schrodinger.application.desmond.packages.restraint.cross_link module

Module to generate cross link restraints by analyzing a trajectory.

Copyright Schrodinger, LLC. All rights reserved.

class schrodinger.application.desmond.packages.restraint.cross_link.CrossLinkRestraint(A=None, B=None, C=None, a=None, b=None, c=None)

Bases: object

__init__(A=None, B=None, C=None, a=None, b=None, c=None)

A, B, and C are indices of the ligand’s atoms, and a, b, and c are of the receptor’s.

asMsjSetting(fc, sigma, schedule_name, lambda_state, schedule_dihed_name=None)

Parameters

• fc (list or tuple with 3 elements) – Force constants of the stretch, the angle, and the dihedral restraints.

• sigma (list or tuple with 3 elements) – Sigmas of the stretch, the angle, and the dihedral restraints.

• schedule_name (str) – Lambda schedule name of the restraints

• lambda_state (int) – Must be either 0 or 1. 0 represent the reference state, whereas 1 the mutant state.

• schedule_dihed_name – Name of the dihed schedule or use schedule_name if not set.

Return type

str

Returns

Msj settings of the restraints.

property atoms

Returns indices of atoms currently included in this restraint.

property variance

Returns sum of all variances.

static findBest(model, tr, *, ligand_asl, receptor_asl, r_clone=4, min_angle=10.0, verbose=False, use_bonded_atoms=False) → Optional[schrodinger.application.desmond.packages.restraint.cross_link.CrossLinkRestraint]

Examine the trajectory, and find and return the “best” cross-link restraint between the ligand molecule and the receptor molecule. Three atoms from the ligand molecule and three atoms from the receptor molecule will be selected. We denote the three ligand atoms as A, B, and C, the three receptor atoms as a, b, and c. Relative restraints will be applied to the following geometries:

• 1 stretch restraint: A-a distance

• 2 angle restraints: BAa and Aab angles

• 3 dihedral restraints: CBAa, BAab, Aabc dihedral angles

Only the given ligand atoms (lig_atoms) will be considered for the ligand atoms of the restraint, whereas all “protein” atoms will be considered for the receptor atoms of the restraint. We use the ASL expression “protein” to find protein atoms. It’s OK if the lig_atoms is part of the result of that expression.

Caveats:

• This won’t work if the receptor is NOT a protein.

• We assumed that there are at least 3 atoms in the ligand molecule and 3 atoms in the receptor molecule(s).

The “best” criteria are the following:

1. To satisfy the requirement of Desmond’s midpoint algorithm, all atoms are close to each other (i.e., within a sphere of radius of r_clone). This is mainly for the efficiency of the Desmond backend.

2. No ill geometries such as colinear structures

3. The variance of the restraint is the least.

Parameters

• model (cms.Cms) – Simulation system

• tr (list[traj.Frame]) – The trajectory to examine

• r_clone (float) – Radius of particle / home box visibility (Desmond’s definition). Its value is half of the real space cutoff distance. We use 4 (Angstroms) as a safe default, assuming the cutoff distance is 8 which is a bit less than the typical value. The exact value doesn’t matter, but it’s better to be less as opposed (to greater) than the actual r_clone used in the simulation.

• min_angle (float) – Mininum angle (in degrees) away from 0 or 180 degrees.

• use_bonded_atoms – Set to True to choose ‘ABC’ and ‘abc’ atoms that are bonded together and form an angle. The order of the atoms does not matter, just that they are bonded together. Default of False will not place restrictions on how these atoms are connected.

Parma ligand_asl

ASL expression to specify candidate ligand atoms for the restraint

Parma receptor_asl

ASL expression to specify candidate receptor atoms for the restraint

Return type

CrossLinkRestraint

class schrodinger.application.desmond.packages.restraint.cross_link.CrossLinkRestraintCentroid(A=None, B=None, C=None, a=None, b=None, c=None)

Bases: schrodinger.application.desmond.packages.restraint.cross_link.CrossLinkRestraint

Generate restraints using the centroid method. See findBest for more details.

property variance

Returns sum of all variances.

static findBest(cms_model: schrodinger.application.desmond.cms.Cms, tr: List[traj.TrajFrame], *, ligand_asl: str, receptor_asl: str, r_clone=9999, min_angle=45.0) → Optional[CrossLinkRestraint]

Generate restraints using the centroid of the binding pocket and the ligand as the basis for the restraint candidates. These candidates are then filtered to pick the one that results in the minimal variance for the restraint terms over the input trajectory.

