Molecular docking screens using comparative models of proteins

Abstract

Two orders of magnitude more protein sequences can be modeled by comparative modeling than have been determined by X-ray crystallography and NMR spectroscopy. Investigators have nevertheless been cautious about using comparative models for ligand discovery because of concerns about model errors. We suggest how to exploit comparative models for molecular screens, based on docking against a wide range of crystallographic structures and comparative models with known ligands. To account for the variation in the ligand-binding pocket as it binds different ligands, we calculate "consensus" enrichment by ranking each library compound by its best docking score against all available comparative models and/or modeling templates. For the majority of the targets, the consensus enrichment for multiple models was better than or comparable to that of the holo and apo X-ray structures. Even for single models, the models are significantly more enriching than the template structure if the template is paralogous and shares more than 25% sequence identity with the target.

Figure 1. Composition of the benchmark

(a) Distribution of the target-template sequence identity for holo templates (black bars) and apo templates (red bars). (b) Distribution of the target-template binding site sequence identity. (c) Distribution of N-DOPE statistical potential score for comparative models (black and red bars for models based on holo and apo templates, respectively) and target X-ray structures (empty blue bars). (d) Distribution of root-mean-square deviation of the non-hydrogen atoms in binding site residues (RMSD_bs) between a comparative model and a target X-ray structure.

Figure 2. Model features do not predict docking success

Circles and triangles correspond to models built from holo- and apo-templates, respectively.

Figure 3. Enrichment plots for the 38 protein targets

Enrichment curves for the holo X-ray structure (black line), the apo X-ray structure (blue line), the consensus enrichment for multiple models (red line), and random selection (dotted line).

Figure 3. Enrichment plots for the 38 protein targets

Enrichment curves for the holo X-ray structure (black line), the apo X-ray structure (blue line), the consensus enrichment for multiple models (red line), and random selection (dotted line).

Figure 4. Comparing ligand enrichments for comparative models and their templates

Circles and triangles correspond to models based on holo- and apo-templates, respectively. (a, b) Scatter plots of the difference between the enrichments for a comparative model and the corresponding template ( Δ log AUC_m-t = log AUC_model - log AUC_template ) versus the target-template sequence identity. (c, d) Scatter plots of Δ log AUC_m-t versus the difference between the enrichments for the target holo X-ray structure and the template ( Δ log AUC_x-t = log AUC_x-ray - log AUC_template ).

Figure 5. Sample enrichment curves

For 8 targets (6 enzymes, one of which is a kinase, and 2 hormone receptors), enrichment curves are plotted for the holo X-ray structure (dotted line), the consensus based on multiple models (black line), and each single model (brown lines).

Figure 6a. Binding poses of 6 protein targets

For each target, the docking pose of one known binder with one comparative model of the target was selected. The ligand in complex with the crystallographic structure of the target protein was always located in the background. The targets include two hormone receptors AR and RXRa, four enzymes DHFR, NA, PNP and SAHH.

Figure 6b. 2D images of ligands in Figure 5a

The ligands used in Figure 5a are presented. For AR, the ligands crystallized in the structures of target proteins are the same as the docked ligands. For the other 5 targets, the X-ray structure ligands are shown on top of the docked ligands.