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

Presenilin homologues in the {gamma}-secretase complex play a pivotal role in substrate binding and processing, impacting {beta}-amyloid (A{beta}) peptide generation in Alzheimers disease. We conducted a molecular simulation study to determine substrate preferences between presenilin-1 (PS1) and presenilin-2 (PS2) {gamma}-secretase enzymes for amyloid precursor protein (APP) and Notch1 processing. Using homology modelling, we generated PS1- and PS2-{gamma}-secretase models bound to substrates in the A{beta}40 and A{beta}42 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-{gamma}-secretase exhibited increased conformational flexibility and preferential binding energy for initiating the A{beta}42 pathway compared to PS1-{gamma}-secretase. Additionally, Notch1 exhibits a preference for binding to PS2-{gamma}-secretase over PS1-{gamma}-secretase. This study provides valuable insights into the conformational dynamics of {gamma}-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-{gamma}-secretase in structure-based drug design efforts, with implications for stabilizing or destabilizing specific states during APP processing.