Computational generation inhibitor-bound conformers of p38 MAP kinase and comparison with experiments.
The p38 MAP kinases play a critical role in regulating stress-activated pathways, and serve as molecular targets for controlling inflammatory diseases. Computer-aided efforts for developing p38 inhibitors have been hampered by the necessity to include the enzyme conformational flexibility in ligand docking simulations. A useful strategy in such complicated cases is to perform ensemble-docking provided that a representative set of conformers is available for the target protein either from computations or experiments. We explore here the abilities of two computational approaches, molecular dynamics (MD) simulations and anisotropic network model (ANM) normal mode analysis, for generating potential ligand-bound conformers starting from the apo state of p38, and benchmark them against the space of conformers (or the reference modes of structural changes) inferred from principal component analysis of 134 experimentally resolved p38 kinase structures. ANM-generated conformations are found to provide a significantly better coverage of the inhibitor-bound conformational space observed experimentally, compared to MD simulations performed in explicit water, suggesting that ANM-based sampling of conformations can be advantageously employed as input structural models in docking simulations.
Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, 3501 Fifth Ave, Suite 3064 BST3, Pittsburgh, PA, USA. ahb12@pitt.edu
Ahmet
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Bakan
Ivet
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Bahar
D016880:Anisotropy; D001051:Apoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D019295:Computational Biology; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D014867:Water; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
D001051:Apoenzymes; D007527:Isoenzymes; D008024:Ligands; D047428:Protein Kinase Inhibitors; D014867:Water; D048051:p38 Mitogen-Activated Protein Kinases