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The standard ligand_dock application (http://www.rosettacommons.org/manuals/archive/rosetta3.2.1_user_guide/app_ligand_dock.html) allows the definition of various pockets through the -start_from and -uniform_trans flags. If you just have one pocket, I believe you can simply start with a structure with the ligand in the center of the pocket, omit the -start_from flag, and then specify the size of the pocket with the -uniform_trans flag. (I tend to use the arls.py to set things up, and it takes care of most things automatically.)
The covalently bound cofactor is a little more of an issue. Although I’ve never used ligand docking with multiple non-protein ligands, I believe that the non-docked ligand isn’t allowed rigid body movement. I would suggest first trying to model the covalent cofactor as a non-covalent additional ligand. You may have a bit of an issue with the residue wanting to repack to relieve the steric clash (ligand docking always keeps the backbone fixed), but if the attachment point is far enough from the ligand docking site, it might not be an issue. Alternatively, you just remove some of the ligand atoms. If those methods won’t work for you (e.g. if the attachment point is involved in ligand binding), you could try modeling the covalent cofactor as a non-canonical amino acid, but that can be a bit tricky, and it’s easiest to just avoid it.
Although not mentioned in the body, you also mentioned protein design in your subject line. My recommendation is that if you’re looking for mutations, you should use the enzyme_design application (http://www.rosettacommons.org/manuals/archive/rosetta3.2.1_user_guide/app_enzyme_design.html). Despite the name, it should work for ligand binder design in addition to enzyme design.