prepare

Suite of functions to prepare simulations (docking, free energy) from crystal structures from Fragalysis. It has two functions: receptors (working), omm (not working).

Install

Requires numpy, rich and openeye-toolkits which you will have to install separately.

> git clone https://github.com/ChoderaLab/fah_prep
> cd fah_prep
> pip install -e . 

prepare receptors

Overview

Prepare receptors, protein and ligand PDB/SDF files using the Open Eye toolkits, Spruce inparticular. receptors takes a set of crystal structures which contain ligands and prepares Spruce 'Design Units' by building loops, adding hydrogens and determining protonation states etc. See the Spruce thand OEChem/OEBio documentation for more details. The design unit, apo protein, ligand and receptor objects are then saved as output.

Warning

This function is currently hard-coded to work with the Mpro data. In particular:

1. If a data source can't be found it will download the Mpro data from a variable called FRAGALYSIS_URL which is set in prepare/constants.py to be: https://fragalysis.diamond.ac.uk/media/targets/Mpro.zip.
2. Mpro is a dimer, but some structures (those with an x in them, e.g., Mpro-x1119.pdb) have been crystallized as monomers. If the structure is an x form , then the monomer form is created, along with a dimer form. The dimer form is created from the PDB REMARK_350 in the PDB. This is added, if necessary, using the variable REMARK_350 in prepare/constants.py.
3. The options, particular to Mpro, for the Spruce design units are hard-coded in the function get_options() in prepare/receptors.py.
4. The PDB remark SEQRES is added into the PDB if it is not present. This can be found in the variables SEQRES_MONOMER and SEQRES_DIMER defined in prepare/constants.py.
5. Two forms of each structure are created in prepare_receptor, one with a charged catalytic dyad (with thiolate as a suffix) and a neutral dyad between Cys-145 and His-41.
6. The following functions and classes also have some reference to Mpro:
   1. PreparationConfig - the create_dimer slot is for Mpro (or other dimer/monomer systems)
   2. OutputPaths - the ..._thiolate slots are for the charged catalytic dyad of Mpro.
   3. crystal_series - x/N/P seems to be a Mpro thing - but I'm not sure. These are Xchem nomenclature so could refer to something more universal.
   4. au_is_dimeric - this could be universal if you could be sure that dimers were represented by a chain A and B. need to check PDB naming conventions with the Xchem folks.
   5. clean_pdb - could be universal but some of the function calls within it might need changing. e.g., adding the symmetry header for x forms.
   6. create_output_filenames - please nuke this it's a horrible hack.
   7. write_docking_system - the is_thiolate flag is Mpro specific.
   8. create_dyad - this could be universal if the state argument is parsed correctly. Dyads with histidine are fairly common. The options at the bottom of this function are slightly mysterious to me. bypass_atoms is crucial here, but it doesn't necessarily need the return variable to be captured as everything is done by reference.
   9. options_consistent - first check is universal, second is Mpro depending on conventions of naming (see previous notes).
   10. download_fraglaysis_latest - hard-coded file name - should just be generic then it can be universal.
   11. define_prep_configs - could be universal with slight adjustments (e.g., remove the loop over monomer/dimer).
7. The following functions may be redundant (due to improvements in Spruce):
   1. rebuild_c_termial - this just deletes the C terminal so Spruce rebuilds it.

Usage

prepare receptors -i path/to/Mpro -f 'Mpro-P0047*.pdb' -o ./receptors

• -i path to structures directory. Will download from Xchem website if not present. Default ./MPro.

• -f glob filter for files. Should be stipulated relative to -i. Default aligned/Mpro-*_0?/Mpro-*_0?_bound.pdb - i.e., all aligned structures.

• -o output directory to place the prepared files. Doesn't need to exist. Default ./receptors

• -n denotes dry run. In this case structures files are downloaded and all the combinations of inputs/outputs are printed to console.

• If the structure is a monomer, then it will create a dimer and a monomer form.

• If the structure is a dimer, it will only produce a dimer form.

• A log file is created for each structure which captures all the Open Eye output.

• No alignment is done.

• All solvent molecules e.g., DMSO and water, are currently removed. There is the option for retaining the crystallographic waters, but this is currently hard-coded to be off.

• When alternate structures are available, only the first (as defined by Spruce) is used.

Known bugs/problems:

• There are no unit tests. I have tested the creation of the ligand and protein pdb forms in the P0008/9 structures for monomer and dimer by looking at the structures in PyMol and checking the dyads are protonated as expected.
• With dimers, the chain containing the ligand site is unpredicatable. e.g., if there is a ligand in both chain A and chain B then it is not clear which chain will contain the receptor site in the design unit.
• The design units created by Spruce appear to relabel chains (e.g., chain A -> chain B & chain B -> chain A).
• dry-run option doesn't take into account inconsistent options.

To do:

• Implement better logger. Currently uses the OpenEye logger which isn't great.
• Use multiprocessing to perform calculations. Potential issue here as naive implementation with current

prepare omm

WIP. Performs OpenMM minimization. The code for this is in prepare/dynamics.py but is not currently integrated into prepare.