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Development of the first model of a phosphorylated, ATP/Mg2+-containing B-Raf monomer by molecular dynamics simulations: a tool for structure-based design

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Abstract

A model of phosphorylated and ATP-containing B-Raf protein kinase is needed as a tool for the structure-based design of new allosteric inhibitors, since no crystal structure of such a system has been resolved. Here, we present the development of such a model as well as a thorough analysis of its structural features. This model was prepared using a systematic molecular dynamics approach considering the presence or absence of both the phosphate group at the Thr599 site and the ATP molecule. Then, different structural features (i.e. DFG motif, Mg2+ binding loop, activation loop, phosphorylation site and αC-helix region) were analysed for each trajectory to validate the aimed 2pBRAF_ATP model. Moreover, the structure and activating interactions of this 2pBRAF_ATP model were found to be in agreement with previously reported information. Finally, the model was further validated by means of a molecular docking study with our previously developed lead compound I confirming that this ATP-containing, phosphorylated protein model is suitable for further structure-based design studies.

Graphical abstract: Development of the first model of a phosphorylated, ATP/Mg2+-containing B-Raf monomer by molecular dynamics simulations: a tool for structure-based design

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Publication details

The article was received on 25 Jul 2017, accepted on 02 Nov 2017 and first published on 02 Nov 2017


Article type: Paper
DOI: 10.1039/C7CP05038K
Citation: Phys. Chem. Chem. Phys., 2017, Advance Article
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    Development of the first model of a phosphorylated, ATP/Mg2+-containing B-Raf monomer by molecular dynamics simulations: a tool for structure-based design

    V. Previtali, C. Trujillo, J. Boisson, H. Khartabil, E. Hénon and I. Rozas, Phys. Chem. Chem. Phys., 2017, Advance Article , DOI: 10.1039/C7CP05038K

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