def test_SmilesConstraints_class():
obj = smi.SmilesConstraints(
"../pele_platform/Examples/constraints/4qnr_prep.pdb",
"CN1CC[NH+](CC1)CCO",
"LIG",
"Z",
33.5,
)
smarts_from_smiles = obj.convert_to_smarts("CN1CC[NH+](CC1)CCO")
smarts_from_smarts = obj.convert_to_smarts(
"[#6]-[#7]1-[#6]-[#6]-[#7H+](-[#6]-[#6]-1)-[#6]-[#6]-[#8]")
ligand = obj.extract_ligand(obj.input_pdb, obj.resname)
matches = obj.get_matches(smarts_from_smiles, ligand)
constraints = obj.build_constraints(matches, ligand, obj.spring_constant,
obj.chain)
assert (smarts_from_smiles == smarts_from_smarts ==
"[#6]-[#7]1-[#6]-[#6]-[#7H+](-[#6]-[#6]-1)-[#6]-[#6]-[#8]")
assert matches == ((9, 0, 1, 2, 3, 4, 5, 6, 7, 8), )
assert constraints == SMILES_CONSTR
def run_adaptive(args: YamlParser):
"""
Main function to prepare and launch the simulation.
1) Create Parameters - variables, folders, logger...
2) Prepare ligand and receptor
3) Launch simulation
4) Analyse simulation
"""
builder = ParametersBuilder()
parameters = builder.build_adaptive_variables(args)
parameters.create_files_and_folders()
shutil.copy(args.yamlfile, parameters.pele_dir)
missing_residues = []
if parameters.adaptive_restart and not parameters.only_analysis:
with helpers.cd(parameters.pele_dir):
adaptiveSampling.main(parameters.ad_ex_temp)
parameters.logger.info("Simulation run successfully (:\n\n")
args.adaptive_restart = False
elif not parameters.only_analysis and not parameters.restart:
parameters.logger.info(
"System: {}; Platform Functionality: {}\n\n".format(
parameters.residue, parameters.software))
pdb_checker.PDBChecker(parameters.system).check_negative_residues()
# Create inputs directory
if not os.path.exists(parameters.inputs_dir):
os.mkdir(parameters.inputs_dir)
if parameters.perturbation:
syst = sp.SystemBuilder.build_system(
parameters.system,
args.mae_lig,
args.residue,
parameters.pele_dir,
inputs_dir=parameters.inputs_dir)
else:
syst = sp.SystemBuilder(parameters.system,
None,
None,
parameters.pele_dir,
inputs_dir=parameters.inputs_dir)
parameters.logger.info("Prepare complex {}".format(syst.system))
# If user overrides 'system' with 'input'
if parameters.input:
parameters.inputs_simulation = []
for input in parameters.input:
input_path = os.path.join(parameters.inputs_dir,
os.path.basename(input))
shutil.copy(input, input_path)
if parameters.no_ppp:
input_proc = input_path
else:
input_proc, missing_residues, _, _, _ = ppp.main(
input_path,
parameters.
inputs_dir, # to ensure it goes to pele_dir/inputs, not pele_dir
output_pdb=[
"",
],
charge_terminals=args.charge_ter,
no_gaps_ter=args.gaps_ter,
constrain_smiles=None,
ligand_pdb=parameters.ligand_ref)
input_proc = os.path.basename(input_proc)
input_proc = os.path.join(parameters.inputs_dir, input_proc)
parameters.inputs_simulation.append(input_proc)
parameters.adap_ex_input = ", ".join([
'"' + input + '"' for input in parameters.inputs_simulation
]).strip('"')
# If randomization in necessary (PPI, site_finder, global exploration)...
elif args.full or args.randomize or args.ppi or args.site_finder:
ligand_positions, box_radius, box_center = rd.randomize_starting_position(
parameters, args.box_center, args.box_radius)
if parameters.no_ppp:
receptor = syst.system
else:
receptor, missing_residues, _, _, _ = ppp.main(
syst.system,
parameters.
