DockRank: ranking docked conformations using partner-specific sequence homology-based protein interface prediction

Abstract

Selecting near-native conformations from the immense number of conformations generated by docking programs remains a major challenge in molecular docking. We introduce DockRank, a novel approach to scoring docked conformations based on the degree to which the interface residues of the docked conformation match a set of predicted interface residues. DockRank uses interface residues predicted by partner-specific sequence homology-based protein-protein interface predictor (PS-HomPPI), which predicts the interface residues of a query protein with a specific interaction partner. We compared the performance of DockRank with several state-of-the-art docking scoring functions using Success Rate (the percentage of cases that have at least one near-native conformation among the top m conformations) and Hit Rate (the percentage of near-native conformations that are included among the top m conformations). In cases where it is possible to obtain partner-specific (PS) interface predictions from PS-HomPPI, DockRank consistently outperforms both (i) ZRank and IRAD, two state-of-the-art energy-based scoring functions (improving Success Rate by up to 4-fold); and (ii) Variants of DockRank that use predicted interface residues obtained from several protein interface predictors that do not take into account the binding partner in making interface predictions (improving success rate by up to 39-fold). The latter result underscores the importance of using partner-specific interface residues in scoring docked conformations. We show that DockRank, when used to re-rank the conformations returned by ClusPro, improves upon the original ClusPro rankings in terms of both Success Rate and Hit Rate. DockRank is available as a server at http://einstein.cs.iastate.edu/DockRank/.

Keywords: docking scoring functions; homo-interologs; partner-specific protein-protein interface residue prediction; protein complex structure prediction; protein-protein docking; sequence homologs.

Figure 1

Success rates of DockRank and other scoring schemes on the ZDock3-BM3 decoy set plotted against the top m conformations. The x-axis is plotted on a logarithmic scale to emphasize the region of top ranks. The Success Rate of DockRank (red, using predicted interface residues from a partner-specific predictor, PS-HomPPI) is compared with two energy-based scoring functions, IRAD (black) and ZRank (yellow), and with variants of DockRank using interface residues predicted by three state-of-the-art protein interface residue predictors: NPS-HomPPI (pink), PrISE (green), and meta-PPISP (blue). NPS-HomPPI, PrISE, and meta-PPISP are nonpartner-specific (NPS) interface predictors. The success rate of DockRank's scoring function supplied with partner-specific actual interface residues (labeled as “PS-Act Int,” gray-dashed line) is plotted to define the upper bound of DockRank's scoring function. Studied here are 67 docking cases that have at least one hit (a conformation with I–RMSD ≤ 2:5å) among 54,000 candidate decoys and for which PS-HomPPI is able to return interface predictions.

Figure 2

I-RMSDs of top ranked conformations selected by different docking scoring methods on the ZDock3-BM3 decoy set. The lower (Q1), middle (Q2), and upper (Q3) quartiles of each box are 25th, 50th, and 75th percentile. Interquartile range IQR is Q3–Q1. Any data value that lies more than 1.5 × IQR lower than the first quartile or 1.5 × IQR higher than the third quartile is considered an outlier, which is labeled with a red cross. The whiskers extend to the largest and smallest value that is not an outlier. Averages are marked by green dots. Studied here are 67 cases for which ZDock 3.0 is able to generate at least one hit (I–RMSD 2:5Å) and for which PS-HomPPI is able to return interface predictions. DockRank's scoring function supplied with actual partner-specific interfaces (PS-Act Int) set the lower bound of I-RMSDs of top ranked conformations that DockRank's scoring function can select.

Figure 3

Success rates of DockRank and ClusPro scoring functions on the ClusPro2-BM3_31 decoy set plotted against the top m conformations. The x-axis is plotted on a logarithmic scale to emphasize the region of top ranks. ClusPro scoring functions (default cluster-size based, center energy-based, lowest energy-based) were applied on the original docked conformations (10⁹ docked conformations per docking case) generated by ClusPro's underlying docking program, PIPER. DockRank was applied on the docked conformations (30 of the 10⁹ docked conformations per case) output by ClusPro scoring functions. The success rate of DockRank's scoring function supplied with partner-specific interface-based ranking (gray-dashed line) is also plotted to show the upper bound of the success rate of DockRank's scoring function. Studied here are 31 cases for which ClusPro 2.0 is able to return at least one hit (a docked conformation with L–RMSD 10Å) and for which PSHomPPI is able to return interface predictions. We limited m (the number of top ranked conformations) to 9, since ClusPro returned only nine conformations for one of the docking cases, 1PPE.

Figure 4

The difference between the averages of L-RMSDs of top models between DockRank and ClusPro Rank on each case of the ClusPro2-BM3_45 decoy set. Positive values correspond to cases where the top five ranked DockRank conformations have a lower average L-RMSD than those ranked by ClusPro.

Figure 5

The top conformations ranked by DockRank and ClusPro for docking case 1ML0. The red ribbon is the receptor. (A) The highest ranked models selected by ClusPro (ligand shown as gold ribbon) and DockRank (ligand shown as blue ribbon), with the bound ligand that is included in the BM3 dataset (pink surface representation). (B) The top five ranked models (ribbons) with two bound ligands from PISA. Figure generated using PYMOL [70].

Figure 6

The rankings of top 10 selected models by DockRank and the CAPRI scorers.

Figure 7

The interface prediction of PS-HomPPI on the ZDock3-BM3 decoy set in different interface prediction confidence zones. A docking case with more than one receptor-ligand chain pair may have predicted interfaces from different confidence zones. Only cases with predictions in a single confidence zone and with at least one hit are studied here. Fifty-eight cases have only Safe Zone interface predictions, out of which ZDock 3.0 is able to generate at least one hit for 48 cases. Fourteen cases have only Twilight Zone interface predictions, out of which 10 cases have at least one hit. Two cases have only Dark Zone interface predictions, of which two cases have at least one hit.