Characterizing Interactions between γ-Secretase and Amyloid-β Peptides

Shu-Yu Chen^1*, Martin Zacharias¹

¹Physics, Technical University of Munich, Munich, Bavaria, Germany

* Presenter:Shu-Yu Chen, email:shuyu.chen@tum.de

Amyloid-β peptides are generated upon cleavages of β- and γ-secretase on amyloid precursor protein and are known for their engagement in the Alzheimer’s diseases pathology. γ-secretase produces amyloid-β in lengths of 37-43 amino acids within a biological membrane. The longer products are prone to aggregate and form neurotoxic fibrils and cause cell death. Hence understanding how γ-secretase secretes amyloid-β is of both pathological and biological interest. We performed extensive molecular dynamics simulations with advanced sampling and homology modeling techniques to study the interaction between γ-secretase and amyloid-β peptides based on the cryo-EM structure released in early 2019. We provide a mechanistic explanation of why γ-secretase cleaves amyloid-β in steps of three residues and how enzyme-substrate interaction and membrane-substrate interaction modulate the length of the secreted amyloid-β products. With a good agreement with the experimental results from the literature, we expected our work to facilitate the development of small molecules combating Alzheimer’s disease.

Keywords: Molecular Dynamics, Intramembrane Proteaolysis, γ-Secretase, Amyloid-β, Alzheimer’s Disease