inputs_dir, # to ensure it goes to pele_dir/input, not pele_dir
output_pdb=[
"",
],
charge_terminals=args.charge_ter,
no_gaps_ter=args.gaps_ter,
constrain_smiles=None,
ligand_pdb=parameters.ligand_ref)
inputs = rd.join(receptor,
ligand_positions,
parameters.residue,
output_folder=parameters.inputs_dir)
parameters.input = [
os.path.join(parameters.inputs_dir, inp) for inp in inputs
]
if args.gpcr_orth or args.out_in:
randomization_box_radius, randomization_box_center = rd.set_box(
args.final_site if args.final_site else
args.orthosteric_site, ligand_positions, parameters.system)
if not args.box_center:
parameters.box_center = randomization_box_center
if not args.box_radius:
parameters.box_radius = randomization_box_radius
else:
parameters.box_center = box_center
parameters.box_radius = box_radius
parameters.adap_ex_input = ", ".join(
['"' + input + '"' for input in parameters.input]).strip('"')
hp.silentremove(ligand_positions)
# Prepare System
if parameters.no_ppp or parameters.input: # No need to run system through PPP, if we already preprocessed
# parameters.input
if parameters.input:
# If we have more than one input
for input in parameters.input:
try:
shutil.copy(input, parameters.inputs_dir)
except shutil.SameFileError: # systems that go through randomization are already moved
pass
else:
shutil.copy(parameters.system, parameters.inputs_dir)
else:
parameters.nonstandard.extend(hp.find_nonstd_residue(syst.system))
parameters.system, missing_residues, _, _, _ = ppp.main(
syst.system,
parameters.inputs_dir,
output_pdb=[
"",
],
charge_terminals=args.charge_ter,
no_gaps_ter=args.gaps_ter,
mid_chain_nonstd_residue=parameters.nonstandard,
skip=parameters.skip_prep,
back_constr=parameters.ca_constr,
constrain_smiles=None,
ligand_pdb=parameters.ligand_ref,
ca_interval=parameters.ca_interval)
parameters.constraints = alpha_constraints.retrieve_constraints(
parameters.system,
interval=parameters.ca_interval,
back_constr=parameters.ca_constr,
ter_constr=parameters.terminal_constr)
# Metal constraints
if not args.no_metal_constraints:
metal_constraints, parameters.external_constraints = mc.main(
args.external_constraints,
os.path.join(
parameters.inputs_dir,
parameters.adap_ex_input.split(",")[0].strip().strip('"')),
syst.system,
permissive=parameters.permissive_metal_constr,
all_metals=args.constrain_all_metals,
external=parameters.external_constraints,
logger=parameters.logger)
parameters.external_constraints = hp.retrieve_constraints_for_pele(
parameters.external_constraints, parameters.system)
metal_constraints_json = hp.retrieve_constraints_for_pele(
metal_constraints,
os.path.join(
parameters.inputs_dir,
parameters.adap_ex_input.split(",")[0].strip().strip('"')))
parameters.external_constraints.extend(metal_constraints_json)
else:
parameters.external_constraints = hp.retrieve_constraints_for_pele(
parameters.external_constraints, parameters.system)
# Keep JSON ordered by having first title and then constraints
if parameters.external_constraints:
parameters.constraints = (parameters.constraints[0:1] +
parameters.external_constraints +
parameters.constraints[1:])
if parameters.remove_constraints:
parameters.constraints = ""
parameters.logger.info(f"Complex {parameters.system} prepared\n\n")
# Ligand/metal and solvent parameters
if (parameters.perturbation or
parameters.sidechain_perturbation) and parameters.use_peleffy:
