Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Jan 15;32(1):81-98.
doi: 10.1002/jcc.21601.

Predicting the accuracy of protein-ligand docking on homology models

Annalisa Bordogna  1 , Alessandro Pandini, Laura Bonati
Affiliations

Predicting the accuracy of protein-ligand docking on homology models

Annalisa Bordogna et al. J Comput Chem. .

Abstract

Ligand-protein docking is increasingly used in Drug Discovery. The initial limitations imposed by a reduced availability of target protein structures have been overcome by the use of theoretical models, especially those derived by homology modeling techniques. While this greatly extended the use of docking simulations, it also introduced the need for general and robust criteria to estimate the reliability of docking results given the model quality. To this end, a large-scale experiment was performed on a diverse set including experimental structures and homology models for a group of representative ligand-protein complexes. A wide spectrum of model quality was sampled using templates at different evolutionary distances and different strategies for target-template alignment and modeling. The obtained models were scored by a selection of the most used model quality indices. The binding geometries were generated using AutoDock, one of the most common docking programs. An important result of this study is that indeed quantitative and robust correlations exist between the accuracy of docking results and the model quality, especially in the binding site. Moreover, state-of-the-art indices for model quality assessment are already an effective tool for an a priori prediction of the accuracy of docking experiments in the context of groups of proteins with conserved structural characteristics.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Distributions of some calculated indices of model quality for the modeling set: a) RMSD, b) GDT_HA, c) RMSD-s, and d) ACS.
Figure 2
Figure 2
Correlation between some calculated model quality indices (a) RMSD, b) RMSD-s) and the model-template sequence identity (Seq_Id). Four cases with RMSD-s values higher than 12 Å were excluded from the plot b) for a clearer representation.
Figure 3
Figure 3
Distribution of the dRMSD index of docking results for the whole test set.
Figure 4
Figure 4
Uridylate kinase - adenosine monophosphate complex (PDB ID: 1UKZ). Binding geometries obtained by docking calculations compared to the experimental geometry (red sticks): a) ligand docking pose (green sticks) for the protein experimental structure (green cartoons); b) ligand docking pose (light blue sticks) for a protein model of high quality (cyan cartoons); c) ligand docking pose (yellow sticks) for a protein model of medium quality (yellow cartoons); d) ligand docking pose (blue sticks) for a protein model of low quality (blue cartoons).
Figure 5
Figure 5
Docking results: a) relation between dRMSD values for the best scored poses (dRMSD) and the minimum dRMSD values obtained (mindRMSD); b) relation between the AutoDock scores for the best scored poses (best score) and AutoDock scores for poses with the minimum dRMSD values (score mindRMSD).
Figure 6
Figure 6
Plots of docking dRMSD vs. three calculated quality indices: GDT_HA, RMSD-s and dRMSD-s. Different symbols represent the three subsets of ligand-protein complexes reported in Table 3 (see text). The Spearman correlation coefficients for the whole test set and for each subset are reported in Table 3.
Figure 7
Figure 7
Plot of docking dRMSD vs. model-template sequence identity (Seq_Id).
Figure 8
Figure 8
Modeling, docking, and docking accuracy prediction results for the complex between the human cellular retinol-binding protein II and retinol (PDB ID: 2RCT). a) and b) Experimental structure of the complex (gray), superimposed to the models obtained by using 1ICN (red) and 1OPA (blue) as templates; c) plot of predicted docking dRMSD (dRMSD-predicted) vs. calculated dRMSD (dRMSD); in black, values for the models in the subset 1CBS + 1FEN, in red and in blue, values for the models of 2RCT obtained by using 1ICN and 1OPA as templates, respectively.
Figure 9
Figure 9
Some docking results for the 1EJN + 1TNG subset of protein–ligand complexes: Urokinase-type plasminogen activator - N-(1-adamantyl)-N′-(4-guanidinobenzyl) urea complex + Trypsin - Aminomethylcyclohexane complex. a) The two experimental structures of the complexes upon structural superimposition of the proteins: 1EJN, protein and ligand are colored in green; 1TNG, protein in cyan, ligand in blue; b), d) 1TNG: two binding geometries obtained by docking calculations for protein models of different qualities (models are colored in purple and ligands in pink), compared to the experimental geometry (cyan and blue); c), e) 1EJN: two binding geometries obtained by docking calculations for protein models of different qualities (yellow and orange), compared to the experimental geometry (green).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Kitchen DB, Decornez H, Furr JR, Bajorath J. Nat Rev Drug Discov. 2004;3:935. - PubMed
    1. Warren GL, Andrews CW, Capelli A, Clarke B, LaLonde J, Lambert MH, Lindvall M, Nevins N, Semus SF, Senger S, Tedesco G, Wall ID, Woolven JM, Peishoff CE, Head MS. J Med Chem. 2006;49:5912. - PubMed
    1. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE. Nucleic Acids Res. 2000;28:235. - PMC - PubMed
    1. Levitt M. Proc Natl Acad Sci USA. 2007;104:3183. - PMC - PubMed
    1. Kopp J, Bordoli L, Battey JND, Kiefer F, Schwede T. Proteins. 2007;69(Suppl 8):38. - PubMed

Publication types

LinkOut - more resources

-