See CrossLinkRestraint.findBest for more details.

__init__(A=None, B=None, C=None, a=None, b=None, c=None)

A, B, and C are indices of the ligand’s atoms, and a, b, and c are of the receptor’s.

asMsjSetting(fc, sigma, schedule_name, lambda_state, schedule_dihed_name=None)

Parameters

• fc (list or tuple with 3 elements) – Force constants of the stretch, the angle, and the dihedral restraints.

• sigma (list or tuple with 3 elements) – Sigmas of the stretch, the angle, and the dihedral restraints.

• schedule_name (str) – Lambda schedule name of the restraints

• lambda_state (int) – Must be either 0 or 1. 0 represent the reference state, whereas 1 the mutant state.

• schedule_dihed_name – Name of the dihed schedule or use schedule_name if not set.

Return type

str

Returns

Msj settings of the restraints.

property atoms

Returns indices of atoms currently included in this restraint.

class schrodinger.application.desmond.packages.restraint.cross_link.CrossLinkRestraintInteraction(A=None, B=None, C=None, a=None, b=None, c=None)

Bases: schrodinger.application.desmond.packages.restraint.cross_link.CrossLinkRestraint

Generate restraints using the interactions between the receptor and ligand. See findBest for more details.

property variance

Returns sum of all variances.

static findBest(msys_model: msys.System, cms_model: schrodinger.application.desmond.cms.Cms, tr: List[traj.TrajFrame], *, ligand_asl: str, receptor_asl: str, min_angle=45.0, freq_cutoff=0.5, max_variance=9999, max_dist_variance=16.0, num_traj_segments=3) → Optional[CrossLinkRestraint]

Uses the protein-ligand interactions to determine the cross link restraints. These interactions include hydrogen bonds and salt bridge interactions. The candidates are considered by picking the ones with the most consistent interactions throughout the input trajectory. Then the candidates are filtered based on the sum of the variance for all terms, and the A-a distance variance. Then the candidates are filtered to pick the one that results in the minimal overall variance.

See CrossLinkRestraint.findBest for more details.

Parameters

• freq_cutoff – Interactions must be present at least this fraction of the trajectory to be considered for the restraint. The default is 0.5.

• max_variance – The maximum variance to allow the interaction to be used as the restraint. The default is 9999 (mixed units).

• max_dist_variance – The maximum variance to allow for the A-a distance. Default is 4.0**2 (in Angstrom**2).

• num_traj_segments – Split the trajectory into num_traj_segments segments for the analysis.

__init__(A=None, B=None, C=None, a=None, b=None, c=None)

A, B, and C are indices of the ligand’s atoms, and a, b, and c are of the receptor’s.

asMsjSetting(fc, sigma, schedule_name, lambda_state, schedule_dihed_name=None)

Parameters

• fc (list or tuple with 3 elements) – Force constants of the stretch, the angle, and the dihedral restraints.

• sigma (list or tuple with 3 elements) – Sigmas of the stretch, the angle, and the dihedral restraints.

• schedule_name (str) – Lambda schedule name of the restraints

• lambda_state (int) – Must be either 0 or 1. 0 represent the reference state, whereas 1 the mutant state.

• schedule_dihed_name – Name of the dihed schedule or use schedule_name if not set.

Return type

str

Returns

Msj settings of the restraints.

property atoms

Returns indices of atoms currently included in this restraint.

class schrodinger.application.desmond.packages.restraint.cross_link.FragmentLinkingRestraint(A: int, B: int, a: int, b: int, Aa: float, BAa: float, Aab: float)

Bases: object

__init__(A: int, B: int, a: int, b: int, Aa: float, BAa: float, Aab: float)

Container for the stretch restraint Aa and the angle restraints BAa and Aab. The parameters A B a and b are the atom indicies for the restraints.

