macrocyclize.py Command Help
Command: $SCHRODINGER/run -FROM psp macrocyclize.py
usage:
To run the macrocyclization script:
$SCHRODINGER/run -FROM psp macrocyclize.py -inp_mae <mae> [options]
To show the built-in sidechain bridges for peptide mode and spacer SMILES for small molecule mode:
$SCHRODINGER/run -FROM psp macrocyclize.py -show_bridges_and_spacers
To write the default parameter file for a given mode:
$SCHRODINGER/run -FROM psp macrocyclize.py [--mode <mode>] -write_param_file
To write a parameter file a given mode and optionally overwrite values:
$SCHRODINGER/run -FROM psp macrocyclize.py [--mode <mode>] [--param_file <file>] -write_param_file
Macrocyclize a small molecule or peptide by specifying the chemistry of the
linker and the attachment points both for the linker and target molecule.
In Small Molecule (sm) mode the linker is built up of repeating building blocks
up to a calculated or set length. By default, a small pre-defined library of building
blocks will be used. Further building blocks from this library can be selected with the
'-spacers' parameter. Alternatively, custom building blocks can be specified by
providing SMILES strings; each SMILES string should start and end with the
placeholder `Ge` element to signify the attachment points. Initially, linkers
are created by combining all possible combinations of building blocks up to a
certain length. The minimum and maximum number of building blocks to combine
are, by default, determined based on the distance between the attachment points
of the target molecule, or they can be directly specified. Linkers with a certain
resulting chemistry can be discarded by providing SMARTS strings. The generated
linkers are attached to the target molecule and energy minimized. Highly
strained linker conformations and linkers containing excluded chemistries are
discarded.
In Peptide mode the linker is fully specified by SMILES strings, i.e. there is
no notion of building blocks. By default, all linkers in a pre-defined library
are generated, where some entries require atom property annotation to specify
the attachment point. Specific linkers can be requested either by providing numbers
that correspond to entries in the pre-defined library or directly by SMILES
strings. When providing SMILES strings, each SMILES string should start and end
with CC, specifying the C-alpha and C-beta of the linker. Generated linkers are
attached to the target and energy minimized, with highly strained linker
conformations being discarded.
To inspect the pre-defined library of building blocks and peptide linkers use
the -show_bridges_and_spacers option. To further fine-tune the workflow, specific
parameters can be adjusted using a parameter file or by overwriting individual
parameters with the '-parameter' argument. Inspect the available parameters and
their associated values with the -write_param_file option. Atoms in the final
cyclized structures are annotated with the 'Is_linker_atom' property for downstream
identification.
options:
-h, --help show this help message and exit
-inp_mae INP_MAE, --inp_mae INP_MAE
Input Maestro file; must contain the linear compound either alone or in complex
-write_param_file, --write_param_file
Write an example parameter file for the specified mode; includes all defaults as explicit key-value pairs. Use together with '-mode' to see mode-specific parameters.
-out_mae OUT_MAE, --out_mae OUT_MAE
Output file name; if unspecified, a name ending in .cyclizations.maegz will be automatically generated
-show_bridges_and_spacers, --show_bridges_and_spacers
Display example sidechain bridges and spacer SMILES.
