TAB1 binding induced p38 alpha conformation change: an accelerated molecular dynamics simulation study

p38 alpha mitogen-activated protein kinase (MAPK) undergoes autophosphorylation induced by the binding of TGF beta-activated kinase 1 binding protein 1 (TAB1) in myocardial ischemia. Investigation of the conformational transformations in p38 alpha triggered by TAB1 binding is motivated by the need to find selective p38 alpha activation inhibitors to treat myocardial ischemia. Herein, the conformational transformations of p38 alpha were studied via all-atom accelerated molecular dynamics simulations and principal component analysis. With the binding of TAB1, the conformational changes of p38 alpha auto-activation were characterized by the movement of the activation loop (A-loop) away from the alpha G helix toward the alpha F, alpha E helixes and L16-loop. In addition, a diverse intermediate state with an extensional and phosphorylated A-loop different from the transition intermediate state was explored. The conformational changes, including the A-loop alpha-structure breaking and the stronger hydrogen bond network formation, are accompanied by the extension of the A-loop and more intramolecular interactions in p38 alpha. TAB1 correlates with other regions of p38 alpha that are distal from the TAB1-binding site, including the A-loop, alpha C helix, and L16-loop, which regulates the intramolecular correlation of p38 alpha. And, the phosphorylation further enhances the correlations between the A-loop and the other regions of p38 alpha. The correlation results imply the regulation process of p38 alpha conformational transformations. These findings will improve our understanding of the autophosphorylation of kinase and facilitate the development of selective inhibitors for the treatment of ischemic injury.