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

Viola Previtali, Cristina Trujillo, Jean Charles Boisson, Hassan Khartabil, Eric Hénon, Isabel Rozas

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)31177-31185
Number of pages9
Journal Physical Chemistry Chemical Physics
Volume19
Issue number46
DOIs
Publication statusPublished - 2017

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