-jobname JOBNAME, -JOBNAME JOBNAME, -j JOBNAME
Set the base name of outputs
-v show program's version number and exit
Macrocyclization Options:
-target_asl TARGET_ASL, --target_asl TARGET_ASL
ASL for selecting the cyclizable region; default = 'ligand'. If used with the '--target_asl2' option, specifies the first ligand portion to target
-target_asl2 TARGET_ASL2, --target_asl2 TARGET_ASL2
ASL for selecting an additional ligand during linking-mode
-mode {sm,peptide}, --mode {sm,peptide}
Choice of actions: small molecule cyclization or sidechain bridge enumeration; default = 'sm'
-propose_limbs {text,file}, --propose_limbs {text,file}
Show only limb pairs where macrocyclization appears tenable; choose between writing directly to log or to a separate file
-param_file PARAM_FILE, --param_file PARAM_FILE
Load a file containing cyclization parameters (use -write_param_file to generate a sample file); this is an alternative to specifying key-value pairs using the '--parameter' option
-parameter PARAMETER, --parameter PARAMETER
Pass any keyword-value pair for cyclization, in the form <keyword>=<value>
-out_fmt {full,pvref,pv,ligsonly,allligs,none}, --out_fmt {full,pvref,pv,ligsonly,allligs,none}
Structures to output:
'full' (default): All ligands and reference, with the receptor in every frame
'pvref': Pose Viewer-like file with the reference and receptor in the first frame, ligands only in the remainder
'pv': Pose Viewer-like file with the receptor in the first frame, ligands only in the remainder
'ligsonly': Only the cyclized ligands
'allligs': Reference ligand and cyclized ligands
'none': Do not save the output file
Small Molecule Mode:
-limb_atoms LIMB_ATOMS, --limb_atoms LIMB_ATOMS
Define macrocyclization limb vectors by atom indices, e.g. '15-2_17-21' to specify the 15-2 vector and the 17-21 vector as the limbs to pair for cyclization; the limbs should be terminal atoms
-potential_limb_asls POTENTIAL_LIMB_ASLS, --potential_limb_asls POTENTIAL_LIMB_ASLS
4 ASL queries used to define macrocyclization limb vectors, each separated by the '_' character. Each pair of ASLs selects the vector along which the linker should be built. Default = '(atom.mtype C3)_(atom.element H)_(atom.mtype C3)_(atom.element H)', which specifies SP3 Carbon-Hydrogen vectors. The ASLs may include SMARTS patterns
-spacers SPACERS, --spacers SPACERS
Specify spacers from the pre-defined library; provide a comma-separated list of spacer indices, e.g. '1,2,3'; use '-show_bridges_and_spacers' to show the list of avaliable spacers; by default, the methyl, PEG and amide linkers are used
-spacer_smiles SPACER_SMILES, --spacer_smiles SPACER_SMILES
Specify spacer SMILES strings for small molecule cyclization. Use [Ge] for connection points and make sure the SMILES string starts and ends with a connection point: e.g. '[Ge]CCO[Ge]_[Ge]/C=C/[Ge]'; if not specified, a predefined library of spacers will be used. Use '-show_bridges_and_spacers' to show the list of default spacers.
-spacer_smiles_from_file SPACER_SMILES_FROM_FILE, --spacer_smiles_from_file SPACER_SMILES_FROM_FILE
Read spacer SMILES strings from a text file instead of specifying '--spacer_smiles'; each line should contain a single SMILES string
-max_blocks MAX_BLOCKS, --max_blocks MAX_BLOCKS
Maximum number of spacer blocks to use
-min_blocks MIN_BLOCKS, --min_blocks MIN_BLOCKS
Minimum number of spacer blocks to use
-exclude_cyclization_smarts EXCLUDE_CYCLIZATION_SMARTS, --exclude_cyclization_smarts EXCLUDE_CYCLIZATION_SMARTS
Optionally specify SMARTS patterns to be excluded from cyclizations linker chains; use '_' to separate them, e.g. 'OO_NN'
Peptide Mode:
-sidechain_bridges SIDECHAIN_BRIDGES, --sidechain_bridges SIDECHAIN_BRIDGES
Optionally select pre-defined sidechain bridges for peptide cyclization; provide a comma-separated list of bridge indices, e.g. '1,2,3'; use '-show_bridges_and_spacers' to show the list of pre-defined bridges; all pre-defined bridges are used by default and will cyclize between L-L amino acids only.
-sidechain_bridge_smiles SIDECHAIN_BRIDGE_SMILES, --sidechain_bridge_smiles SIDECHAIN_BRIDGE_SMILES
Instead of using the builtin bridges, build bridges using SMILES strings that indicate the bridge chemistry, e.g. use 'CCSSCC_CCCCC(=O)NCCCCC' to represent a Cysteine bridge and Leu-Glu Lactam bridge.
