Is it possible to dock protein-ligand complexes?

[lightdock]

Is it possible to dock protein-ligand complexes?

[JorgeRoel]

Hi @h-midlothian,

First, thanks for your interest in using LightDock. As you may noticed, the current scoring functions in LightDock do not support ligand docking. However, there is a trick that might be of your interest. Assuming that you have your ligand already docked, you could replace the space that the ligand occupies by "dummy" beads and assign desired attractive/repulsive parameters to those "dummy" beads in the scoring function. For example, you could do so by placing a bead on the center-of-mass of a given group of atoms, or alternatively, convert each atom into a dummy bead. By doing this you will explictly account for the ligand during the docking. The implementation would be similar as in our membrane docking protocol. Please see (https://www.nature.com/articles/s41467-020-20076-5) and https://github.com/lightdock/lightdock/blob/master/lightdock/scoring/fastdfire/driver.py (especially the MMB-BJ entity that accounts for membrane beads).

As for the second question, in the beta version of the webserver https://server.lightdock.org/ , we have a final minimization step using openMM that seems to work rather well. You may think of a similar protocol to further refine your docked structures.

[brianjimenez]

In addition to what @JorgeRoel mentioned, there are two experimental branches on the LightDock-Rust repository to account for DUMMY beads (dummy) and ligands (pydock): https://github.com/lightdock/lightdock-rust/branches
We did some internal tests, but still far from a stable version of the code point of view. There is a dummify script in place (https://github.com/lightdock/lightdock/blob/fd_spr_vision/bin/lgd_dummify.py) and the ligand is parametrized as an alanine in the pydock branch on the Rust version. However, please take a look at those and let us know if you have any further question.

[h-midlothian]

Thanks for your replies. I tried to use the dummify.py script suggested by @brianjimenez and found the small molecules were successfully set as dummy atoms, and I set the dummy residues as passive restraints then. However, when I tried lightdock3_setup.py for the next step, there were still warnings like [pdb] WARNING: Possible problem: [ResidueNonStandardError] Can not check non-standard residue MMY.900, and below are the traceback lines:

Traceback (most recent call last):
  File "/home/cadd/.local/bin/lightdock3_setup.py", line 141, in <module>
    starting_points_files = calculate_starting_positions(
  File "/home/cadd/.local/lib/python3.8/site-packages/lightdock/prep/simulation.py", line 182, in calculate_starting_positions
    starting_points_files = calculate_initial_poses(
  File "/home/cadd/.local/lib/python3.8/site-packages/lightdock/prep/poses.py", line 450, in calculate_initial_poses
    swarm_centers = apply_restraints(
  File "/home/cadd/.local/lib/python3.8/site-packages/lightdock/prep/poses.py", line 273, in apply_restraints
    ca.x + translation[0],
AttributeError: 'NoneType' object has no attribute 'x'

So I wonder what else I should do apart from setting the dummy atoms. Should I change the allowed residue list?

[brianjimenez]

This might be a problem on the version/branch of LightDock used. Please update to the latest release (0.9.3) and try again. LightDock Python versions does not (yet) support DUMMY beads, please use the Rust version instead.

[h-midlothian]

OK. Hopefully, the Python version will support this function in the near future. Thanks.