def _create_phase(self, phase, reference_system, positions, atom_indices, thermodynamic_state, protocols=None, options=None, mpicomm=None):
"""
Create a repex object for a specified phase.
Parameters
----------
phase : str
The phase being initialized (one of ['complex', 'solvent', 'vacuum'])
reference_system : simtk.openmm.System
The reference system object from which alchemical intermediates are to be construcfted.
positions : list of simtk.unit.Qunatity objects containing (natoms x 3) positions (as np or lists)
The list of positions to be used to seed replicas in a round-robin way.
atom_indices : dict
atom_indices[phase][component] is the set of atom indices associated with component, where component is ['ligand', 'receptor']
thermodynamic_state : ThermodynamicState
Thermodynamic state from which reference temperature and pressure are to be taken.
protocols : dict of list of AlchemicalState, optional, default=None
If specified, the alchemical protocol protocols[phase] will be used for phase 'phase' instead of the default.
options : dict of str, optional, default=None
If specified, these options will override default repex simulation options.
"""
# Combine simulation options with defaults to create repex options.
repex_options = dict(self.default_options.items() + options.items())
# Make sure positions argument is a list of coordinate snapshots.
if hasattr(positions, 'unit'):
# Wrap in list.
positions = [positions]
# Check the dimensions of positions.
for index in range(len(positions)):
# Make sure it is recast as a np array.
positions[index] = unit.Quantity(np.array(positions[index] / positions[index].unit), positions[index].unit)
[natoms, ndim] = (positions[index] / positions[index].unit).shape
if natoms != reference_system.getNumParticles():
raise Exception("positions argument must be a list of simtk.unit.Quantity of (natoms,3) lists or np array with units compatible with nanometers.")
# Create metadata storage.
metadata = dict()
# Make a deep copy of the reference system so we don't accidentally modify it.
reference_system = copy.deepcopy(reference_system)
# TODO: Use more general approach to determine whether system is periodic.
is_periodic = self._is_periodic(reference_system)
# Make sure pressure is None if not periodic.
if not is_periodic: thermodynamic_state.pressure = None
# Compute standard state corrections for complex phase.
metadata['standard_state_correction'] = 0.0
# TODO: Do we need to include a standard state correction for other phases in periodic boxes?
if phase == 'complex-implicit':
# Impose restraints for complex system in implicit solvent to keep ligand from drifting too far away from receptor.
logger.debug("Creating receptor-ligand restraints...")
reference_positions = positions[0]
if self.restraint_type == 'harmonic':
restraints = HarmonicReceptorLigandRestraint(thermodynamic_state, reference_system, reference_positions, atom_indices['receptor'], atom_indices['ligand'])
elif self.restraint_type == 'flat-bottom':
restraints = FlatBottomReceptorLigandRestraint(thermodynamic_state, reference_system, reference_positions, atom_indices['receptor'], atom_indices['ligand'])
else:
raise Exception("restraint_type of '%s' is not supported." % self.restraint_type)
force = restraints.getRestraintForce() # Get Force object incorporating restraints
reference_system.addForce(force)
metadata['standard_state_correction'] = restraints.getStandardStateCorrection() # standard state correction in kT
elif phase == 'complex-explicit':
# For periodic systems, we do not use a restraint, but must add a standard state correction for the box volume.
# TODO: What if the box volume fluctuates during the simulation?
box_vectors = reference_system.getDefaultPeriodicBoxVectors()
box_volume = thermodynamic_state._volume(box_vectors)
STANDARD_STATE_VOLUME = 1660.53928 * unit.angstrom**3
metadata['standard_state_correction'] = np.log(STANDARD_STATE_VOLUME / box_volume) # TODO: Check sign.
# Use default alchemical protocols if not specified.
if not protocols:
protocols = self.default_protocols
# Create alchemically-modified states using alchemical factory.
logger.debug("Creating alchemically-modified states...")
#factory = AbsoluteAlchemicalFactory(reference_system, ligand_atoms=atom_indices['ligand'], test_positions=positions[0], platform=repex_options['platform'])
factory = AbsoluteAlchemicalFactory(reference_system, ligand_atoms=atom_indices['ligand'])
alchemical_states = protocols[phase]
alchemical_system = factory.alchemically_modified_system
thermodynamic_state.system = alchemical_system
# Check systems for finite energies.
finite_energy_check = False
if finite_energy_check:
logger.debug("Checking energies are finite for all alchemical systems.")
integrator = openmm.VerletIntegrator(1.0 * unit.femtosecond)
context = openmm.Context(alchemical_system, integrator)
context.setPositions(positions[0])
for alchemical_state in alchemical_states:
AbsoluteAlchemicalFactory.perturbContext(context, alchemical_state)
potential = context.getState(getEnergy=True).getPotentialEnergy()
if np.isnan(potential / unit.kilocalories_per_mole):
raise Exception("Energy for system %d is NaN." % index)
del context, integrator
logger.debug("All energies are finite.")
