title: Deciphering common failures in molecular docking of ligand-protein complexes.
abstract: Common failures in predicting crystal structures of ligand-protein complexes are investigated for three ligand-protein systems by a combined thermodynamic and kinetic analysis of the binding energy landscapes. Misdocked predictions in ligand-protein docking are classified as 'soft' and 'hard' failures. While a soft failure arises when the search algorithm is unable to find the global energy minimum corresponding to the crystal structure, a hard failure results from a flaw of the energy function to qualify the crystal structure as the predicted lowest energy conformation in docking simulations. We find that neither the determination of a single structure with the lowest energy nor finding the most common binding mode is sufficient to predict crystal structures of the complexes, which belong to the category of hard failures. In a proposed hierarchical approach, structural similarity clustering of the conformations, generated from equilibrium simulations with the simplified energy function, is followed by energy refinement with the AMBER force field. This protocol, that involves a hierarchy of energy functions, resolves some common failures in ligand-protein docking and detects crystallographic binding modes that were not found during docking simulations.
authors.affiliation: Agouron Pharmaceuticals, Inc, A Warner-Lambert Company, San Diego, CA 92121-1111, USA. verk@agouron.com
authors.forename: G M
authors.initials: GM
authors.lastname: Verkhivker
authors.forename: D
authors.initials: D
authors.lastname: Bouzida
authors.forename: D K
authors.initials: DK
authors.lastname: Gehlhaar
authors.forename: P A
authors.initials: PA
authors.lastname: Rejto
authors.forename: S
authors.initials: S
authors.lastname: Arthurs
authors.forename: A B
authors.initials: AB
authors.lastname: Colson
authors.forename: S T
authors.initials: ST
authors.lastname: Freer
authors.forename: V
authors.initials: V
authors.lastname: Larson
authors.forename: B A
authors.initials: BA
authors.lastname: Luty
authors.forename: T
authors.initials: T
authors.lastname: Marrone
authors.forename: P W
authors.initials: PW
authors.lastname: Rose
mesh_terms: D003461:Crystallography; D005964:Glucosyltransferases / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D008320:Maltose / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D008024:Ligands; D011506:Proteins; D008320:Maltose; D005964:Glucosyltransferases; C019963:cyclomaltodextrin glucanotransferase