def __init__(self, store_directory):
"""
Initialize YANK object with default parameters.
Parameters
----------
store_directory : str
The storage directory in which output NetCDF files are read or written.
"""
# Record that we are not yet initialized.
self._initialized = False
# Store output directory.
self._store_directory = store_directory
# Public attributes.
self.restraint_type = 'flat-bottom' # default to a flat-bottom restraint between the ligand and receptor
self.randomize_ligand = False
self.randomize_ligand_sigma_multiplier = 2.0
self.randomize_ligand_close_cutoff = 1.5 * unit.angstrom # TODO: Allow this to be specified by user.
self.mc_displacement_sigma = 10.0 * unit.angstroms
# Set internal variables.
self._phases = list()
self._store_filenames = dict()
# Default alchemical protocols.
self.default_protocols = dict()
self.default_protocols['vacuum'] = AbsoluteAlchemicalFactory.defaultVacuumProtocol()
self.default_protocols['solvent-implicit'] = AbsoluteAlchemicalFactory.defaultSolventProtocolImplicit()
self.default_protocols['complex-implicit'] = AbsoluteAlchemicalFactory.defaultComplexProtocolImplicit()
self.default_protocols['solvent-explicit'] = AbsoluteAlchemicalFactory.defaultSolventProtocolExplicit()
self.default_protocols['complex-explicit'] = AbsoluteAlchemicalFactory.defaultComplexProtocolExplicit()
# Default options for repex.
self.options = YankOptions()
self.options.default['number_of_equilibration_iterations'] = 0
self.options.default['number_of_iterations'] = 100
self.options.default['timestep'] = 2.0 * unit.femtoseconds
self.options.default['collision_rate'] = 5.0 / unit.picoseconds
self.options.default['minimize'] = False
self.options.default['show_mixing_statistics'] = True # this causes slowdown with iteration and should not be used for production
self.options.default['platform'] = None
self.options.default['displacement_sigma'] = 1.0 * unit.nanometers # attempt to displace ligand by this stddev will be made each iteration
return
class Yank(object):
"""
A class for managing alchemical replica-exchange free energy calculations.
"""
def __init__(self, store_directory):
"""
Initialize YANK object with default parameters.
Parameters
----------
store_directory : str
The storage directory in which output NetCDF files are read or written.
"""
# Record that we are not yet initialized.
self._initialized = False
# Store output directory.
self._store_directory = store_directory
# Public attributes.
self.restraint_type = 'flat-bottom' # default to a flat-bottom restraint between the ligand and receptor
self.randomize_ligand = False
self.randomize_ligand_sigma_multiplier = 2.0
self.randomize_ligand_close_cutoff = 1.5 * unit.angstrom # TODO: Allow this to be specified by user.
self.mc_displacement_sigma = 10.0 * unit.angstroms
# Set internal variables.
self._phases = list()
self._store_filenames = dict()
# Default alchemical protocols.
self.default_protocols = dict()
self.default_protocols['vacuum'] = AbsoluteAlchemicalFactory.defaultVacuumProtocol()
self.default_protocols['solvent-implicit'] = AbsoluteAlchemicalFactory.defaultSolventProtocolImplicit()
self.default_protocols['complex-implicit'] = AbsoluteAlchemicalFactory.defaultComplexProtocolImplicit()
self.default_protocols['solvent-explicit'] = AbsoluteAlchemicalFactory.defaultSolventProtocolExplicit()
self.default_protocols['complex-explicit'] = AbsoluteAlchemicalFactory.defaultComplexProtocolExplicit()
# Default options for repex.
self.options = YankOptions()
self.options.default['number_of_equilibration_iterations'] = 0
self.options.default['number_of_iterations'] = 100
self.options.default['timestep'] = 2.0 * unit.femtoseconds
self.options.default['collision_rate'] = 5.0 / unit.picoseconds
self.options.default['minimize'] = False
self.options.default['show_mixing_statistics'] = True # this causes slowdown with iteration and should not be used for production
self.options.default['platform'] = None
self.options.default['displacement_sigma'] = 1.0 * unit.nanometers # attempt to displace ligand by this stddev will be made each iteration
return
def _find_phases_in_store_directory(self):
"""
Build a list of phases in the store directory.
Parameters
----------
store_directory : str
The directory to examine for stored phase datafiles.
Returns
-------
phases : list of str
The names of phases found.