ligand_parametrizer = parametrizer.Parametrizer.from_parameters(
parameters)
ligand_parametrizer.parametrize_ligands_from(
pdb_file=syst.system, ppp_file=parameters.system)
elif (parameters.perturbation or parameters.sidechain_perturbation
) and not parameters.use_peleffy:
# Parametrize the ligand
ligand_params = lg.LigandParametrization(parameters)
ligand_params.generate()
# Parametrize missing residues identified by PPP
for res, __, _ in missing_residues:
if res != args.residue and res not in parameters.skip_ligand_prep:
parameters.logger.info(
"Creating template for residue {}".format(res))
with hp.cd(parameters.pele_dir):
mr.create_template(parameters, res)
parameters.logger.info(
"Template {}z created\n\n".format(res))
# Covalent residue parametrization should not run in refinement simulation
if parameters.covalent_residue and os.path.basename(
parameters.pele_dir) != "2_refinement":
parametrizer.parametrize_covalent_residue(
parameters.pele_data,
parameters.pele_dir,
parameters.gridres,
parameters.residue_type,
parameters.residue,
ppp_system=parameters.system)
if parameters.ligand_conformations:
ligand_conformations.LigandConformations(
path=parameters.ligand_conformations,
system=parameters.system,
resname=parameters.residue,
forcefield=parameters.forcefield,
pele_dir=parameters.pele_dir).generate()
# Create simulation box, if performing perturbation
if parameters.perturbation and parameters.box:
box = bx.BoxSetter(parameters.box_center, parameters.box_radius,
parameters.ligand_ref, parameters.logger)
parameters.box = box.generate_json()
else:
parameters.box = ""
# Solvent parameters
solvent = sv.ImplicitSolvent(
parameters.solvent,
parameters.obc_tmp,
parameters.template_folder,
parameters.obc_file,
parameters.logger,
)
solvent.generate()
# Build PCA
if parameters.pca_traj:
pca_obj = pca.PCA(parameters.pca_traj, parameters.pele_dir)
parameters.pca = pca_obj.generate(parameters.logger)
# Core constraints based on SMILES string
if parameters.constrain_core:
smiles_input_pdb = os.path.join(
parameters.inputs_dir,
parameters.adap_ex_input.split(",")[0])
smiles = smiles_constraints.SmilesConstraints(
smiles_input_pdb, parameters.constrain_core,
parameters.residue, parameters.chain,
parameters.constrain_core_spring)
smi_constraint = smiles.run()
parameters.constraints = (parameters.constraints[0:1] +
smi_constraint +
parameters.constraints[1:])
# Waters
input_waters = [
input.strip().strip('"')
for input in parameters.adap_ex_input.split(",")
]
input_waters = [
os.path.join(parameters.inputs_dir, inp) for inp in input_waters
]
water_obj = wt.WaterIncluder(
input_waters,
parameters.n_waters,
user_waters=parameters.waters,
ligand_perturbation_params=parameters.parameters,
water_center=args.water_center,
water_radius=parameters.water_radius,
allow_empty_selectors=parameters.allow_empty_selectors,
water_temp=parameters.water_temp,
water_trials=parameters.water_trials,
water_overlap=parameters.water_overlap,
water_constr=parameters.water_constr,
test=parameters.test,
water_freq=parameters.water_freq,
ligand_residue=parameters.residue)
water_obj.run()
parameters.parameters = water_obj.ligand_perturbation_params
parameters.water_ids_to_track = water_obj.water_ids_to_track
# Check if atoms need mapping due to preprocessing
args = AtomMapper(args, parameters, syst.system).run()
