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Ligand docking at specific orientation

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Ligand docking at specific orientation

Hi all,

I am trying to use RosettaLigand to dock a rod-shaped molecule into a protein binder with a deep, narrow binding pocket. Due to some experimental limitations, the ligand can be bound only in specific orientation - a ligand edge that is conjugated to an attached large molecule should be headed to the protein surface.

I have placed the ligand in the right orientation at the starting point. I don't want to use constraint file with random distances' constraints as is could be limiting and problematic, so I tried to limit the rmsd in the transform mover; to not use the initial_perturb option (or to use it only with small-angle perturbation); to limit the translations and orientations in the HighResDocker mover - and I still get flipped orientation. I also tried using the DiffAtomBurial filter but inspecting manually the results, it doesn't seem to work as expected. I then moved to use translate-rotate-slide together because of the ability to limit the degrees in the rotate mover. However, even limiting the degrees in rotate to 30 results in flipped orientations (even if I stop the protocol after slide together, meaning with no further high-res docking and minimization). The logs suggest that only the phi and psi but not theta are indeed limited. I am not quite sure how the axes of rotations are defined in relative to the ligand, but I guess they are not defined well with respect to the specific orientation I wish to maintain. Is there a way to influence this? Or maybe some other way to tackle this specific-orientation problem (without using cstfile and without severe restrictions on the movements in the "correct" axes, as the binding pocket is quite deep)?

Many thanks,


Post Situation: 
Mon, 2020-04-13 20:46

Are you suppling rotamers for the params file? These get used as shortcuts in some steps, like repacking I think. So maybe removing the rotamer line from your topology file will fix the bad behaviour?

Also, given your ligand I am guessing it might be best switching from internal coordinates to cartesian.

However, for covalent attachments you will need a constraint file to make sure the attachment is not bent unnaturally —one distance and two angles and maybe one dihedral at stregth 5 will fix it.

Mon, 2020-05-04 02:02