Development of the first model of a phosphorylated, ATP/Mg 2+ -containing B-Raf monomer by molecular dynamics simulations: a tool for structure-based design - Archive ouverte HAL Access content directly
Journal Articles Physical Chemistry Chemical Physics Year : 2017

Development of the first model of a phosphorylated, ATP/Mg 2+ -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.

Dates and versions

hal-02505102 , version 1 (11-03-2020)

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Viola Previtali, Cristina Trujillo, Jean-Charles Boisson, Hassan Khartabil, Eric Henon, et al.. Development of the first model of a phosphorylated, ATP/Mg 2+ -containing B-Raf monomer by molecular dynamics simulations: a tool for structure-based design. Physical Chemistry Chemical Physics, 2017, 19 (46), pp.31177-31185. ⟨10.1039/C7CP05038K⟩. ⟨hal-02505102⟩
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