Parameters

• Aa – Value for the stretch restraint in Angstrom.

• BAa – Value for the first angle restraint in degrees.

• Aab – Value for the second angle restraint in degrees.

asMsjSetting(fc, sigma, schedule_name, lambda_state, atom_asl_dict)

Parameters

• fc (list or tuple with 2 elements) – Force constants of the stretch and the angle restraints.

• sigma (list or tuple with 2 elements) – Sigmas of the stretch and the angle restraints.

• schedule_name (str) – Lambda schedule name of the restraints

• lambda_state (int) – Must be 0, 1 or None. 0 means to apply the restraints to the reference state, whereas 1 means to apply the restraints to the mutant state. None means to use regular nonalchemical restraints, which are fixed regardless of lambda.

• atom_asl_dict (dict) – If not None, specify the atom names ‘A’, ‘B’, ‘a’, ‘b’, as the keys and the corresponding restraint asl as the values. Default of None means to use the atom numbers as the asl.

Return type

str

Returns

Msj settings of the restraints.

classmethod findRestraint(ct, fragment0_asl, fragment1_asl) → schrodinger.application.desmond.packages.restraint.cross_link.FragmentLinkingRestraint

Given a structure and the fragment0_asl/fragment1_asl asls, find the restraint that

1. minimizes the distance for the stretch term between fragments

2. maximizes the distance between the stretch term atom, and the atom used for the angle term within each fragment.

schrodinger.application.desmond.packages.restraint.cross_link.gen_cross_link_restraint(model, tr, *, ligand_asl, receptor_asl, r_clone=4, min_angle=10.0, use_bonded_atoms=False) → schrodinger.application.desmond.packages.restraint.cross_link.CrossLinkRestraint

A cross-link restraint comprises one stretch restraint, two angle restraints, and three dihedral restraints between two molecules, which typically are the ligand and the receptor. A cross link restraint will completely restrain the relative distance and orientation of the two molecules.

N.B.: A cross link restraint requires to identify three atoms from the receptor (denoted as a, b, and c), and three from the ligand (denoted as A, B, and C). If any of the two molecules are too small to not even have three non-terminal atoms, this function will NOT work, and a RuntimeError exception will be raised. Also the ligand atoms and the receptor atoms should NOT have overlaps, otherwise a RuntimeError exception will be raised.

Parameters

• tr (list of traj.Frame) – A MD simulation trajectory that we will analyze to find out the optimal 6 atoms and the equilibrium values for the cross-link restraint.

• use_bonded_atoms – See CrossLinkRestraint.findBest for information on this parameter.

Parma ligand_asl

ASL expression to specify candidate ligand atoms for the restraint

Parma receptor_asl

ASL expression to specify candidate receptor atoms for the restraint

Return type

CrossLinkRestraint

schrodinger.application.desmond.packages.restraint.cross_link.gen_cross_link_restraint_centroid(model: schrodinger.application.desmond.cms.Cms, tr: List[traj.TrajFrame], *, ligand_asl: str, receptor_asl: str, min_angle=45.0) → schrodinger.application.desmond.packages.restraint.cross_link.CrossLinkRestraintCentroid

Generate cross link restraints using the centroid method. See gen_cross_link_restraint for more detail.

schrodinger.application.desmond.packages.restraint.cross_link.gen_cross_link_restraint_interaction(msys_model: msys.System, model: schrodinger.application.desmond.cms.Cms, tr: List[traj.TrajFrame], *, ligand_asl: str, receptor_asl: str, min_angle=45.0) → schrodinger.application.desmond.packages.restraint.cross_link.CrossLinkRestraintInteraction

Generate cross link restraints looking at hydrogen bonds and salt bridges to determine the atoms to use for the restraint. See gen_cross_link_restraint for more detail.

Parameters

msys_model – Msys model used to analyze the trajectory.

Raises

• RuntimeError – If the input asls or structures are invalid.

• CrossLinkGenerationError – If a suitable restraint could not be generated.