Akt (also called protein kinase B-PKB) is a key component of the phosphoinositide-3-kinase signaling pathway, which is responsible for cell proliferation and survival and is a novel target for antioncogenic indications. In its fully activated state, Akt is phosphorylated on the activation loop (A-loop) at residue Thr 309. We used molecular dynamics (MD) simulations and elastic network model normal-mode analysis (ENM-NMA) to study the initial stages of the active-inactive transition in the kinase catalytic domain. We first carried out MD simulations of the active phosphorylated Akt in complex with its ligands under different protonation states of His 196, the phosphothreonine-coordinating residue found in the αC helix. Analysis of trajectories suggested that the doubly protonated His 196 is most compatible with the crystallographic structure. Next we studied the dynamic processes involved in Akt inactivation: detachment of the ligands and A-loop dephosphorylation resulted in MD trajectories with increased mobility, particularly in the N-lobe and in the HJ-αG region of the C-lobe, and in stronger correlation and anticorrelation of motions. The first principal motions derived from the trajectories of phosphorylated and dephosphorylated apo structures were similar to each other but differed from the first principal motions derived from the complex trajectory. A rather large number of principal components obtained from MD trajectories and of ENM-NMA modes is required to describe the active-inactive conformational change of the kinase. The results are discussed in the context of related computational studies of kinase dynamics and kinase-specific inhibitor design.