# Randomize ligand position if requested, but only for implicit solvent systems.
if self.randomize_ligand and (phase == 'complex-implicit'):
logger.debug("Randomizing ligand positions and excluding overlapping configurations...")
randomized_positions = list()
nstates = len(systems)
for state_index in range(nstates):
positions_index = np.random.randint(0, len(positions))
current_positions = positions[positions_index]
new_positions = ModifiedHamiltonianExchange.randomize_ligand_position(current_positions,
atom_indices['receptor'], atom_indices['ligand'],
self.randomize_ligand_sigma_multiplier * restraints.getReceptorRadiusOfGyration(),
self.randomize_ligand_close_cutoff)
randomized_positions.append(new_positions)
positions = randomized_positions
if self.randomize_ligand and (phase == 'complex-explicit'):
logger.warning("Ligand randomization requested, but will not be performed for explicit solvent simulations.")
# Identify whether any atoms will be displaced via MC, unless option is turned off.
mc_atoms = None
if self.mc_displacement_sigma:
mc_atoms = list()
if 'ligand' in atom_indices:
mc_atoms = atom_indices['ligand']
# Set up simulation.
# TODO: Support MPI initialization?
logger.debug("Creating replica exchange object...")
store_filename = os.path.join(self._store_directory, phase + '.nc')
self._store_filenames[phase] = store_filename
simulation = ModifiedHamiltonianExchange(store_filename, mpicomm=mpicomm)
simulation.create(thermodynamic_state, alchemical_states, positions,
displacement_sigma=self.mc_displacement_sigma, mc_atoms=mc_atoms,
options=repex_options, metadata=metadata)
# Initialize simulation.
# TODO: Use the right scheme for initializing the simulation without running.
#logger.debug("Initializing simulation...")
#simulation.run(0)
# TODO: Process user-supplied options.
# Clean up simulation.
del simulation
return
def _create_phase(self, thermodynamic_state, alchemical_phase):
"""
Create a repex object for a specified phase.
Parameters
----------
thermodynamic_state : ThermodynamicState (System need not be defined)
Thermodynamic state from which reference temperature and pressure are to be taken.
alchemical_phase : AlchemicalPhase
The alchemical phase to be created.
"""
# We add default repex options only on creation, on resume repex will pick them from the store file
repex_parameters = {
'number_of_equilibration_iterations': 0,
'number_of_iterations': 100,
'timestep': 2.0 * unit.femtoseconds,
'collision_rate': 5.0 / unit.picoseconds,
'minimize': False,
'show_mixing_statistics':
True, # this causes slowdown with iteration and should not be used for production
'displacement_sigma': 1.0 * unit.
nanometers # attempt to displace ligand by this stddev will be made each iteration
}
repex_parameters.update(self._repex_parameters)
# Convenience variables
positions = alchemical_phase.positions
reference_system = copy.deepcopy(alchemical_phase.reference_system)
atom_indices = alchemical_phase.atom_indices
alchemical_states = alchemical_phase.protocol
# If temperature and pressure are specified, make sure MonteCarloBarostat is attached.
if thermodynamic_state.temperature and thermodynamic_state.pressure:
forces = {
reference_system.getForce(index).__class__.__name__:
reference_system.getForce(index)
for index in range(reference_system.getNumForces())
}
if 'MonteCarloAnisotropicBarostat' in forces:
raise Exception(
'MonteCarloAnisotropicBarostat is unsupported.')
if 'MonteCarloBarostat' in forces:
logger.debug(
'MonteCarloBarostat found: Setting default temperature and pressure.'
)
barostat = forces['MonteCarloBarostat']
# Set temperature and pressure.
try:
barostat.setDefaultTemperature(
thermodynamic_state.temperature)
except AttributeError: # versions previous to OpenMM7.1
barostat.setTemperature(thermodynamic_state.temperature)
barostat.setDefaultPressure(state.pressure)
else:
# Create barostat and add it to the system if it doesn't have one already.
logger.debug('MonteCarloBarostat not found: Creating one.')