# Metrics builder - builds JSON strings for PELE to be able to
# track atom distances, RMSD, etc.
metrics = mt.MetricBuilder()
parameters.metrics = (metrics.distance_to_atom_json(
os.path.join(
parameters.inputs_dir,
parameters.adap_ex_input.split(",")[0].strip().strip('"'),
),
args.atom_dist,
) if args.atom_dist else "")
parameters.native = (metrics.rmsd_to_json(
args.native, parameters.chain) if args.native else "")
parameters.local_nonbonding_energy = metrics.local_nonbonding_energy_json(
parameters.covalent_residue, parameters.nonbonding_radius)
# metal polarisation
if parameters.polarize_metals:
mp.change_metal_charges(
parameters.template_folder,
parameters.forcefield,
parameters.polarization_factor,
parameters.system,
)
# Predict cluster values in a short equilibration
if parameters.cluster_conditions == "auto":
preequilibration = PreEquilibrator(args, parameters)
parameters.cluster_conditions = preequilibration.run()
# Point adaptive.conf to input dir
parameters.adap_ex_input = os.path.join(parameters.inputs_dir,
parameters.adap_ex_input)
# Fill in simulation templates
adaptive = ad.SimulationBuilder(parameters.ad_ex_temp,
parameters.pele_exit_temp,
parameters.topology)
adaptive.generate_inputs(parameters, water_obj)
# Run simulation only if we are not in debug mode
if not parameters.debug:
parameters.logger.info("Running Simulation")
adaptive.run()
parameters.logger.info("Simulation run successfully (:\n\n")
elif parameters.restart and not parameters.only_analysis:
# Start simulation from scratch (unlike adaptive_restart) but use files created in debug mode
parameters.logger.info(
f"Launching simulation from {parameters.pele_dir}")
adaptive = ad.SimulationBuilder(parameters.ad_ex_temp,
parameters.pele_exit_temp,
parameters.topology)
adaptive.run()
parameters.logger.info("Simulation run successfully (:\n\n")
# Run analysis
if parameters.analyse and not parameters.debug:
from pele_platform.analysis import Analysis
# Retrieve water IDs to track from existing pele.conf, if running analysis only
if parameters.only_analysis:
parameters.water_ids_to_track = wt.water_ids_from_conf(
parameters.pele_temp)
analysis_folder = os.path.join(parameters.pele_dir, "results")
analysis = Analysis.from_parameters(parameters)
analysis.generate(
analysis_folder,
clustering_type=parameters.clustering_method.lower(),
bandwidth=parameters.bandwidth,
analysis_nclust=parameters.analysis_nclust,
max_top_clusters=parameters.max_top_clusters,
min_population=parameters.min_population,
max_top_poses=parameters.max_top_poses,
top_clusters_criterion=parameters.top_clusters_criterion,
representatives_criterion=parameters.
cluster_representatives_criterion)
return parameters
def run_adaptive(args):
"""
Main function to prepare and launch the simulation.
1) Create EnviroBuilder - variables, folders, logger...
2) Prepare ligand and receptor
3) Launch simulation
4) Analyse simulation
"""
builder = ParametersBuilder()
parameters = builder.build_adaptive_variables(args)
parameters.create_files_and_folders()
shutil.copy(args.yamlfile, parameters.pele_dir)
if parameters.adaptive_restart and not parameters.only_analysis:
with helpers.cd(parameters.pele_dir):
adaptiveSampling.main(parameters.ad_ex_temp)
parameters.logger.info("Simulation run successfully (:\n\n")
elif not parameters.only_analysis:
parameters.logger.info(
"System: {}; Platform Functionality: {}\n\n".format(
parameters.residue, parameters.software))
# Create inputs directory
if not os.path.exists(parameters.inputs_dir):
os.mkdir(parameters.inputs_dir)
if parameters.perturbation:
syst = sp.SystemBuilder.build_system(
parameters.system,
args.mae_lig,
args.residue,
parameters.pele_dir,
inputs_dir=parameters.inputs_dir,
)
else:
syst = sp.SystemBuilder(
parameters.system,
None,
None,
parameters.pele_dir,
inputs_dir=parameters.inputs_dir,
)
parameters.logger.info("Prepare complex {}".format(syst.system))
# If user overrides 'system' with 'input'
if parameters.input:
parameters.inputs_simulation = []
for input in parameters.input:
input_path = os.path.join(parameters.inputs_dir,
os.path.basename(input))
shutil.copy(input, input_path)
if parameters.no_ppp:
input_proc = input_path
else:
input_proc = os.path.basename(
ppp.main(
input_path,
parameters.
inputs_dir, # to ensure it goes to pele_dir/inputs, not pele_dir
output_pdb=[
"",
],
charge_terminals=args.charge_ter,
no_gaps_ter=args.gaps_ter,
constrain_smiles=None,
ligand_pdb=parameters.ligand_ref,
)[0])
input_proc = os.path.join(parameters.inputs_dir, input_proc)
parameters.inputs_simulation.append(input_proc)
parameters.adap_ex_input = ", ".join([
'"' + input + '"' for input in parameters.inputs_simulation
]).strip('"')
# If randomization in necessary (PPI, site_finder, global exploration)...
elif args.full or args.randomize or args.ppi:
ligand_positions, box_radius, box_center = rd.randomize_starting_position(
parameters.ligand_ref,
parameters.receptor,
outputfolder=parameters.inputs_dir,
nposes=parameters.poses,
test=parameters.test,
user_center=parameters.center_of_interface,
logger=parameters.logger,
)
if not args.gpcr_orth:
parameters.box_center = box_center
parameters.box_radius = box_radius
if parameters.no_ppp:
receptor = syst.system
else:
receptor = ppp.main(
syst.system,
parameters.
