DrugScorePPI knowledge-based potentials used as scoring and objective function in protein-protein docking

Abstract

The distance-dependent knowledge-based DrugScore(PPI) potentials, previously developed for in silico alanine scanning and hot spot prediction on given structures of protein-protein complexes, are evaluated as a scoring and objective function for the structure prediction of protein-protein complexes. When applied for ranking "unbound perturbation" ("unbound docking") decoys generated by Baker and coworkers a 4-fold (1.5-fold) enrichment of acceptable docking solutions in the top ranks compared to a random selection is found. When applied as an objective function in FRODOCK for bound protein-protein docking on 97 complexes of the ZDOCK benchmark 3.0, DrugScore(PPI)/FRODOCK finds up to 10% (15%) more high accuracy solutions in the top 1 (top 10) predictions than the original FRODOCK implementation. When used as an objective function for global unbound protein-protein docking, fair docking success rates are obtained, which improve by ∼ 2-fold to 18% (58%) for an at least acceptable solution in the top 10 (top 100) predictions when performing knowledge-driven unbound docking. This suggests that DrugScore(PPI) balances well several different types of interactions important for protein-protein recognition. The results are discussed in view of the influence of crystal packing and the type of protein-protein complex docked. Finally, a simple criterion is provided with which to estimate a priori if unbound docking with DrugScore(PPI)/FRODOCK will be successful.

Figure 1. Distance-dependent pair-potentials of DrugScore^PPI (straight line) and DrugScore (dashed).

(A) Charged interactions between atoms of types N.pl3 and O.co2; (B) polar interactions between two atoms of type O.3; (C) aromatic interactions between two atoms of type C.ar. For reasons of comparison, the potentials were aligned to a value of zero at a distance of 5 Å.

Figure 2. Computed scoring values of decoys from the “unbound perturbation” dataset using DrugScore^PPI.

(A) Serine protease/prosegment complex (PDB-ID 1PPE); (B) trypsin/trypsin inhibitor complex (PDB ID 1SPB). The scoring values are given as a function of the rmsd from the native structure; small rmsd values denote near native-like protein-protein configurations.

Figure 3. Biologically relevant protein-protein complexes and non-specific protein-protein interactions arising from crystal contacts.

The receptor (ligand) in protein-protein complexes provided in the ZDOCK benchmark 3.0 is colored in cyan (green); receptor (ligand) molecules arising from crystal contacts are colored in white (black). Docking solutions are depicted in magenta. (A) Extracellular domain of the human TGF-beta type II receptor complexed with TGF-beta3 (PDB-ID 1KTZ). The docking solution was found on rank 6 when both receptor structures were considered for the docking. (B) RAC1-GDP complexed with ligand arfaptin (PDB-ID 1I4D). The docking solution was found on rank 3 when both receptor structures were considered for the docking. (C) Human cyclophillin A complexed with the amino-terminal domain of the HIV-1 capsid (PDB-ID 1AK4). The docking solution was found on rank 4 when a set of three receptor structures were considered for the docking. (D) E. coli IIIGlc complexed with glycerol kinase (PDB-ID 1GLA). The docking solution was found on rank 1 although only the native receptor was considered for the docking.

Figure 4. Predictions of unbound protein-protein docking obtained with DrugScore^PPI/FRODOCK on the top 10 scoring ranks.

(A) Medium accuracy complex of MT-SP1/matriptase (cyan) and bovine pancreatic trypsin inhibitor (PDB ID: 1EAW). (B) Acceptable accuracy complex of ribonuclease A (cyan) and a ribonuclease inhibitor. (PDB ID: 1DFJ). In (A) and (B) ligand configurations in the crystal complex are depicted in green, and predicted ligand configurations are colored in magenta. (C) Bound crystal complex of human H-Ras (cyan) and human SOS-1 (green) (PDB ID: 1BKD) onto which the unbound ligand (orange) was aligned. Due to a large conformational change of a loop in the interface (see black ellipse) the generation of a near-native structure failed.