Mechanism of substrate processing of γ-secretase and influence by modulators studied using Molecular Dynamics simulations

• Applicant: Professor Dr. Martin Zacharias
• Subject Area: Biophysics ; Bioinformatics and Theoretical Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 546851530

The intramembrane protease γ-secretase (GSEC) is an aspartyl-protease that performs the final step of the controlled intramembrane cleavage of many single-span type-1 transmembrane proteins. It includes also the cleavage of the C-terminal fragment (C99) of the amyloid precursor protein (APP). The consecutive cleavage process yields Aβ peptides of different lengths that can form toxic aggregates and are likely involved in Alzheimer’s disease (AD), a chronic neurodegenerative disease. An understanding of the GSEC cleavage process in molecular detail is of fundamental importance for understanding the onset and progression of AD and for the potential development of AD treatments. Although the structure of GSEC in apo and in substrate-bound form has been determined recently the mechanism and process of sequential APP cleavage is not fully understood. In the proposed project we will use Molecular Dynamics (MD) simulation methods to better understand the mechanism of sequential substrate cleavage of GSEC. This will be achieved by targeted MD simulations to move the peptide substrate through the substrate binding channel and characterize the associated free energy profile and how it is influenced by enzyme and substrate mutations. Furthermore, we will investigate the binding of known modulator (imidazole based GSM) molecules that can improve the cleavage efficiency (processivity) and how these GSMs also influence the active site by a so far unknown allosteric coupling mechanism. In addition, we will try to identify putative binding sites of other types of GSMs (e.g. acidic GSM) in GSEC and search for new GSM compounds. The computational/theoretical work will be performed and experimentally evaluated in close collaboration with our experimental partner, Dr. Lucia Chávez Gutiérrez (KU Leuven).

• DFG Programme: Research Grants