-sidechain_bridge_attachments SIDECHAIN_BRIDGE_ATTACHMENTS, --sidechain_bridge_attachments SIDECHAIN_BRIDGE_ATTACHMENTS
Optionally specify non-L attachments (D or N peptoid) for each custom sidechain bridge(s). For each side chain bridge, specify the attachment pairs that should be iterated over e.g. for 2 given bridges, 'L-D,D-L_D-D' will use all L-D and D-L attachments for the first bridge and D-D attachments for the second bridge. The total number of groups separated by '_' must match the number of custom sidechain bridges. The Default is all possible L/D combinations for each bridge.
Job Control Options:
-HOST <hostname> Run job remotely on the indicated host entry.
-WAIT Do not return a prompt until the job completes.
-D, -DEBUG Show details of Job Control operation.
-NOJOBID Run the job directly, without Job Control layer.
Standard Options:
-NJOBS NJOBS Divide the overall job into NJOBS subjobs.
-RETRIES RETRIES If a subjob fails for any reason, it will be retried RETRIES times. (Default: 2)
-NOLAUNCH Set up subjob inputs, but don't run the jobs.
Examples:
1. For a ligand that matches the default 'ligand' target ASL, generate cyclizations between all SP3-hybridized carbons using
minimally 3 and maximally 5 units of the default pre-defined building blocks:
$SCHRODINGER/run -FROM psp macrocyclize.py input.mae -mode sm -min_blocks 3 -max_blocks 5
2. For a ligand that matches the default 'ligand' target ASL, generate cyclizations that are attached along the bond vectors
of atoms 31 and 32, and atoms 45 and 46 using the pre-defined library spacers 1, 2, and 3:
$SCHRODINGER/run -FROM psp macrocyclize.py input.mae -mode sm -limb_atoms 31-32_45-46 -spacers 1,2,3
3. For a ligand that matches the default 'ligand' target ASL, generate cyclizations that are attached along the bond vectors
of atoms 31 and 32, and atoms 45 and 46 using custom building blocks:
$SCHRODINGER/run -FROM psp macrocyclize.py input.mae -mode sm -limb_atoms 31-32_45-46 -spacer_smiles "[Ge]CC[Ge]_[Ge]C(=O)C[Ge]"
4. For a ligand that matches the target ASL '(chain.name P)', generate cyclizations that are attached along the bond vectors
of atoms 31 and 32, and atoms 45 and 46 using building blocks specified from a file:
$SCHRODINGER/run -FROM psp macrocyclize.py input.mae -mode sm -limb_atoms 31-32_45-46 -spacer_smiles_from_file spacers.txt
5. Cyclize a peptide with all built-in sidechain bridges between residues 16 to 38 in chain P:
$SCHRODINGER/run -FROM psp macrocyclize.py input.maegz -target_asl '(chain.name P) AND (res.num 16-38)' -mode peptide
6. Cyclize a peptide defined by chain P between residues 16 to 38 with cysteine bridges:
$SCHRODINGER/run -FROM psp macrocyclize.py input.maegz -target_asl '(chain.name P) AND (res.num 16-38)' -mode peptide -sidechain_bridges 1
7. Cyclize a peptide defined by chain P between residues 16 to 38 with cysteine bridges or Lys-Glu lactam bridges:
$SCHRODINGER/run -FROM psp macrocyclize.py input.maegz -target_asl '(chain.name P) AND (res.num 16-38)' -mode peptide -sidechain_bridges 1,7
8. For a ligand that matches the default 'ligand' target ASL, generate cyclizations between all SP3-hybridized carbons but specifiy specific
cyclization parameters. For example, we can increase the maximum number of linker-site combinations to trial for cyclization:
$SCHRODINGER/run -FROM psp macrocyclize.py input.mae -mode sm -min_blocks 3 -max_blocks 5 -parameter 'max_enumerations=800000'
9. Cyclize a peptide between all L-D, L-L and D-D amino acid combinations with a cysteine linker defined by a SMILES string:
$SCHRODINGER/run -FROM psp macrocyclize.py input.mae -mode peptide -sidechain_bridge_smiles CCSSCC -sidechain_bridge_attachments L-D,L-L,D-D