Estimation of the protein-ligand interaction energy for model building and validation

Acta Crystallogr D Struct Biol. 2017 Mar 1;73(Pt 3):195-202. doi: 10.1107/S2059798317003400. Epub 2017 Mar 6.


Macromolecular X-ray crystallography is one of the main experimental techniques to visualize protein-ligand interactions. The high complexity of the ligand universe, however, has delayed the development of efficient methods for the automated identification, fitting and validation of ligands in their electron-density clusters. The identification and fitting are primarily based on the density itself and do not take into account the protein environment, which is a step that is only taken during the validation of the proposed binding mode. Here, a new approach, based on the estimation of the major energetic terms of protein-ligand interaction, is introduced for the automated identification of crystallographic ligands in the indicated binding site with ARP/wARP. The applicability of the method to the validation of protein-ligand models from the Protein Data Bank is demonstrated by the detection of models that are `questionable' and the pinpointing of unfavourable interatomic contacts.

Keywords: ARP/wARP; LigEnergy; automated identification of crystallographic ligands; protein–ligand interaction energy; protein–ligand interactions; structure validation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Databases, Protein
  • Drug Discovery
  • Ligands
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Conformation
  • Proteins / chemistry*
  • Proteins / metabolism
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / metabolism
  • Thermodynamics*


  • Ligands
  • Proteins
  • Small Molecule Libraries