') # Select only one (largest) altloc altlocs = set(structure.getAltlocs()) try: best_altloc = max(altlocs, key=lambda a: structure.select(f'altloc "{a}"').numAtoms()) structure = structure.select(f'altloc "{best_altloc}"') except TypeError: # Strange thing that happens only once in the beginning sometimes... best_altloc = max(altlocs, key=lambda a: structure.select(f'altloc "{a}"').numAtoms()) structure = structure.select(f'altloc "{best_altloc}"') return prepare_protein(structure, to_exclude=[], verbose=verbose) def prepare_protein(input_structure, to_exclude=[], verbose=False): structure = input_structure.copy() # Remove residues with bad atoms if verbose and len(to_exclude) > 0: print(f'Removing {len(to_exclude)} residues...') for resnum, chain_id, icode in to_exclude: exclude_selection = f'not (chain {chain_id} and resnum {resnum})' structure = structure.select(exclude_selection) # Write new PDB content to the stream stream = StringIO() prody.writePDBStream(stream, structure) stream.seek(0) # Sanitize rdprot = Chem.MolFromPDBBlock(stream.read(), sanitize=False, removeHs=False) try: Chem.SanitizeMol(rdprot) plfprot = plf.Molecule(rdprot) return plfprot except Chem.AtomValenceException as e: atom_num = int(e.args[0].replace('Explicit valence for atom # ', '').split()[0]) info = rdprot.GetAtomWithIdx(atom_num).GetPDBResidueInfo() resnum = info.GetResidueNumber() chain_id = info.GetChainId() icode = f'"{info.GetInsertionCode()}"' to_exclude_next = to_exclude + [(resnum, chain_id, icode)] if verbose: print(f'[{len(to_exclude_next)}] Removing broken residue with atom={atom_num}, resnum={resnum}, chain_id={chain_id}, icode={icode}') return prepare_protein(input_structure, to_exclude=to_exclude_next) def prepare_ligand(mol): Chem.SanitizeMol(mol) mol = Chem.AddHs(mol, addCoords=True) ligand_plf = plf.Molecule.from_rdkit(mol) return ligand_plf def sdf_reader(sdf_path, proress_bar=False): supp = Chem.SDMolSupplier(sdf_path, removeHs=True, sanitize=False) for mol in tqdm(supp) if progress_bar else supp: yield prepare_ligand(mol) def profile_detailed( ligand_plf, protein_plf, interaction_list=INTERACTION_LIST, ligand_name='ligand', protein_name='protein' ): fp = Fingerprint(interactions=interaction_list) fp.run_from_iterable(lig_iterable=[ligand_plf], prot_mol=protein_plf, progress=False) profile = [] for ligand_residue in ligand_plf.residues: for protein_residue in protein_plf.residues: metadata = fp.metadata(ligand_plf[ligand_residue], protein_plf[protein_residue]) for int_name, int_metadata in metadata.items(): for int_instance in int_metadata: profile.append({ 'ligand': ligand_name, 'protein': protein_name, 'ligand_residue': str(ligand_residue), 'protein_residue': str(protein_residue), 'interaction': int_name, 'alias': INTERACTION_ALIASES[int_name], 'ligand_atoms': ','.join(map(str, int_instance['indices']['ligand'])), 'protein_atoms': ','.join(map(str, int_instance['indices']['protein'])), 'ligand_orig_atoms': ','.join(map(str, int_instance['parent_indices']['ligand'])), 'protein_orig_atoms': ','.join(map(str, int_instance['parent_indices']['protein'])), 'distance': int_instance['distance'], 'plane_angle': int_instance.get('plane_angle', None), 'normal_to_centroid_angle': int_instance.get('normal_to_centroid_angle', None), 'intersect_distance': int_instance.get('intersect_distance', None), 'intersect_radius': int_instance.get('intersect_radius', None), 'pi_ring': int_instance.get('pi_ring', None), }) return pd.DataFrame(profile) def map_orig_atoms_to_new(atoms, mol): orig2new = dict() for atom in mol.GetAtoms(): orig2new[atom.GetUnsignedProp("mapindex")] = atom.GetIdx() atoms = list(map(int, atoms.split(','))) new_atoms = ','.join(map(str, [orig2new[atom] for atom in atoms])) return new_atoms def visualize(profile, ligand_plf, protein_plf): metadata = dict() for _, row in profile.iterrows(): if 'ligand_atoms' not in row: row['ligand_atoms'] = map_orig_atoms_to_new(row['ligand_orig_atoms'], ligand_plf) if 'protein_atoms' not in row: row['protein_atoms'] = map_orig_atoms_to_new(row['protein_orig_atoms'], protein_plf[row['residue']]) namenum, chain = row['residue'].split('.') name = namenum[:3] num = int(namenum[3:]) protres = ResidueId(name=name, number=num, chain=chain) key = (ResidueId(name='UNL', number=1, chain=None), protres) metadata.setdefault(key, dict()) interaction = { 'indices': { 'ligand': tuple(map(int, row['ligand_atoms'].split(','))), 'protein': tuple(map(int, row['protein_atoms'].split(','))), }, 'parent_indices': { 'ligand': tuple(map(int, row['ligand_atoms'].split(','))), 'protein': tuple(map(int, row['protein_atoms'].split(','))), }, 'distance': row['distance'], } # if row['plane_angle'] is not None: # interaction['plane_angle'] = row['plane_angle'] # if row['normal_to_centroid_angle'] is not None: # interaction['normal_to_centroid_angle'] = row['normal_to_centroid_angle'] # if row['intersect_distance'] is not None: # interaction['intersect_distance'] = row['intersect_distance'] # if row['intersect_radius'] is not None: # interaction['intersect_radius'] = row['intersect_radius'] # if row['pi_ring'] is not None: # interaction['pi_ring'] = row['pi_ring'] metadata[key].setdefault(row['alias'], list()).append(interaction) ifp = IFP(metadata) fp = Fingerprint(interactions=INTERACTION_LIST, vicinity_cutoff=8.0) fp.ifp = {0: ifp} Complex3D.COLORS.update(INTERACTION_COLORS) v = fp.plot_3d(ligand_mol=ligand_plf, protein_mol=protein_plf, frame=0) return v