barostat = openmm.MonteCarloBarostat(
thermodynamic_state.pressure,
thermodynamic_state.temperature)
reference_system.addForce(barostat)
# Check the dimensions of positions.
for index in range(len(positions)):
n_atoms, _ = (positions[index] / positions[index].unit).shape
if n_atoms != reference_system.getNumParticles():
err_msg = "Phase {}: number of atoms in positions {} and and " \
"reference system differ ({} and {} respectively)"
err_msg.format(alchemical_phase.name, index, n_atoms,
reference_system.getNumParticles())
logger.error(err_msg)
raise RuntimeError(err_msg)
# Inizialize metadata storage.
metadata = dict()
# Store a serialized copy of the reference system.
metadata['reference_system'] = openmm.XmlSerializer.serialize(
reference_system)
metadata['topology'] = utils.serialize_topology(
alchemical_phase.reference_topology)
# TODO: Use more general approach to determine whether system is periodic.
is_periodic = self._is_periodic(reference_system)
is_complex_explicit = len(atom_indices['receptor']) > 0 and is_periodic
is_complex_implicit = len(
atom_indices['receptor']) > 0 and not is_periodic
# Make sure pressure is None if not periodic.
if not is_periodic: thermodynamic_state.pressure = None
# Create a copy of the system for which the fully-interacting energy is to be computed.
# For explicit solvent calculations, an enlarged cutoff is used to account for the anisotropic dispersion correction.
fully_interacting_system = copy.deepcopy(reference_system)
if is_periodic:
# Expand cutoff to maximum allowed
# TODO: Should we warn if cutoff can't be extended enough?
# TODO: Should we extend to some minimum cutoff rather than the maximum allowed?
box_vectors = fully_interacting_system.getDefaultPeriodicBoxVectors(
)
max_allowed_cutoff = 0.499 * max([
max(vector) for vector in box_vectors
]) # TODO: Correct this for non-rectangular boxes
logger.debug(
'Setting cutoff for fully interacting system to maximum allowed (%s)'
% str(max_allowed_cutoff))
for force_index in range(fully_interacting_system.getNumForces()):
force = fully_interacting_system.getForce(force_index)
if hasattr(force, 'setCutoffDistance'):
force.setCutoffDistance(max_allowed_cutoff)
if hasattr(force, 'setCutoff'):
force.setCutoff(max_allowed_cutoff)
# Construct thermodynamic state
fully_interacting_state = copy.deepcopy(thermodynamic_state)
fully_interacting_state.system = fully_interacting_system
# Compute standard state corrections for complex phase.
metadata['standard_state_correction'] = 0.0
# TODO: Do we need to include a standard state correction for other phases in periodic boxes?
if is_complex_implicit:
# Impose restraints for complex system in implicit solvent to keep ligand from drifting too far away from receptor.
logger.debug("Creating receptor-ligand restraints...")
reference_positions = positions[0]
if self._restraint_type == 'harmonic':
restraints = HarmonicReceptorLigandRestraint(
thermodynamic_state, reference_system, reference_positions,
atom_indices['receptor'], atom_indices['ligand'])
elif self._restraint_type == 'flat-bottom':
restraints = FlatBottomReceptorLigandRestraint(
thermodynamic_state, reference_system, reference_positions,
atom_indices['receptor'], atom_indices['ligand'])
else:
raise Exception("restraint_type of '%s' is not supported." %
self._restraint_type)
force = restraints.getRestraintForce(
) # Get Force object incorporating restraints
reference_system.addForce(force)
metadata[
'standard_state_correction'] = restraints.getStandardStateCorrection(
) # standard state correction in kT
elif is_complex_explicit:
# For periodic systems, we do not use a restraint, but must add a standard state correction for the box volume.
# TODO: What if the box volume fluctuates during the simulation?
box_vectors = reference_system.getDefaultPeriodicBoxVectors()
box_volume = thermodynamic_state._volume(box_vectors)
STANDARD_STATE_VOLUME = 1660.53928 * unit.angstrom**3
metadata['standard_state_correction'] = -np.log(
STANDARD_STATE_VOLUME / box_volume)
# Create alchemically-modified states using alchemical factory.
logger.debug("Creating alchemically-modified states...")
try:
alchemical_indices = atom_indices[
'ligand_counterions'] + atom_indices['ligand']
except KeyError:
alchemical_indices = atom_indices['ligand']
factory = AbsoluteAlchemicalFactory(reference_system,
ligand_atoms=alchemical_indices,
**self._alchemy_parameters)
alchemical_system = factory.alchemically_modified_system
thermodynamic_state.system = alchemical_system
# Check systems for finite energies.
# TODO: Refactor this into another function.
finite_energy_check = False
if finite_energy_check:
logger.debug(
"Checking energies are finite for all alchemical systems.")
integrator = openmm.VerletIntegrator(1.0 * unit.femtosecond)
context = openmm.Context(alchemical_system, integrator)
context.setPositions(positions[0])
for alchemical_state in alchemical_states:
AbsoluteAlchemicalFactory.perturbContext(
context, alchemical_state)
potential = context.getState(
getEnergy=True).getPotentialEnergy()
if np.isnan(potential / unit.kilocalories_per_mole):
raise Exception("Energy for system %d is NaN." % index)
del context, integrator
logger.debug("All energies are finite.")
# Randomize ligand position if requested, but only for implicit solvent systems.
if self._randomize_ligand and is_complex_implicit:
logger.debug(
"Randomizing ligand positions and excluding overlapping configurations..."
