Ensemble docking

Polgar T., Keseril G.M., Ensemble docking into flexible active sites. Critical evaluation of FlexE against JNK-3 and (3-secretase. J. Chem. Inf. Model. 2006, 46, 1795-1805. 

Huang, S.-Y., Zou, X. Ensemble docking of multiple protein structures Considering protein structural variations in molecular docking. Proteins 2007, 66, 399 421. 

Key words Pocketome, Chemical biology, Flexible docking, Ensemble docking, Drug screening,... 

Fig. 8. The accuracy of the ligand binding pose prediction for different ensemble sizes. The tors reflect the fraction of the ligands that dock correctly using traditional ensemble docking and 4D docking for varying ensemble size, compared to the accuracy of a single-receptor cross-docking.

Because the receptor conformations are changed concurrently with the ligand conformations, a 4D simulation convergence time is comparable with that of a single receptor docking, and is significantly shorter than for the traditional ensemble docking ... 

Fig. 9. Unlike the traditional ensemble docking, the 4D protocol docks the ligand into a set of receptor conformations in a single docking run.

The additional advantage of this technology over the traditional ensemble docking comes from the possibility of choosing the moves by biased probability of individual pocket conformations Pmnf = exp(- AEconf/RT)/Z. Equal probability conformations represent an extreme case of infinite effective temperature. 

Rao, S., Sanschagrin, P.C., Greenwood, J.R., Repasky, M.P., Sherman, W., and Farid, R. (2008) Improving database enrichment through ensemble docking. Journal of Computer-Aided Molecular Design, 22, 621-627. 

Approaches for fully flexible docking either follow a conformational selection or an induced fit concept (Figure 8.3). Ensemble docking implements the principle of conformational selection and relies on the protein structural change occurring before the ligand binds to the protein. The ensemble of input protein conformations... 

Fig. 5 A cartoon illustration of ensemble docking, where five individual protein structures are superimposed to create a single scoring parameter for the docked ligand. Ensemble docking minimizes the computational effort since a single docking occurs to select the best conformer instead of five separate molecular docking simulations. (Reprinted with permission from [118], copyright 2007 by John Wiley and Sons)...

In cases in which the active site structure is known, an alternative approach would be geometry optimization and calculation of descriptors for the effector molecule-active site ensemble. Docking of the effector molecule in the active site can be done manually using computer-generated structures (Murcia et al. 2006 Huey et al. 2007 Weber et al. 2006 Tucinardi et al. 2007). 

How to) Profit from Molecular Dynamics-based Ensemble Docking... 

Docking to multiple receptor conformations (sometimes abbreviated MRC [8]) can be applied on a set of conformations from any source. Experimentally different X-ray conformations or NMR solution stmctures can represent the same biomolecular system. NMR solution stmctures and conformations sampled during an MD simulation represent a valid thermodynamic ensemble, e.g., a canonical ensemble, for simulations with constant number of particles, volume, and temperature. Although, a collection of X-ray stmctures is not a valid thermodynamic ensemble, docking to multiple X-ray stmctures is sometimes also termed ensemble docking. 

Several practical questions arise along this ensemble docking workflow where different strategies can be followed. Moreover, we will discuss that they ate not only practical questions but are directly related to the underlying theoiy and should be considered regarding the physical interpretation of final results. 

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