Simulating the γ-secretase enzyme: Recent advances and future directions.

γ-secretase is an intra-membrane aspartyl protease involved in the production of amyloid-β peptides. Aberrant cleavage of the 99-residue C-terminal fragment of the amyloid precursor protein leads to the formation of a 42-amino-acid isoform (Aβ42). Further oligomerization and aggregation of this isoform is implicated in the onset and progression of Alzheimer's disease. Recent elucidation of γ-secretase by cryo-electron microscopy techniques have opened a new horizon in the structural and dynamic characterization of the enzyme. Currently, only a few molecular dynamics studies have been carried out to explore the mechanism of substrate recognition and entry, or the transition between active and inactive states of the catalytic subunit. Herein, we briefly review the computational approaches and their most relevant findings. The general picture of the current GS simulation studies will open new questions to understand the behavior of the enzyme dynamics and explain the modulation mechanisms for the treatment of Alzheimer's disease.