)
randomized_positions = list()
nstates = len(alchemical_states)
for state_index in range(nstates):
positions_index = np.random.randint(0, len(positions))
current_positions = positions[positions_index]
new_positions = ModifiedHamiltonianExchange.randomize_ligand_position(
current_positions, atom_indices['receptor'],
atom_indices['ligand'],
self._randomize_ligand_sigma_multiplier *
restraints.getReceptorRadiusOfGyration(),
self._randomize_ligand_close_cutoff)
randomized_positions.append(new_positions)
positions = randomized_positions
if self._randomize_ligand and is_complex_explicit:
logger.warning(
"Ligand randomization requested, but will not be performed for explicit solvent simulations."
)
# Identify whether any atoms will be displaced via MC, unless option is turned off.
mc_atoms = None
if self._mc_displacement_sigma:
mc_atoms = list()
if 'ligand' in atom_indices:
mc_atoms = atom_indices['ligand']
# Set up simulation.
# TODO: Support MPI initialization?
logger.debug("Creating replica exchange object...")
store_filename = os.path.join(self._store_directory,
alchemical_phase.name + '.nc')
self._store_filenames[alchemical_phase.name] = store_filename
simulation = ModifiedHamiltonianExchange(store_filename)
simulation.create(thermodynamic_state,
alchemical_states,
positions,
displacement_sigma=self._mc_displacement_sigma,
mc_atoms=mc_atoms,
options=repex_parameters,
metadata=metadata,
fully_interacting_state=fully_interacting_state)
# Initialize simulation.
# TODO: Use the right scheme for initializing the simulation without running.
#logger.debug("Initializing simulation...")
#simulation.run(0)
# Clean up simulation.
del simulation
# Add to list of phases that have been set up.
self._phases.append(alchemical_phase.name)
return
def _create_phase(self, phase, reference_system, positions, atom_indices, thermodynamic_state, protocols=None):
"""
Create a repex object for a specified phase.
Parameters
----------
phase : str
The phase being initialized (one of ['complex', 'solvent', 'vacuum'])
reference_system : simtk.openmm.System
The reference system object from which alchemical intermediates are to be construcfted.
positions : list of simtk.unit.Qunatity objects containing (natoms x 3) positions (as np or lists)
The list of positions to be used to seed replicas in a round-robin way.
atom_indices : dict
atom_indices[phase][component] is the set of atom indices associated with component, where component
is ['ligand', 'receptor', 'complex', 'solvent', 'ligand_counterions']
thermodynamic_state : ThermodynamicState
Thermodynamic state from which reference temperature and pressure are to be taken.
protocols : dict of list of AlchemicalState, optional, default=None
If specified, the alchemical protocol protocols[phase] will be used for phase 'phase' instead of the default.
"""
# We add default repex options only on creation, on resume repex will pick them from the store file
repex_parameters = {
'number_of_equilibration_iterations': 0,
'number_of_iterations': 100,
'timestep': 2.0 * unit.femtoseconds,
'collision_rate': 5.0 / unit.picoseconds,
'minimize': False,
'show_mixing_statistics': True, # this causes slowdown with iteration and should not be used for production
'displacement_sigma': 1.0 * unit.nanometers # attempt to displace ligand by this stddev will be made each iteration
}
repex_parameters.update(self._repex_parameters)
# Make sure positions argument is a list of coordinate snapshots.
if hasattr(positions, 'unit'):
# Wrap in list.
positions = [positions]
# Check the dimensions of positions.
for index in range(len(positions)):
# Make sure it is recast as a np array.
positions[index] = unit.Quantity(np.array(positions[index] / positions[index].unit), positions[index].unit)
[natoms, ndim] = (positions[index] / positions[index].unit).shape
if natoms != reference_system.getNumParticles():
raise Exception("positions argument must be a list of simtk.unit.Quantity of (natoms,3) lists or np array with units compatible with nanometers.")
# Create metadata storage.
metadata = dict()
# Make a deep copy of the reference system so we don't accidentally modify it.
reference_system = copy.deepcopy(reference_system)
# TODO: Use more general approach to determine whether system is periodic.
is_periodic = self._is_periodic(reference_system)
# Make sure pressure is None if not periodic.
if not is_periodic: thermodynamic_state.pressure = None
# Compute standard state corrections for complex phase.
metadata['standard_state_correction'] = 0.0
# TODO: Do we need to include a standard state correction for other phases in periodic boxes?
if phase == 'complex-implicit':
# Impose restraints for complex system in implicit solvent to keep ligand from drifting too far away from receptor.
logger.debug("Creating receptor-ligand restraints...")
