Can I dock peptides as ligands in Glide?

Glide has a limit on the size of the ligand: it can handle ligands with up to 300 atoms and 50 rotatable bonds. Peptide ligands often exceed these limits. If any your peptide ligands are within the 300 atom limit, you can decrease the number of rotatable bonds sampled by freezing amide bonds at their input conformations (on the Settings tab of the Ligand Docking panel). This might help you get under the 50 rotatable bond limit. You can also decrease the number of rotatable bonds by applying torsional constraints (on the Torsional Constraints tab of the Ligand Docking panel). For example, to freeze the peptide backbone, use the SMARTS pattern "C(=O)-NH-C-C(=O)-NH" and constrain all torsions in the pattern.

Docking does become increasingly difficult the more flexible the ligand becomes, due to the enormous ligand conformational space involved. An alternative to flexible docking is to run a rigid docking job, which doesn't do conformational sampling of the ligand. You can run such a job even if the ligand has more than 50 rotatable bonds. To explore the ligand conformation space, you would have to generate the conformations beforehand with another program (e.g., MacroModel) and use them as input for your Glide rigid-docking job.

Our best tool for investigating docking of ligands which cross these limits might be a conformational search with the LLMOD method (large-scale low-mode sampling) in MacroModel, which you could do in the context of Embrace, for obtaining protein-ligand binding information. The LLMOD sampling method is designed to treat large, flexible structures, although you can limit the search to the interaction areas using the substructure feature. You could follow this type of conformational search with Prime side-chain predictions and/or loop sampling at the protein-ligand interface, if needed. This method would also be useful for generating a set of peptide conformers for rigid docking with Glide.

Keywords: peptide-protein docking, Component interactions, peptide ligands, LLMOD method

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