Modeling water molecules in protein-ligand docking using GOLD

J Med Chem. 2005 Oct 6;48(20):6504-15. doi: 10.1021/jm050543p.


We implemented a novel approach to score water mediation and displacement in the protein-ligand docking program GOLD. The method allows water molecules to switch on and off and to rotate around their three principal axes. A constant penalty, sigma(p), representing the loss of rigid-body entropy, is added for water molecules that are switched on, hence rewarding water displacement. We tested the methodology in an extensive validation study. First, sigma(p) is optimized against a training set of 58 protein-ligand complexes. For this training set, our algorithm correctly predicts water mediation/displacement in approximately 92% of the cases. We observed small improvements in the quality of the predicted binding modes for water-mediated complexes. In the second part of this work, an entirely independent set of 225 complexes is used. For this test set, our algorithm correctly predicts water mediation/displacement in approximately 93% of the cases. Improvements in binding mode quality were observed for individual water-mediated complexes.

MeSH terms

  • Algorithms
  • Bacterial Proteins / chemistry
  • Binding Sites
  • Carrier Proteins / chemistry
  • Factor Xa / chemistry
  • HIV Protease / chemistry
  • Ligands*
  • Lipoproteins / chemistry
  • Models, Molecular*
  • Molecular Conformation
  • Protein Binding
  • Proteins / chemistry*
  • Thymidine Kinase / chemistry
  • Water / chemistry*


  • Bacterial Proteins
  • Carrier Proteins
  • Ligands
  • Lipoproteins
  • Proteins
  • oligopeptide-binding protein, bacteria
  • Water
  • Thymidine Kinase
  • Factor Xa
  • HIV Protease