inputs_dir, # to ensure it goes to pele_dir/input, not pele_dir
output_pdb=[
"",
],
charge_terminals=args.charge_ter,
no_gaps_ter=args.gaps_ter,
constrain_smiles=None,
ligand_pdb=parameters.ligand_ref,
)[0]
inputs = rd.join(
receptor,
ligand_positions,
parameters.residue,
output_folder=parameters.inputs_dir,
)
inputs = [
os.path.join(parameters.inputs_dir, inp) for inp in inputs
]
parameters.adap_ex_input = ", ".join(
['"' + input + '"' for input in inputs]).strip('"')
hp.silentremove(ligand_positions)
# Prepare System
if (
parameters.no_ppp or parameters.input
): # No need to run system through PPP, if we already preprocessed parameters.input
missing_residues = []
if parameters.input:
# If we have more than one input
for input in parameters.input:
shutil.copy(input, parameters.inputs_dir)
else:
shutil.copy(parameters.system, parameters.inputs_dir)
else:
parameters.nonstandard.extend(hp.find_nonstd_residue(syst.system))
parameters.system, missing_residues, _, _, _ = ppp.main(
syst.system,
parameters.inputs_dir,
output_pdb=[
"",
],
charge_terminals=args.charge_ter,
no_gaps_ter=args.gaps_ter,
mid_chain_nonstd_residue=parameters.nonstandard,
skip=parameters.skip_prep,
back_constr=parameters.ca_constr,
constrain_smiles=None,
ligand_pdb=parameters.ligand_ref,
ca_interval=parameters.ca_interval,
)
parameters.constraints = alpha_constraints.retrieve_constraints(
parameters.system,
interval=parameters.ca_interval,
back_constr=parameters.ca_constr,
ter_constr=parameters.terminal_constr,
)
# Metal constraints
if not args.no_metal_constraints:
metal_constraints, parameters.external_constraints = mc.main(
args.external_constraints,
os.path.join(
parameters.inputs_dir,
parameters.adap_ex_input.split(",")[0].strip().strip('"'),
),
syst.system,
permissive=parameters.permissive_metal_constr,
all_metals=args.constrain_all_metals,
external=parameters.external_constraints,
logger=parameters.logger,
)
parameters.external_constraints = hp.retrieve_constraints_for_pele(
parameters.external_constraints, parameters.system)
metal_constraints_json = hp.retrieve_constraints_for_pele(
metal_constraints,
os.path.join(
parameters.inputs_dir,
parameters.adap_ex_input.split(",")[0].strip().strip('"'),
),
)
parameters.external_constraints.extend(metal_constraints_json)
else:
parameters.external_constraints = hp.retrieve_constraints_for_pele(
parameters.external_constraints, parameters.system)
# Keep JSON ordered by having first title and then constraints
if parameters.external_constraints:
parameters.constraints = (parameters.constraints[0:1] +
parameters.external_constraints +
parameters.constraints[1:])
if parameters.remove_constraints:
parameters.constraints = ""
parameters.logger.info("Complex {} prepared\n\n".format(
parameters.system))
# Ligand parameters and simulation box
if parameters.perturbation:
ligand_params = lg.LigandParametrization(parameters)
ligand_params.generate()
box = bx.BoxSetter(
parameters.box_center,
parameters.box_radius,
parameters.ligand_ref,
parameters.logger,
)
parameters.box = box.generate_json()
else:
parameters.box = ""
# Parametrize missing residues
for res, __, _ in missing_residues:
if res != args.residue and res not in parameters.skip_ligand_prep:
parameters.logger.info(
"Creating template for residue {}".format(res))
with hp.cd(parameters.pele_dir):
mr.create_template(parameters, res)
parameters.logger.info("Template {}z created\n\n".format(res))
# Solvent parameters
solvent = sv.ImplicitSolvent(
parameters.solvent,
parameters.obc_tmp,
parameters.template_folder,
parameters.obc_file,
parameters.logger,
)
solvent.generate()
# Build PCA
if parameters.pca_traj:
