Development of the first model of a phosphorylated, ATP/Mg2+-containing B-Raf monomer by molecular dynamics simulations: a tool for structure-based design. Issue 46 (15th November 2017)

• Record Type: Journal Article
• Authors: Previtali, Viola; Trujillo, Cristina; Boisson, Jean-Charles; Khartabil, Hassan; Hénon, Eric; Rozas, Isabel
• Is Part Of: Physical chemistry chemical physics. Volume 19:Issue 46(2017)
• Page Start: 31177
• Page End: 31185
• Publication Date: 2017-11-15
• Subjects: Chemistry, Physical and theoretical -- Periodicals; 541.3
• DOI: 10.1039/c7cp05038k
• Languages: English
• ISSNs: 1463-9076

Abstract

Abstract : A model of phosphorylated and ATP-containing B-Raf protein kinase is needed as a tool for structure-based design of new allosteric inhibitors, since no crystal structure of such a system has been resolved. 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, Mg 2+ binding loop, activation loop, phosphorylation site and αC-helix region) were analysed for each trajectory to validate the aimed2pBRAF_ATP model. Moreover, the structure and activating interactions of this2pBRAF_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 compoundI confirming that this ATP-containing, phosphorylated protein model is suitable for further structure-based design studies.