How does activation loop phosphorylation modulate catalytic activity in the cAMP‐dependent protein kinase: A theoretical study

Phosphorylation mediates the function of many proteins and enzymes. In the catalytic subunit of cAMP‐dependent protein kinase, phosphorylation of Thr 197 in the activation loop strongly influences its catalytic activity. In order to provide theoretical understanding about this important regulatory process, classical molecular dynamics simulations and ab initio QM/MM calculations have been carried out on the wild‐type PKA–Mg₂ ATP–substrate complex and its dephosphorylated mutant, T197A. It was found that pThr 197 not only facilitates the phosphoryl transfer reaction by stabilizing the transition state through electrostatic interactions but also strongly affects its essential protein dynamics as well as the active site conformation.