pca_obj = pca.PCA(parameters.pca_traj, parameters.pele_dir)
parameters.pca = pca_obj.generate(parameters.logger)
# Core constraints based on SMILES string
if parameters.constrain_core:
smiles_input_pdb = os.path.join(
parameters.inputs_dir,
parameters.adap_ex_input.split(",")[0])
smiles = smiles_constraints.SmilesConstraints(
smiles_input_pdb,
parameters.constrain_core,
parameters.residue,
parameters.chain,
parameters.constrain_core_spring,
)
smi_constraint = smiles.run()
parameters.constraints = (parameters.constraints[0:1] +
smi_constraint +
parameters.constraints[1:])
# Waters
input_waters = [
input.strip().strip('"')
for input in parameters.adap_ex_input.split(",")
]
input_waters = [
os.path.join(parameters.inputs_dir, inp) for inp in input_waters
]
water_obj = wt.WaterIncluder(
input_waters,
parameters.n_waters,
user_waters=parameters.waters,
ligand_perturbation_params=parameters.parameters,
water_center=args.water_center,
water_radius=parameters.water_radius,
allow_empty_selectors=parameters.allow_empty_selectors,
water_temp=parameters.water_temp,
water_trials=parameters.water_trials,
water_overlap=parameters.water_overlap,
water_constr=parameters.water_constr,
test=parameters.test,
water_freq=parameters.water_freq,
ligand_residue=parameters.residue,
)
water_obj.run()
parameters.parameters = water_obj.ligand_perturbation_params
# Check if atoms need mapping due to preprocessing
args = AtomMapper(args, parameters, syst.system).run()
# Metrics builder - builds JSON strings for PELE to be able to track atom distances, RMSD, etc.
metrics = mt.MetricBuilder()
parameters.metrics = (metrics.distance_to_atom_json(
os.path.join(
parameters.inputs_dir,
parameters.adap_ex_input.split(",")[0].strip().strip('"'),
),
args.atom_dist,
) if args.atom_dist else "")
parameters.native = (metrics.rsmd_to_json(
args.native, parameters.chain) if args.native else "")
# interaction restrictions
# TODO this is not the place to initialize parameters for the interaction restrictions
if args.interaction_restrictions:
interaction_restrictions = ir.InteractionRestrictionsBuilder()
interaction_restrictions.parse_interaction_restrictions(
parameters.system, args.interaction_restrictions)
parameters.met_interaction_restrictions = (
interaction_restrictions.metrics_to_json())
parameters.interaction_restrictions = (
interaction_restrictions.conditions_to_json())
else:
parameters.met_interaction_restrictions = ""
parameters.interaction_restrictions = ""
# metal polarisation
if parameters.polarize_metals:
mp.change_metal_charges(
parameters.template_folder,
parameters.forcefield,
parameters.polarization_factor,
parameters.system,
)
# Point adaptive.conf to input dir
parameters.adap_ex_input = os.path.join(parameters.inputs_dir,
parameters.adap_ex_input)
# Fill in simulation templates
adaptive = ad.SimulationBuilder(parameters.ad_ex_temp,
parameters.pele_exit_temp,
parameters.topology)
adaptive.generate_inputs(parameters, water_obj)
# Run simulation only if we are not in debug mode
if not parameters.debug:
parameters.logger.info("Running Simulation")
adaptive.run()
parameters.logger.info("Simulation run successfully (:\n\n")
# Run analysis
if parameters.analyse and not parameters.debug:
from pele_platform.analysis import Analysis
analysis_folder = os.path.join(parameters.pele_dir, "results")
analysis = Analysis.from_parameters(parameters)
analysis.generate(analysis_folder,
clustering_type=parameters.clustering_method.lower(),
bandwidth=parameters.bandwidth,
analysis_nclust=parameters.analysis_nclust,
max_top_clusters=parameters.max_top_clusters,
min_population=parameters.min_population)
return parameters