Dataset Information

FiberDock: Flexible induced-fit backbone refinement in molecular docking.

ABSTRACT: Upon binding, proteins undergo conformational changes. These changes often prevent rigid-body docking methods from predicting the 3D structure of a complex from the unbound conformations of its proteins. Handling protein backbone flexibility is a major challenge for docking methodologies, as backbone flexibility adds a huge number of degrees of freedom to the search space, and therefore considerably increases the running time of docking algorithms. Normal mode analysis permits description of protein flexibility as a linear combination of discrete movements (modes). Low-frequency modes usually describe the large-scale conformational changes of the protein. Therefore, many docking methods model backbone flexibility by using only few modes, which have the lowest frequencies. However, studies show that due to molecular interactions, many proteins also undergo local and small-scale conformational changes, which are described by high-frequency normal modes. Here we present a new method, FiberDock, for docking refinement which models backbone flexibility by an unlimited number of normal modes. The method iteratively minimizes the structure of the flexible protein along the most relevant modes. The relevance of a mode is calculated according to the correlation between the chemical forces, applied on each atom, and the translation vector of each atom, according to the normal mode. The results show that the method successfully models backbone movements that occur during molecular interactions and considerably improves the accuracy and the ranking of rigid-docking models of protein-protein complexes. A web server for the FiberDock method is available at: http://bioinfo3d.cs.tau.ac.il/FiberDock.

SUBMITTER: Mashiach E

PROVIDER: S-EPMC4290165 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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FiberDock: Flexible induced-fit backbone refinement in molecular docking.

Mashiach Efrat E Nussinov Ruth R Wolfson Haim J HJ

Proteins 20100501 6

Upon binding, proteins undergo conformational changes. These changes often prevent rigid-body docking methods from predicting the 3D structure of a complex from the unbound conformations of its proteins. Handling protein backbone flexibility is a major challenge for docking methodologies, as backbone flexibility adds a huge number of degrees of freedom to the search space, and therefore considerably increases the running time of docking algorithms. Normal mode analysis permits description of pro ...[more]

PMID: 20077569

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Project description:Background: Indicaxanthin, a betaxanthin belonging to the betalain class of compounds, has been recently demonstrated to exert significant antiproliferative effects inducing apoptosis of human melanoma cells through the inhibition of NF-κB as the predominant pathway. Specifically, Indicaxanthin inhibited IκBα degradation in A375 cells. In resting cells, NF-κB is arrested in the cytoplasm by binding to its inhibitor protein IκBα. Upon stimulation, IκBα is phosphorylated by the IKK complex, and degraded by the proteasome, liberating free NF-κB into the nucleus to initiate target gene transcription. Inhibition of the IKK complex leads to the arrest of the NF-κB pathway. Methods: To acquire details at the molecular level of Indicaxanthin's inhibitory activity against hIKKβ, molecular modeling and simulation techniques including induced-fit docking (IFD), binding pose metadynamics (BPMD), molecular dynamics simulations, and MM-GBSA (molecular mechanics-generalized Born surface area continuum solvation) have been performed. Results: The computational calculations performed on the active and inactive form, and the allosteric binding site of hIKKβ, revealed that Indicaxanthin inhibits prevalently the active form of the hIKKβ. MM-GBSA computations provide further evidence of Indicaxanthin's stability inside the active binding pocket with a binding free energy of -22.2 ± 4.3 kcal/mol with respect to the inactive binding pocket with a binding free energy of -20.7 ± 4.7 kcal/mol. BPMD and MD simulation revealed that Indicaxanthin is likely not an allosteric inhibitor of hIKKβ. Conclusion: As a whole, these in silico pieces of evidence show that Indicaxanthin can inhibit the active form of the hIKKβ adding novel mechanistic insights on its recently discovered ability to impair NF-κB signaling in melanoma A375 cells. Moreover, our results suggest the phytochemical as a new lead compound for novel, more potent IKKβ inhibitors to be employed in the treatment of cancer and inflammation-related conditions.

Dataset Information

FiberDock: Flexible induced-fit backbone refinement in molecular docking.

Publications

FiberDock: Flexible induced-fit backbone refinement in molecular docking.

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