Conformational docking

With most filters the vast majority of compounds can be dismissed very quickly from consideration of the 2D molecular graph. This avoids the slow steps of generating 3D conformations, docking, and scoring. 

In addition to protein-protein complexes, one CAPRI target was a protein-RNA complex, and three were homo-oligomers. Target T33, the protein-RNA complex, contained a segment of ribosomal RNA, and the predictors were given coordinates taken from an X-ray structure of the ribosome. Because the RNA of the target complex has a different sequence and a very different conformation, docking predictions were expected to fail. They did. 

An overview of docking programs is given in Tabic 10.4-3. Depending on the way the conformational flexibility of the ligand is treated, docking can be either rigid or flexible. 

Genetic algorithms can also be used to perform molecular docking [Judson et d. 1994 Jont et d. 1995b Oshiro et d. 1995]. Each chromosome codes not only for the internal conform tion of the ligand as described in Section 9.9.1 but also for the orientation of the ligand withi the receptor site. Both the orientation and the internal conformation will thus vary as th populations evolve. The score of each docked structure within the site acts as the fitnes function used to select the individuals for the next iteration. 

GeUiaar D K, G M Verkhivker, P A Rejto, C J Sherman, D B Fogel, L J Fogel and S T Freer 1995 Molecular Recognition of the Inhibitor AG-1343 by HFV-l Protease Conformationally FlexibL Docking by Evolutionary Programming. Chemistry and Biology 2 317-324. 

A successful application of GA to conformation sampling is, for example, as a part of flexible docking [12-14], It should be noted, however, that none of the three sampling methods discussed above, MD, MC, and GA, was shown to outperform the other two in any general way. In fact, a comparison of the three methods in the context of flexible docking showed similar efficiency for all three [12], although specific advantages are likely to exist for particular apphcations. 

DM Lorber, BK Shoichet. Flexible ligand docking using conformational ensembles. Protein Sci 7 938-950, 1998. 

The NHR contains also the conserved Calcineurin docking site, PxlxIT, required for the physical interaction of NEAT and Calcineurin. Dephosphorylation of at least 13 serines residues in the NHR induces a conformational change that exposes the nuclear localization sequences (NLS), allowing the nuclear translocation of NEAT. Rephosphorylation of these residues unmasks the nuclear export sequences that direct transport back to the cytoplasm. Engagement of receptors such as the antigen receptors in T and B cells is coupled to phospholipase C activation and subsequent production of inositol triphosphate. Increased levels of inositol triphosphate lead to the initial release of intracellular stores of calcium. This early increase of calcium induces opening of the plasma membrane calcium-released-activated-calcium (CRAC) channels,... 

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