reference_positions = positions[0]
if self._restraint_type == 'harmonic':
restraints = HarmonicReceptorLigandRestraint(thermodynamic_state, reference_system, reference_positions, atom_indices['receptor'], atom_indices['ligand'])
elif self._restraint_type == 'flat-bottom':
restraints = FlatBottomReceptorLigandRestraint(thermodynamic_state, reference_system, reference_positions, atom_indices['receptor'], atom_indices['ligand'])
else:
raise Exception("restraint_type of '%s' is not supported." % self._restraint_type)
force = restraints.getRestraintForce() # Get Force object incorporating restraints
reference_system.addForce(force)
metadata['standard_state_correction'] = restraints.getStandardStateCorrection() # standard state correction in kT
elif phase == 'complex-explicit':
# For periodic systems, we do not use a restraint, but must add a standard state correction for the box volume.
# TODO: What if the box volume fluctuates during the simulation?
box_vectors = reference_system.getDefaultPeriodicBoxVectors()
box_volume = thermodynamic_state._volume(box_vectors)
STANDARD_STATE_VOLUME = 1660.53928 * unit.angstrom**3
metadata['standard_state_correction'] = - np.log(STANDARD_STATE_VOLUME / box_volume)
# Use default alchemical protocols if not specified.
if not protocols:
protocols = self.default_protocols
# Create alchemically-modified states using alchemical factory.
logger.debug("Creating alchemically-modified states...")
try:
alchemical_indices = atom_indices['ligand_counterions'] + atom_indices['ligand']
except KeyError:
alchemical_indices = atom_indices['ligand']
factory = AbsoluteAlchemicalFactory(reference_system, ligand_atoms=alchemical_indices,
**self._alchemy_parameters)
alchemical_states = protocols[phase]
alchemical_system = factory.alchemically_modified_system
thermodynamic_state.system = alchemical_system
# Check systems for finite energies.
# TODO: Refactor this into another function.
finite_energy_check = False
if finite_energy_check:
logger.debug("Checking energies are finite for all alchemical systems.")
integrator = openmm.VerletIntegrator(1.0 * unit.femtosecond)
context = openmm.Context(alchemical_system, integrator)
context.setPositions(positions[0])
for alchemical_state in alchemical_states:
AbsoluteAlchemicalFactory.perturbContext(context, alchemical_state)
potential = context.getState(getEnergy=True).getPotentialEnergy()
if np.isnan(potential / unit.kilocalories_per_mole):
raise Exception("Energy for system %d is NaN." % index)
del context, integrator
logger.debug("All energies are finite.")
# Randomize ligand position if requested, but only for implicit solvent systems.
if self._randomize_ligand and (phase == 'complex-implicit'):
logger.debug("Randomizing ligand positions and excluding overlapping configurations...")
randomized_positions = list()
nstates = len(alchemical_states)
for state_index in range(nstates):
positions_index = np.random.randint(0, len(positions))
current_positions = positions[positions_index]
new_positions = ModifiedHamiltonianExchange.randomize_ligand_position(current_positions,
atom_indices['receptor'], atom_indices['ligand'],
self._randomize_ligand_sigma_multiplier * restraints.getReceptorRadiusOfGyration(),
self._randomize_ligand_close_cutoff)
randomized_positions.append(new_positions)
positions = randomized_positions
if self._randomize_ligand and (phase == 'complex-explicit'):
logger.warning("Ligand randomization requested, but will not be performed for explicit solvent simulations.")
# Identify whether any atoms will be displaced via MC, unless option is turned off.
mc_atoms = None
if self._mc_displacement_sigma:
mc_atoms = list()
if 'ligand' in atom_indices:
mc_atoms = atom_indices['ligand']
# Set up simulation.
# TODO: Support MPI initialization?
logger.debug("Creating replica exchange object...")
store_filename = os.path.join(self._store_directory, phase + '.nc')
self._store_filenames[phase] = store_filename
simulation = ModifiedHamiltonianExchange(store_filename)
simulation.create(thermodynamic_state, alchemical_states, positions,
displacement_sigma=self._mc_displacement_sigma, mc_atoms=mc_atoms,
options=repex_parameters, metadata=metadata)
# Initialize simulation.
# TODO: Use the right scheme for initializing the simulation without running.
#logger.debug("Initializing simulation...")
#simulation.run(0)
# Clean up simulation.
del simulation
# Add to list of phases that have been set up.
self._phases.append(phase)
return
def _create_phase(self,
phase,
reference_system,
positions,
atom_indices,
thermodynamic_state,
protocols=None,
options=None,
mpicomm=None):
"""
Create a repex object for a specified phase.
Parameters
----------
phase : str
The phase being initialized (one of ['complex', 'solvent', 'vacuum'])
reference_system : simtk.openmm.System
The reference system object from which alchemical intermediates are to be construcfted.
positions : list of simtk.unit.Qunatity objects containing (natoms x 3) positions (as np or lists)
The list of positions to be used to seed replicas in a round-robin way.
atom_indices : dict
atom_indices[phase][component] is the set of atom indices associated with component, where component is ['ligand', 'receptor']
thermodynamic_state : ThermodynamicState
Thermodynamic state from which reference temperature and pressure are to be taken.
protocols : dict of list of AlchemicalState, optional, default=None
If specified, the alchemical protocol protocols[phase] will be used for phase 'phase' instead of the default.
options : dict of str, optional, default=None
If specified, these options will override default repex simulation options.
