Toward the Characterization of DAPT Interactions with γ‐Secretase

• Published in: ChemMedChem Vol. 14; no. 10; pp. 1005 - 1010
• Main Authors: Aguayo‐Ortiz, Rodrigo, Guzmán‐Ocampo, Dulce C., Dominguez, Laura
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 17.05.2019
• Subjects: Alzheimer's disease; Amino Acid Sequence; Amyloid; Amyloid beta-Peptides - chemistry; Amyloid Precursor Protein Secretases - metabolism; Aspartic Acid - chemistry; Binding; Catalysis; Catalytic Domain; DAPT inhibitors; Density; Diamines - chemistry; Electron microscopy; Enzyme Inhibitors - chemistry; FEP calculations; Inhibitors; Internalization; Medical treatment; Molecular dynamics; Molecular Dynamics Simulation; Neurodegenerative diseases; Oligomerization; Peptides; presenilin; Presenilin 1; Protein Binding; Protein Conformation; Protonation; Secretase; Substrates; Thermodynamics; Thiazoles - chemistry; umbrella sampling; γ-secretase; FEP calculations; umbrella sampling; DAPT inhibitors; γ-secretase; presenilin
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201900106

DAPT is a potent γ‐secretase (GS) inhibitor that blocks the production of short amyloid‐β (Aβ) peptides. Aggregation and oligomerization of Aβ peptides have been associated with the development and progression of Alzheimer's disease. A recent cryo‐electron microscopy density map disclosed DAPT binding at the GS active site. In this study, we employed the density map data to assign a possible binding pose of DAPT to characterize its dynamic behavior through different molecular dynamics simulation approaches. Our simulations showed a high preference of DAPT for the intramembrane region of the protein and that its entry site is located between TM2 and TM3 of PS1. DAPT interaction with the active site led to a decreased flexibility of key PS1 regions related to the recognition and internalization of GS substrates. Moreover, our study showed that the proximity of DAPT to the catalytic aspartic acids should be able to modify its protonation states, preventing the enzyme from reaching its active form. These results provide valuable information toward understanding the molecular mechanism of a GS inhibitor for the development of novel Alzheimer's disease treatments. PS1–DAPT complex: DAPT is a potent γ‐secretase (GS) inhibitor that blocks the production of short amyloid‐β peptides. In this study, we used cryo‐electron microscopy density map data to assign a possible binding pose for DAPT and characterized its dynamic behavior through various molecular dynamics simulation approaches. Our study provides valuable information toward understanding the molecular mechanism of a GS inhibitor for the development of novel Alzheimer's disease treatments.