Presenilin homologues influence substrate binding and processing by γ-secretase: a molecular simulation study

Abstract

Presenilin homologues in the γ-secretase complex play a pivotal role in substrate binding and processing, impacting β-amyloid (Aβ) peptide generation in Alzheimer's disease. We conducted a molecular simulation study to determine substrate preferences between presenilin-1 (PS1) and presenilin-2 (PS2) γ-secretase enzymes for amyloid precursor protein (APP) and Notch1 processing. Using homology modelling, we generated PS1- and PS2-γ-secretase models bound to substrates in the Aβ40 and Aβ42 generation pathways and Notch1 S3 and S4 cleavage site substrates. Metadynamics simulations and binding free energy calculations were used to explore conformational ensembles and substrate preferences. PS2-γ-secretase exhibited increased conformational flexibility and preferential binding energy for initiating the Aβ42 pathway compared to PS1-γ-secretase. Additionally, Notch1 exhibits a preference for binding to PS2-γ-secretase over PS1-γ-secretase. This study provides valuable insights into the conformational dynamics of γ-secretase bound to different substrates within a cleavage pathway, improving our understanding of substrate processivity. The findings highlight the importance of considering both PS1- and PS2-γ-secretase in structure-based drug design efforts, with implications for stabilizing or destabilizing specific states during APP processing.