"""
# Make sure positions argument is a list of coordinate snapshots.
if hasattr(positions, 'unit'):
# Wrap in list.
positions = [positions]
# Check the dimensions of positions.
for index in range(len(positions)):
# Make sure it is recast as a np array.
positions[index] = unit.Quantity(
np.array(positions[index] / positions[index].unit),
positions[index].unit)
[natoms, ndim] = (positions[index] / positions[index].unit).shape
if natoms != reference_system.getNumParticles():
raise Exception(
"positions argument must be a list of simtk.unit.Quantity of (natoms,3) lists or np array with units compatible with nanometers."
)
# Create metadata storage.
metadata = dict()
# Make a deep copy of the reference system so we don't accidentally modify it.
reference_system = copy.deepcopy(reference_system)
# TODO: Use more general approach to determine whether system is periodic.
is_periodic = self._is_periodic(reference_system)
# Make sure pressure is None if not periodic.
if not is_periodic: thermodynamic_state.pressure = None
# Compute standard state corrections for complex phase.
metadata['standard_state_correction'] = 0.0
# TODO: Do we need to include a standard state correction for other phases in periodic boxes?
if phase == 'complex-implicit':
# Impose restraints for complex system in implicit solvent to keep ligand from drifting too far away from receptor.
if self.verbose: print "Creating receptor-ligand restraints..."
reference_positions = positions[0]
if self.restraint_type == 'harmonic':
restraints = HarmonicReceptorLigandRestraint(
thermodynamic_state, reference_system, reference_positions,
atom_indices['receptor'], atom_indices['ligand'])
elif self.restraint_type == 'flat-bottom':
restraints = FlatBottomReceptorLigandRestraint(
thermodynamic_state, reference_system, reference_positions,
atom_indices['receptor'], atom_indices['ligand'])
else:
raise Exception("restraint_type of '%s' is not supported." %
self.restraint_type)
force = restraints.getRestraintForce(
) # Get Force object incorporating restraints
reference_system.addForce(force)
metadata[
'standard_state_correction'] = restraints.getStandardStateCorrection(
) # standard state correction in kT
elif phase == 'complex-explicit':
# For periodic systems, we do not use a restraint, but must add a standard state correction for the box volume.
# TODO: What if the box volume fluctuates during the simulation?
box_vectors = reference_system.getDefaultPeriodicBoxVectors()
box_volume = thermodynamic_state._volume(box_vectors)
STANDARD_STATE_VOLUME = 1660.53928 * unit.angstrom**3
metadata['standard_state_correction'] = np.log(
STANDARD_STATE_VOLUME / box_volume) # TODO: Check sign.
# Use default alchemical protocols if not specified.
if not protocols:
protocols = self.default_protocols
# Create alchemically-modified states using alchemical factory.
if self.verbose: print "Creating alchemically-modified states..."
factory = AbsoluteAlchemicalFactory(
reference_system, ligand_atoms=atom_indices['ligand'])
systems = factory.createPerturbedSystems(protocols[phase])
# Randomize ligand position if requested, but only for implicit solvent systems.
if self.randomize_ligand and (phase == 'complex-implicit'):
if self.verbose:
print "Randomizing ligand positions and excluding overlapping configurations..."
randomized_positions = list()
nstates = len(systems)
for state_index in range(nstates):
positions_index = np.random.randint(0, len(positions))
current_positions = positions[positions_index]
new_positions = ModifiedHamiltonianExchange.randomize_ligand_position(
current_positions, atom_indices['receptor'],
atom_indices['ligand'],
self.randomize_ligand_sigma_multiplier *
restraints.getReceptorRadiusOfGyration(),
self.randomize_ligand_close_cutoff)
randomized_positions.append(new_positions)
positions = randomized_positions
# Identify whether any atoms will be displaced via MC.
mc_atoms = list()
if 'ligand' in atom_indices:
mc_atoms = atom_indices['ligand']
# Combine simulation options with defaults.
options = dict(self.default_options.items() + options.items())
# Set up simulation.
# TODO: Support MPI initialization?
if self.verbose: print "Creating replica exchange object..."
store_filename = os.path.join(self._store_directory, phase + '.nc')
self._store_filenames[phase] = store_filename
simulation = ModifiedHamiltonianExchange(store_filename,
mpicomm=mpicomm)
simulation.create(thermodynamic_state,
systems,
positions,
displacement_sigma=self.mc_displacement_sigma,
mc_atoms=mc_atoms,
options=options,
metadata=metadata)
simulation.verbose = self.verbose
# Initialize simulation.
# TODO: Use the right scheme for initializing the simulation without running.
#if self.verbose: print "Initializing simulation..."
