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Why is it not possible to return the crystallographic binding pose of the ligand?


Although GOLD is usually highly effective at returning the crystallographically derived pose, there are a number of reasons why GOLD might not succeed. The following represents a non-exhaustive list:

  • The ligand crystallographic pose is actually not correct.
  • The ligand file being docked is incorrectly atom- and bond-typed, or is incorrectly protonated.
  • There are incorrect protein residues. Asn and Gln residues often need to be flipped at the terminal side chain, and His residues need to be in the correct tautomeric form. All protein residues need to be protonated according to physiological pH with allowances made for possible microenvironments in the active site.
  • The scoring function used is not the best for the protein in question. If so, try another scoring function to see if the ligand crystallographic binding pose can be reproduced better.
  • The GOLD docking algorithm returns only very similar binding poses. If so, try using the Diverse Solutions option to find other reasonable binding poses.
  • The ligand is large and has many rotatable bonds. If so, try a longer docking protocol.
  • The ligand is a covalently bound ligand. If so, use the option for docking covalent ligands.
  • The binding site definition is either too small or too large with respect to the ligand being docked.
  • Water mediated hydrogen bonding is important and all the waters have been removed during protein preparation. If so, identify and extract important waters and allow GOLD to optimise these water hydrogen positions for maximum hydrogen bonding to occur.