Conformational selection of protein kinase A revealed by flexible-ligand flexible-protein docking

Journal of Computational Chemistry
Zunnan Huang, Chung F Wong

Abstract

Protein kinases have high structural plasticity: their structure can change significantly, depending on what ligands are bound to them. Rigid-protein docking methods are not capable of describing such effects. Here, we present a new flexible-ligand flexible-protein docking model in which the protein can adopt conformations between two extremes observed experimentally. The model utilized a molecular dynamics-based simulated annealing cycling protocol and a distance-dependent dielectric model to perform docking. By testing this model on docking four diverse ligands to protein kinase A, we found that the ligands were able to dock successfully to the protein with the proper conformations of the protein induced. By imposing relatively soft conformational restraints to the protein during docking, this model reduced computational costs yet permitted essential conformational changes that were essential for these inhibitors to dock properly to the protein. For example, without adequate movement of the glycine-rich loop, it was difficult for the ligands to move from the surface of the protein to the binding site. In addition, these simulations called for better ways to compare simulation results with experiment other than using the popul...Continue Reading

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Citations

Sep 15, 2011·Journal of Chemical Information and Modeling·Anjali D GanjiwaleSudha M Cowsik
Sep 23, 2009·Acta Crystallographica. Section D, Biological Crystallography·Henry van den BedemAshley M Deacon
Aug 28, 2015·Expert Opinion on Drug Discovery·Chung F Wong
Jun 22, 2010·Chemical Biology & Drug Design·Zunnan HuangChung F Wong
Mar 2, 2011·Journal of Molecular Recognition : JMR·Elizabeth YurievPaul A Ramsland
Mar 26, 2010·Archiv der Pharmazie·Matthias RabillerDaniel Rauh

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