#simulation.run(0)
# TODO: Process user-supplied options.
# Clean up simulation.
del simulation
return
def _create_phase(self, thermodynamic_state, alchemical_phase):
"""
Create a repex object for a specified phase.
Parameters
----------
thermodynamic_state : ThermodynamicState (System need not be defined)
Thermodynamic state from which reference temperature and pressure are to be taken.
alchemical_phase : AlchemicalPhase
The alchemical phase to be created.
"""
# We add default repex options only on creation, on resume repex will pick them from the store file
repex_parameters = {
'number_of_equilibration_iterations': 0,
'number_of_iterations': 100,
'timestep': 2.0 * unit.femtoseconds,
'collision_rate': 5.0 / unit.picoseconds,
'minimize': False,
'show_mixing_statistics': True, # this causes slowdown with iteration and should not be used for production
'displacement_sigma': 1.0 * unit.nanometers # attempt to displace ligand by this stddev will be made each iteration
}
repex_parameters.update(self._repex_parameters)
# Convenience variables
positions = alchemical_phase.positions
reference_system = copy.deepcopy(alchemical_phase.reference_system)
atom_indices = alchemical_phase.atom_indices
alchemical_states = alchemical_phase.protocol
# If temperature and pressure are specified, make sure MonteCarloBarostat is attached.
if thermodynamic_state.temperature and thermodynamic_state.pressure:
forces = { reference_system.getForce(index).__class__.__name__ : reference_system.getForce(index) for index in range(reference_system.getNumForces()) }
if 'MonteCarloAnisotropicBarostat' in forces:
raise Exception('MonteCarloAnisotropicBarostat is unsupported.')
if 'MonteCarloBarostat' in forces:
logger.debug('MonteCarloBarostat found: Setting default temperature and pressure.')
barostat = forces['MonteCarloBarostat']
# Set temperature and pressure.
try:
barostat.setDefaultTemperature(thermodynamic_state.temperature)
except AttributeError: # versions previous to OpenMM7.1
barostat.setTemperature(thermodynamic_state.temperature)
barostat.setDefaultPressure(state.pressure)
else:
# Create barostat and add it to the system if it doesn't have one already.
logger.debug('MonteCarloBarostat not found: Creating one.')
barostat = openmm.MonteCarloBarostat(thermodynamic_state.pressure, thermodynamic_state.temperature)
reference_system.addForce(barostat)
# Check the dimensions of positions.
for index in range(len(positions)):
n_atoms, _ = (positions[index] / positions[index].unit).shape
if n_atoms != reference_system.getNumParticles():
err_msg = "Phase {}: number of atoms in positions {} and and " \
"reference system differ ({} and {} respectively)"
err_msg.format(alchemical_phase.name, index, n_atoms,
reference_system.getNumParticles())
logger.error(err_msg)
raise RuntimeError(err_msg)
# Inizialize metadata storage.
metadata = dict()
# Store a serialized copy of the reference system.
metadata['reference_system'] = openmm.XmlSerializer.serialize(reference_system)
metadata['topology'] = utils.serialize_topology(alchemical_phase.reference_topology)
# TODO: Use more general approach to determine whether system is periodic.
is_periodic = self._is_periodic(reference_system)
is_complex_explicit = len(atom_indices['receptor']) > 0 and is_periodic
is_complex_implicit = len(atom_indices['receptor']) > 0 and not is_periodic
# Make sure pressure is None if not periodic.
if not is_periodic: thermodynamic_state.pressure = None
# Create a copy of the system for which the fully-interacting energy is to be computed.
# For explicit solvent calculations, an enlarged cutoff is used to account for the anisotropic dispersion correction.
fully_interacting_system = copy.deepcopy(reference_system)
if is_periodic:
# Expand cutoff to maximum allowed
# TODO: Should we warn if cutoff can't be extended enough?
# TODO: Should we extend to some minimum cutoff rather than the maximum allowed?
box_vectors = fully_interacting_system.getDefaultPeriodicBoxVectors()
max_allowed_cutoff = 0.499 * max([ max(vector) for vector in box_vectors ]) # TODO: Correct this for non-rectangular boxes
logger.debug('Setting cutoff for fully interacting system to maximum allowed (%s)' % str(max_allowed_cutoff))
for force_index in range(fully_interacting_system.getNumForces()):
force = fully_interacting_system.getForce(force_index)
if hasattr(force, 'setCutoffDistance'):
force.setCutoffDistance(max_allowed_cutoff)
if hasattr(force, 'setCutoff'):
force.setCutoff(max_allowed_cutoff)
# Construct thermodynamic state
fully_interacting_state = copy.deepcopy(thermodynamic_state)
fully_interacting_state.system = fully_interacting_system
# Compute standard state corrections for complex phase.
metadata['standard_state_correction'] = 0.0
# TODO: Do we need to include a standard state correction for other phases in periodic boxes?
if is_complex_implicit:
# Impose restraints for complex system in implicit solvent to keep ligand from drifting too far away from receptor.
logger.debug("Creating receptor-ligand restraints...")
