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Proposing Institution

Physik-Departement T38, TUM
Project Manager

ShuYu Chen
James-Franck-Str. 1
85748 Garching
𝛾-Secretase is a transmembrane protease composed of four subunits: nicastrin (NCT), presenilin-1 (PS1), anterior pharynx defective 1, and presenilin enhancer 2. It cleaves a wide range of helical transmembrane spanning substrates among them also amyloid precursor protein (APP) which leads to secretion of beta-amyloid (A-beta) peptides that are involved in the cause of Alzheimer’s disease (AD). Despite the pathological importance and although a high-resolution Cryo-EM structure has been published (without substrate) it is still not clear how APP is cleaved. In addition, inhibitors of 𝛾- secretase developed for AD patients have been proven to produce severe side effects. Early onset of AD is frequently caused by mutations on NCT and, even more frequently, PS1. Understanding how these mutations influence the generation of A-beta peptides therefore is important for further 𝛾- secretase modulator development. The cleavage of APP is achieved by hydrolysis mediated by two asparagine (Asp) residues in the PS1 subunit that need to come to a close distance for catalysis. According to the distance of these Asp residues, PS1 subunit exhibits 2 different states, active state (Asp residues in close distance) and inactive state (large distance between Asp residues). In preliminary simulations we already observed transitions between these two states. The aim of this project is to investigate how different𝛾-secretase mutations influence the active-inactive state transition profile. To study the underlying features of this behavior, it is planned employ both unrestraint simulations but also to drive the transition using umbrella sampling (US) simulations coupled with Hamiltonian replica-exchange molecular dynamics (US-H-REMD) simulation along the distance of the Asp residues as reaction coordinate. By studying the associated free energy profiles, we want to investigate the mechanism of transition between inactive and active states and how mutations influence it and might play a role in causing abnormal APP cleavage.

Impressum, Conny Wendler