"""
phases = list()
fullpaths = glob.glob(os.path.join(self._store_directory, '*.nc'))
for fullpath in fullpaths:
[filepath, filename] = os.path.split(fullpath)
[shortname, extension] = os.path.splitext(filename)
phases.append(shortname)
if len(phases) == 0:
raise Exception("Could not find any valid YANK store (*.nc) files in store directory: %s" % self._store_directory)
return phases
def resume(self, phases=None):
"""
Resume an existing set of alchemical free energy calculations found in current store directory.
Parameters
----------
phases : list of str, optional, default=None
The list of calculation phases (e.g. ['solvent', 'complex']) to resume.
If not specified, all simulations in the store_directory will be resumed.
"""
# If no phases specified, construct a list of phases from the filename prefixes in the store directory.
if phases is None:
phases = self._find_phases_in_store_directory()
self._phases = phases
# Construct store filenames.
self._store_filenames = { phase : os.path.join(self._store_directory, phase + '.nc') for phase in self._phases }
# Ensure we can resume from each store file, processing override options.
for phase in self._phases:
# TODO: Use resume capabaility of repex to resume and modify any parameters we can change.
store_filename = self._store_filenames[phase]
pass
# Record we are now initialized.
self._initialized = True
return
def create(self, phases, systems, positions, atom_indices, thermodynamic_state, protocols=None, options=None, mpicomm=None):
"""
Set up a new set of alchemical free energy calculations for the specified phases.
Parameters
----------
store_directory : str
The storage directory in which output NetCDF files are read or written.
phases : list of str, optional, default=None
The list of calculation phases (e.g. ['solvent', 'complex']) to run.
If resuming, will resume from all NetCDF files ('*.nc') in the store_directory unless specific phases are given.
systems : dict of simtk.openmm.System, optional, default=None
A dict of System objects for each phase, e.g. systems['solvent'] is for solvent phase.
positions : dict of simtk.unit.Quantity arrays (np or Python) with units compatible with nanometers, or dict of lists, optional, default=None
A dict of positions corresponding to each phase, e.g. positions['solvent'] is a single set of positions or list of positions to seed replicas.
Shape must be natoms x 3, with natoms matching number of particles in corresponding system.
atom_indices : dict of dict list of int, optional, default=None
atom_indices[phase][component] is a list of atom indices, for each component in ['ligand', 'receptor', 'complex', 'solvent']
thermodynamic_state : ThermodynamicState (System need not be defined), optional, default=None
Thermodynamic state at which calculations are to be carried out
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.
"""
logger.debug("phases: %s" % phases)
logger.debug("systems: %s" % systems.keys())
logger.debug("positions: %s" % positions.keys())
logger.debug("atom_indices: %s" % atom_indices.keys())
logger.debug("thermodynamic_state: %s" % thermodynamic_state)
# Abort if there are files there already but initialization was requested.
for phase in phases:
store_filename = os.path.join(self._store_directory, phase + '.nc')
if os.path.exists(store_filename):
raise Exception("Store filename %s already exists." % store_filename)
# Create new repex simulations.
for phase in phases:
self._create_phase(phase, systems[phase], positions[phase], atom_indices[phase], thermodynamic_state, protocols=protocols, options=options, mpicomm=mpicomm)
# Record that we are now initialized.
self._initialized = True
return
def _is_periodic(self, system):
"""
Report whether a given system is periodic or not.
Parameters
----------
system : simtk.openmm.System
The system object to examine for periodic forces.
Returns
-------
is_periodic : bool
True is returned if a NonbondedForce object is present with getNonBondedMethod() reporting one of [CutoffPeriodic, Ewald, PME]
"""
is_periodic = False
forces = { system.getForce(index).__class__.__name__ : system.getForce(index) for index in range(system.getNumForces()) }
if forces['NonbondedForce'].getNonbondedMethod in [openmm.NonbondedForce.CutoffPeriodic, openmm.NonbondedForce.Ewald, openmm.NonbondedForce.PME]:
is_periodic = True
return is_periodic
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.
if options is None:
repex_options = dict(self.options.items())
else:
repex_options = dict(self.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)
# 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']) # DEBUG code for testing
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.
# 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(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
# Add to list of phases that have been set up.
self._phases.append(phase)
return
def run(self, niterations_to_run=None, mpicomm=None, options=None):
"""
Run a free energy calculation.
Parameters
----------
niterations_to_run : int, optional, default=None
If specified, only this many iterations will be run for each phase.
