Changes in the free-energy landscape of p38α MAP kinase through its canonical activation and binding events as studied by enhanced molecular dynamics simulations
|Title||Changes in the free-energy landscape of p38α MAP kinase through its canonical activation and binding events as studied by enhanced molecular dynamics simulations|
|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||Kuzmanic, Antonija, Sutto Ludovico, Saladino Giorgio, Nebreda Angel R., Gervasio Francesco L., and Orozco Modesto|
|Secondary Authors||Shan, Yibing|
|Keywords||allostery, kinases, metadynamics, molecular dynamics, p38 kinase, phosphorylation|
p38α is a Ser/Thr protein kinase involved in a variety of cellular processes and pathological conditions, which makes it a promising pharmacological target. Although the activity of the enzyme is highly regulated, its molecular mechanism of activation remains largely unexplained, even after decades of research. By using state-of-the-art molecular dynamics simulations, we decipher the key elements of the complex molecular mechanism refined by evolution to allow for a fine tuning of p38α kinase activity. Our study describes for the first time the molecular effects of different regulators of the enzymatic activity, and provides an integrative picture of the activation mechanism that explains the seemingly contradictory X-ray and NMR data.