reference_positions = positions[0]
if self._restraint_type == 'harmonic':
restraints = HarmonicReceptorLigandRestraint(thermodynamic_state, reference_system, reference_positions, atom_indices['receptor'], atom_indices['ligand'])
elif self._restraint_type == 'flat-bottom':
restraints = FlatBottomReceptorLigandRestraint(thermodynamic_state, reference_system, reference_positions, atom_indices['receptor'], atom_indices['ligand'])
else:
raise Exception("restraint_type of '%s' is not supported." % self._restraint_type)
force = restraints.getRestraintForce() # Get Force object incorporating restraints
reference_system.addForce(force)
metadata['standard_state_correction'] = restraints.getStandardStateCorrection() # standard state correction in kT
elif is_complex_explicit:
# For periodic systems, we do not use a restraint, but must add a standard state correction for the box volume.
# TODO: What if the box volume fluctuates during the simulation?
box_vectors = reference_system.getDefaultPeriodicBoxVectors()
box_volume = thermodynamic_state._volume(box_vectors)
STANDARD_STATE_VOLUME = 1660.53928 * unit.angstrom**3
metadata['standard_state_correction'] = - np.log(STANDARD_STATE_VOLUME / box_volume)
# Create alchemically-modified states using alchemical factory.
logger.debug("Creating alchemically-modified states...")
try:
alchemical_indices = atom_indices['ligand_counterions'] + atom_indices['ligand']
except KeyError:
alchemical_indices = atom_indices['ligand']
factory = AbsoluteAlchemicalFactory(reference_system, ligand_atoms=alchemical_indices,
**self._alchemy_parameters)
alchemical_system = factory.alchemically_modified_system
thermodynamic_state.system = alchemical_system
# Check systems for finite energies.
# TODO: Refactor this into another function.
finite_energy_check = False
if finite_energy_check:
logger.debug("Checking energies are finite for all alchemical systems.")
integrator = openmm.VerletIntegrator(1.0 * unit.femtosecond)
context = openmm.Context(alchemical_system, integrator)
context.setPositions(positions[0])
for alchemical_state in alchemical_states:
AbsoluteAlchemicalFactory.perturbContext(context, alchemical_state)
potential = context.getState(getEnergy=True).getPotentialEnergy()
if np.isnan(potential / unit.kilocalories_per_mole):
raise Exception("Energy for system %d is NaN." % index)
del context, integrator
logger.debug("All energies are finite.")
# Randomize ligand position if requested, but only for implicit solvent systems.
if self._randomize_ligand and is_complex_implicit:
logger.debug("Randomizing ligand positions and excluding overlapping configurations...")
randomized_positions = list()
nstates = len(alchemical_states)
for state_index in range(nstates):
positions_index = np.random.randint(0, len(positions))
current_positions = positions[positions_index]
new_positions = ModifiedHamiltonianExchange.randomize_ligand_position(current_positions,
atom_indices['receptor'], atom_indices['ligand'],
self._randomize_ligand_sigma_multiplier * restraints.getReceptorRadiusOfGyration(),
self._randomize_ligand_close_cutoff)
randomized_positions.append(new_positions)
positions = randomized_positions
if self._randomize_ligand and is_complex_explicit:
logger.warning("Ligand randomization requested, but will not be performed for explicit solvent simulations.")
# Identify whether any atoms will be displaced via MC, unless option is turned off.
mc_atoms = None
if self._mc_displacement_sigma:
mc_atoms = list()
if 'ligand' in atom_indices:
mc_atoms = atom_indices['ligand']
# Set up simulation.
# TODO: Support MPI initialization?
logger.debug("Creating replica exchange object...")
store_filename = os.path.join(self._store_directory, alchemical_phase.name + '.nc')
self._store_filenames[alchemical_phase.name] = store_filename
simulation = ModifiedHamiltonianExchange(store_filename)
simulation.create(thermodynamic_state, alchemical_states, positions,
displacement_sigma=self._mc_displacement_sigma, mc_atoms=mc_atoms,
options=repex_parameters, metadata=metadata,
fully_interacting_state=fully_interacting_state)
# Initialize simulation.
# TODO: Use the right scheme for initializing the simulation without running.
#logger.debug("Initializing simulation...")
#simulation.run(0)
# Clean up simulation.
del simulation
# Add to list of phases that have been set up.
self._phases.append(alchemical_phase.name)
return