This is useful for running simulation incrementally, but may incur a good deal of overhead.
mpicomm : MPI communicator, optional, default=None
If an MPI communicator is passed, an MPI simulation will be attempted.
options : dict of str, optional, default=None
If specified, these options will override any other options.
"""
# Make sure we've been properly initialized first.
if not self._initialized:
raise Exception("Yank must first be initialized by either resume() or create().")
# Handle some logistics necessary for MPI.
if mpicomm:
logger.debug("yank.run starting for MPI...")
# Make sure each thread's random number generators have unique seeds.
# TODO: Do we need to store seed in repex object?
seed = np.random.randint(4294967295 - mpicomm.size) + mpicomm.rank
np.random.seed(seed)
# Run all phases sequentially.
# TODO: Divide up MPI resources among the phases so they can run simultaneously?
for phase in self._phases:
store_filename = self._store_filenames[phase]
# Resume simulation from store file.
simulation = ModifiedHamiltonianExchange(store_filename=store_filename, mpicomm=mpicomm)
simulation.resume(options=options)
# TODO: We may need to manually update run options here if options=options above does not behave as expected.
simulation.run(niterations_to_run=niterations_to_run)
# Clean up to ensure we close files, contexts, etc.
del simulation
return
def status(self):
"""
Determine status of all phases of Yank calculation.
Returns
-------
status : dict
status[phase] contains a dict with information about progress in the calculation for 'phase'
If simulation has not been initialized by a call to resume() or create(), None is returned.
"""
if not self._initialized: return None
status = dict()
for phase in self._phases:
status[phase] = ModifiedReplicaExchange.status_from_store(self._store_filenames[phase])
return status
def analyze(self):
"""
Programmatic interface to retrieve the results of a YANK free energy calculation.
Returns
-------
results : dict
results[phase][component] is the estimate of 'component' of thermodynamic leg 'phase'
'component' can be one of ['DeltaF', 'dDeltaF', 'DeltaH', 'dDeltaH']
DeltaF is the estimated free energy difference
dDeltaF is the statistical uncertainty in DeltaF (one standard error)
DeltaH is the estimated enthalpy difference
dDeltaH is the statistical uncertainty in DeltaH (one standard error)
all quantites are reported in units are kT
If simulation has not been initialized by a call to resume() or create(), None is returned.
"""
if not self._initialized: return None
# TODO: Can we simplify this code by pushing more into analyze.py or repex.py?
import analyze
from pymbar import MBAR, timeseries
import netCDF4 as netcdf
# Storage for results.
results = dict()
logger.debug("Analyzing simulation data...")
# Process each netcdf file in output directory.
for phase in self._phases:
fullpath = self._store_filenames[phase]
# Skip if the file doesn't exist.
if (not os.path.exists(fullpath)): continue
# Read this phase.
simulation = ModifiedHamiltonianExchange(fullpath)
simulation.resume()
# Analyze this phase.
analysis = simulation.analyze()
# Retrieve standard state correction.
analysis['standard_state_correction'] = simulation.metadata['standard_state_correction']
# Store results.
results[phase] = analysis
# Clean up.
del simulation
# TODO: Analyze binding or hydration, depending on what phases are present.
# TODO: Include effects of analytical contributions.
phases_available = results.keys()
if set(['solvent', 'vacuum']).issubset(phases_available):
# SOLVATION FREE ENERGY
results['solvation'] = dict()
results['solvation']['Delta_f'] = results['solvent']['Delta_f'] + results['vacuum']['Delta_f']
# TODO: Correct in different ways depending on what reference conditions are desired.
results['solvation']['Delta_f'] += results['solvent']['standard_state_correction'] + results['vacuum']['standard_state_correction']
results['solvation']['dDelta_f'] = np.sqrt(results['solvent']['dDelta_f']**2 + results['vacuum']['Delta_f']**2)
if set(['ligand', 'complex']).issubset(phases_available):
# BINDING FREE ENERGY
results['binding'] = dict()
# Compute binding free energy.
results['binding']['Delta_f'] = (results['solvent']['Delta_f'] + results['solvent']['standard_state_correction']) - (results['complex']['Delta_f'] + results['complex']['standard_state_correction'])
results['binding']['dDelta_f'] = np.sqrt(results['solvent']['dDelta_f']**2 + results['complex']['dDelta_f']**2)
return results