Probing the Mechanisms of Inhibitors Binding to Presenilin Homologue Using Molecular Dynamics Simulations.

γ-secretase is an intramembrane proteolytic enzyme that is mainly involved in the cleavage and hydrolysis of the amyloid precursor (APP). The catalytic subunit presenilin 1 (PS1) is the catalytic subunit of γ-secretase. Since it was found that PS1 is responsible for Aβ-producing proteolytic activity, which is involved in Alzheimer's disease, it is believed that reducing the activity of PS1 and preventing or delaying the production of Aβ could help treat Alzheimer's disease. Consequently, in recent years, researchers have begun investigating the potential clinical efficacy of PS1 inhibitors. Currently, most PS1 inhibitors are only used as a tool to study the structure and function of PS1, and a few inhibitors with a high selectivity have been tested in clinics. Less-selective PS1 inhibitors were found to not only inhibit Aβ production but also inhibit Notch cleavage, which led to serious adverse events. The archaeal presenilin homologue (PSH) is a surrogate protease of presenilin that is useful for agent screening. In this study, we performed 200 ns molecular dynamics simulations (MD) of four systems to explore the conformational changes of different ligands binding to PSH. Our results indicated that the PSH-L679 system formed 3-10 helices in TM4, loosening up TM4 and allowing substrates to enter the catalytic pocket, thereby making it less inhibitory. Additionally, we found that III-31-C can bring TM4 and TM6 closer, resulting in the contraction of the PSH active pocket. Altogether, these results provide the basis for the potential design of newer PS1 inhibitors.